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Pharmaceuticals, Volume 15, Issue 1 (January 2022) – 108 articles

Cover Story (view full-size image): Lipids play a diverse range of physiological roles. In response to stimuli, lipids affect signaling pathways by often acting as chemical messengers that bind and activate G protein-coupled receptors (GPCRs) studded on the cell surface. In the present review, we specifically focus on the signaling activities of lipids from the perspective of their cognate GPCRs, especially those from class A (rhodopsin-like) GPCRs and their binding and interactions with agonists/antagonists (orthosteric and allosteric). We summarize the latest structural, functional, and dynamical insights gleaned from recently elucidated structures and computational studies. We also discuss the implications of these findings for drug discovery and development as well as present new directions and approaches. View this paper
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Review
Mini-Tablets: A Valid Strategy to Combine Efficacy and Safety in Pediatrics
Pharmaceuticals 2022, 15(1), 108; https://doi.org/10.3390/ph15010108 - 17 Jan 2022
Cited by 1 | Viewed by 1381
Abstract
In the treatment of pediatric diseases, mass-produced dosage forms are often not suitable for children. Commercially available medicines are commonly manipulated and mixed with food by caregivers at home, or extemporaneous medications are routinely compounded in the hospital pharmacies to treat hospitalized children. [...] Read more.
In the treatment of pediatric diseases, mass-produced dosage forms are often not suitable for children. Commercially available medicines are commonly manipulated and mixed with food by caregivers at home, or extemporaneous medications are routinely compounded in the hospital pharmacies to treat hospitalized children. Despite considerable efforts by regulatory agencies, the pediatric population is still exposed to questionable and potentially harmful practices. When designing medicines for children, the ability to fine-tune the dosage while ensuring the safety of the ingredients is of paramount importance. For these purposes solid formulations may represent a valid alternative to liquid formulations for their simpler formula and more stability, and, to overcome the problem of swelling ability, mini-tablets could be a practicable option. This review deals with the different approaches that may be applied to develop mini-tablets intended for pediatrics with a focus on the safety of excipients. Alongside the conventional method of compression, 3D printing appeared particularly appealing, as it allows to reduce the number of ingredients and to avoid both the mixing of powders and intermediate steps such as granulation. Therefore, this technique could be well adaptable to the daily galenic preparations of a hospital pharmacy, thus leading to a reduction of the common practice of off-label preparations. Full article
(This article belongs to the Special Issue Development of Medicines for Rare Pediatric Diseases)
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Article
Synthesis and Anti-Hepatoma Activities of U12 Derivatives Arresting G0/G1 Phase and Inducing Apoptosis by PI3K/AKT/mTOR Pathway
Pharmaceuticals 2022, 15(1), 107; https://doi.org/10.3390/ph15010107 - 17 Jan 2022
Cited by 2 | Viewed by 1017
Abstract
Ursodeoxycholic acid (UDCA) is a first-line clinical drug for the treatment of liver diseases. U12, a derivative of UDCA, showed effective anti-hepatoma activities in previous works. However, the low polarity and large doses limited the druglikeness of U12. In this study, the structural [...] Read more.
Ursodeoxycholic acid (UDCA) is a first-line clinical drug for the treatment of liver diseases. U12, a derivative of UDCA, showed effective anti-hepatoma activities in previous works. However, the low polarity and large doses limited the druglikeness of U12. In this study, the structural modification and optimization of U12 were further investigated and twelve U12 derivatives were synthesized by substitution, esterification and amidation reactions. The evaluation of the cytotoxicity of synthetic derivatives against hepatoma cell lines (HepG2) indicated that U12-I, U12a-d and U12h showed more effective cytotoxic effects on the growth of HepG2 cells than U12, and the preliminary structure–activity relationship was discussed. Among them, U12a exhibited the most potent anti-hepatocellular carcinoma activity. Mechanism studies indicated that U12a inhibited HepG2 cell proliferation by arresting the G0/G1 phase, and suppressed the activation of the PI3K/AKT/mTOR pathway. Further studies showed that U12a induced HepG2 cells apoptosis through activating the caspase signaling pathway. Furthermore, U12a evidently inhibits the growth of HepG2-derived tumor xenografts in vivo without observable adverse effects. Thus, U12a might be considered as a promising candidate for the treatment of hepatocellular carcinoma. Full article
(This article belongs to the Topic Compounds with Medicinal Value)
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Article
Identification of Cyclic Sulfonamides with an N-Arylacetamide Group as α-Glucosidase and α-Amylase Inhibitors: Biological Evaluation and Molecular Modeling
Pharmaceuticals 2022, 15(1), 106; https://doi.org/10.3390/ph15010106 - 17 Jan 2022
Cited by 5 | Viewed by 914
Abstract
Diabetes mellitus (DM), a complicated metabolic disorder, is due to insensitivity to insulin function or reduction in insulin secretion, which results in postprandial hyperglycemia. α-Glucosidase inhibitors (AGIs) and α-amylase inhibitors (AAIs) block the function of digestive enzymes, which delays the carbohydrate hydrolysis process [...] Read more.
Diabetes mellitus (DM), a complicated metabolic disorder, is due to insensitivity to insulin function or reduction in insulin secretion, which results in postprandial hyperglycemia. α-Glucosidase inhibitors (AGIs) and α-amylase inhibitors (AAIs) block the function of digestive enzymes, which delays the carbohydrate hydrolysis process and ultimately helps to control the postprandial hyperglycemia. Diversified 2-(3-(3-methoxybenzoyl)-4-hydroxy-1,1-dioxido-2H-benzo[e][1,2]thiazin-2-yl)-N-arylacetamides were synthesized and evaluated for their in vitro inhibitory potential against α-glucosidase and α-amylase enzymes. The compounds with chloro, bromo and methyl substituents demonstrated good inhibition of α-glucosidase enzymes having IC50 values in the range of 25.88–46.25 μM, which are less than the standard drug, acarbose (IC50 = 58.8 μM). Similarly, some derivatives having chloro, bromo and nitro substituents were observed potent inhibitors of α-amylase enzyme, with IC50 values of 7.52 to 15.06 μM, lower than acarbose (IC50 = 17.0 μM). In addition, the most potent compound, N-(4-bromophenyl)-2-(4-hydroxy-3-(3-methoxybenzoyl)-1,1-dioxido-2H-benzo[e][1,2]thiazin-2-yl)acetamide (12i), was found to be a non-competitive and competitive inhibitor of α-glucosidase and α-amylase enzymes, respectively, during kinetic studies. The molecular docking studies provided the binding modes of active compounds and the molecular dynamics simulation studies of compound 12i in complex with α-amylase also showed that the compound is binding in a fashion similar to that predicted by molecular docking studies. Full article
(This article belongs to the Special Issue Heterocyclic Compounds and Their Application in Therapy)
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Perspective
A 5-Year Study of Lithium and Valproic Acid Drug Monitoring in Patients with Bipolar Disorders in an Italian Clinical Center
Pharmaceuticals 2022, 15(1), 105; https://doi.org/10.3390/ph15010105 - 17 Jan 2022
Viewed by 931
Abstract
Therapeutic drug monitoring (TDM) is an effective tool used to improve the pharmacological treatment in clinical practice, especially to detect subtherapeutic drug plasma concentration (Cp) in order to consider a change of dosage during treatment and reach its putative therapeutic range. In this [...] Read more.
Therapeutic drug monitoring (TDM) is an effective tool used to improve the pharmacological treatment in clinical practice, especially to detect subtherapeutic drug plasma concentration (Cp) in order to consider a change of dosage during treatment and reach its putative therapeutic range. In this study, we report the Cp values of lithium and valproic acid (VPA), alone and in combination, mostly in bipolar patients admitted to an Italian clinical center of the University of Pisa during the years 2016–2020, which include 12,294 samples of VPA, 7449 of lithium and 1118 of both in combination. Lithium and VPA are the most utilized drugs in treating bipolar disorders, and their TDM is strongly recommended by recent guidelines. In relation to lithium Cp monitoring, several studies have underlined that 0.5–0.8 mmol/L is the optimal range for chronic treatment, and below 0.4 mmol/L, it is unlikely to produce a clinical response. For VPA, the therapeutic range is 50–100 μg/mL and a linear correlation between Cp and clinical efficacy has been proposed, where below 50 μg/mL, the clinical efficacy of VPA has not been proven thus far. Toxic levels of both drugs were rarely found in our study, while a high percentage of patients, about one-third, had sub-therapeutic Cp during their treatments. In addition, in several cases of patients receiving multiple blood sampling, the initial subtherapeutic Cp changed only partially without reaching its therapeutic window. In relation to age, we found a higher percentage of lithium and VPA Cp values in range in the adolescents than in the adults and elderly groups. No differences were reported when analyzing the distribution of Cp values in males and females. In conclusion, this present study suggests that TDM is widely used by many specialists, but there is still a window of improvement for optimizing pharmacological treatments in clinical practice. Full article
(This article belongs to the Special Issue Therapeutic Drug Monitoring and Drug-Drug Interactions)
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Article
Coumarin Derivatives Exert Anti-Lung Cancer Activity by Inhibition of Epithelial–Mesenchymal Transition and Migration in A549 Cells
Pharmaceuticals 2022, 15(1), 104; https://doi.org/10.3390/ph15010104 - 17 Jan 2022
Cited by 3 | Viewed by 987
Abstract
A series of coumarin derivatives and isosteres were synthesized from the reaction of triflic intermediates with phenylboronic acids, terminal alkynes, and organozinc compounds through palladium-catalyzed cross-coupling reactions. The in vitro cytotoxic effect of the compounds was evaluated against two non-small cell lung [...] Read more.
A series of coumarin derivatives and isosteres were synthesized from the reaction of triflic intermediates with phenylboronic acids, terminal alkynes, and organozinc compounds through palladium-catalyzed cross-coupling reactions. The in vitro cytotoxic effect of the compounds was evaluated against two non-small cell lung carcinoma (NSCLC) cell lines (A-549 and H2170) and a normal cell line (NIH-3T3) using cisplatin as a reference drug. Additionally, the effects of the most promising coumarin derivative (9f) in reversing the epithelial-to-mesenchymal transition (EMT) in IL-1β-stimulated A549 cells and in inhibiting the EMT-associated migratory ability in A549 cells were also evaluated. 9f had the greatest cytotoxic effect (CC50 = 7.1 ± 0.8 and 3.3 ± 0.5 μM, respectively against A549 and H2170 cells) and CC50 value of 25.8 µM for NIH-3T3 cells. 9f inhibited the IL-1β-induced EMT in epithelial cells by inhibiting the F-actin reorganization, attenuating changes in the actin cytoskeleton reorganization, and downregulating vimentin in A549 cells stimulated by IL-1β. Treatment of A549 cells with 9f at 7 µM for 24 h significantly reduced the migration of IL-1β-stimulated cells, which is a phenomenon confirmed by qualitative assessment of the wound closure. Taken together, our findings suggest that coumarin derivatives, especially compound 9f, may become a promising candidate for lung cancer therapy, especially in lung cancer promoted by NSCLC cell lines. Full article
(This article belongs to the Special Issue Privileged Structures as Leads in Medicinal Chemistry)
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Article
CD44-Targeted Carriers: The Role of Molecular Weight of Hyaluronic Acid in the Uptake of Hyaluronic Acid-Based Nanoparticles
Pharmaceuticals 2022, 15(1), 103; https://doi.org/10.3390/ph15010103 - 17 Jan 2022
Cited by 6 | Viewed by 1048
Abstract
Nanotechnology offers advanced biomedical tools for diagnosis and drug delivery, stressing the value of investigating the mechanisms by which nanocarriers interact with the biological environment. Herein, the cellular response to CD44-targeted nanoparticles (NPs) was investigated. CD44, the main hyaluronic acid (HA) receptor, is [...] Read more.
Nanotechnology offers advanced biomedical tools for diagnosis and drug delivery, stressing the value of investigating the mechanisms by which nanocarriers interact with the biological environment. Herein, the cellular response to CD44-targeted nanoparticles (NPs) was investigated. CD44, the main hyaluronic acid (HA) receptor, is widely exploited as a target for therapeutic purposes. HA NPs were produced by microfluidic platform starting from HA with different molecular weights (Mw, 280, 540, 820 kDa) by polyelectrolyte complexation with chitosan (CS). Thanks to microfluidic technology, HA/CS NPs with the same physical features were produced, and only the effects of HA Mw on CD44-overexpressing cells (human mesenchymal stem cells, hMSCs) were studied. This work provides evidence of the HA/CS NPs biocompatibility regardless the HA Mw and reveals the effect of low Mw HA in improving the cell proliferation. Special attention was paid to the endocytic mechanisms used by HA/CS NPs to enter hMSCs. The results show the notable role of CD44 and the pronounced effect of HA Mw in the NPs’ internalization. HA/CS NPs uptake occurs via different endocytic pathways simultaneously, and most notably, NPs with 280 kDa HA were internalized by clathrin-mediated endocytosis. Instead, NPs with 820 kDa HA revealed a greater contribution of caveolae and cytoskeleton components. Full article
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Article
Synthesis, In Vitro, In Vivo and In Silico Antidiabetic Bioassays of 4-Nitro(thio)phenoxyisobutyric Acids Acting as Unexpected PPARγ Modulators: An In Combo Study
Pharmaceuticals 2022, 15(1), 102; https://doi.org/10.3390/ph15010102 - 15 Jan 2022
Cited by 2 | Viewed by 1413
Abstract
Four isobutyric acids (two nitro and two acetamido derivatives) were prepared in two steps and characterized using spectral analysis. The mRNA concentrations of PPARγ and GLUT-4 (two proteins documented as key diabetes targets) were increased by 3T3-L1 adipocytes treated with compounds 1 [...] Read more.
Four isobutyric acids (two nitro and two acetamido derivatives) were prepared in two steps and characterized using spectral analysis. The mRNA concentrations of PPARγ and GLUT-4 (two proteins documented as key diabetes targets) were increased by 3T3-L1 adipocytes treated with compounds 14, but an absence of in vitro expression of PPARα was observed. Docking and molecular dynamics studies revealed the plausible interaction between the synthesized compounds and PPARγ. In vivo studies established that compounds 14 have antihyperglycemic modes of action associated with insulin sensitization. Nitrocompound 2 was the most promising of the series, being orally active, and one of multiple modes of action could be selective PPARγ modulation due to its extra anchoring with Gln-286. In conclusion, we demonstrated that nitrocompound 2 showed strong in vitro and in vivo effects and can be considered as an experimental antidiabetic candidate. Full article
(This article belongs to the Special Issue Nitro Group Containing Drugs)
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Article
Optimization of Solvent-Free Microwave-Assisted Hydrodiffusion and Gravity Extraction of Morus nigra L. Fruits Maximizing Polyphenols, Sugar Content, and Biological Activities Using Central Composite Design
Pharmaceuticals 2022, 15(1), 99; https://doi.org/10.3390/ph15010099 - 14 Jan 2022
Cited by 4 | Viewed by 842
Abstract
Black mulberry, Morus nigra L. (family: Moraceae), is a healthy food and medicinal plant. Microwave hydrodiffusion and gravity (MHG) is one of the most innovative applications of solvent-free microwave extraction. The aim of this study was to optimize for the first time the [...] Read more.
Black mulberry, Morus nigra L. (family: Moraceae), is a healthy food and medicinal plant. Microwave hydrodiffusion and gravity (MHG) is one of the most innovative applications of solvent-free microwave extraction. The aim of this study was to optimize for the first time the MHG solvent-free extraction of polyphenols and sugars from M. nigra fruits. Optimization was carried out using a central composite design (CCD) with selected responses such as extraction yield, total polyphenol (TPC), flavonoid (TFC), anthocyanin (TAC), and sugar (TSC) contents, in addition to DPPH radical scavenging, and α-glucosidase (AGHi), lipase (Li), and xanthine oxidase (XOi) inhibition as tools to evaluate the best parameters for efficient and rapid extraction of black mulberry. The optimized extract was characterized in terms of the aforementioned parameters to validate the models, and was further analyzed for 36 individual polyphenols using HPLC-MS/MS. The optimized MHG extract was finally compared with traditional extracts, and demonstrated much better performance in terms of TPC, TAC, and Li, while the traditional extracts showed better XOi and AGHi. In conclusion, MHG is a valuable green technique for the production of non-degraded black mulberry polyphenol-rich extract and we suggest its larger use in the pharmaceutical and food industries. Full article
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Article
Inclusion Scenarios and Conformational Flexibility of the SSRI Paroxetine as Perceived from Polymorphism of β-Cyclodextrin–Paroxetine Complex
Pharmaceuticals 2022, 15(1), 98; https://doi.org/10.3390/ph15010098 - 14 Jan 2022
Cited by 1 | Viewed by 890
Abstract
Depression, a global mental health problem, is prevalent during the coronavirus disease 2019 (COVID-19) pandemic and can be efficiently treated by selective serotonin reuptake inhibitors (SSRIs). Our study series aims at forwarding insights on the β-cyclodextrin (β-CD)–SSRI inclusion complexes by X-ray crystallography combined [...] Read more.
Depression, a global mental health problem, is prevalent during the coronavirus disease 2019 (COVID-19) pandemic and can be efficiently treated by selective serotonin reuptake inhibitors (SSRIs). Our study series aims at forwarding insights on the β-cyclodextrin (β-CD)–SSRI inclusion complexes by X-ray crystallography combined with density functional theory (DFT) calculation. Here, we report a new crystal form (II) of the 1:1 β-CD–paroxetine (PXT) complex, which is inspired by the reported 2:1 β-CD–PXT complex (crystal form I), reflecting an elusive phenomenon of the polymorphism in CD inclusion complexes. The β-CD–PXT polymorphism stems from the PXT conformational flexibility, which is defined by torsion angles κ, ε around the -CH2–O- group bridging the A- and C–D-rings, of which those of PXT in I and II are totally different. While PXT (II) in an open V-shaped conformation that has the B-ring shallowly inserted in the β-CD cavity, PXT (I) in a closed U-shaped structure is mostly entirely embedded in the β-CD dimeric cavity, of which the A-ring is deeply inserted in the main β-CD cavity. However, PXT molecules in both crystal forms are similarly maintained in the CD cavity via host–guest N–H···O5/O6 H-bonds and C/O–H···π(B/C) interactions and β-CDs have similar 3D arrangements, channel (II) vs. screw-channel (I). Further theoretical explorations on the β-CD–PXT thermodynamic stabilities and the PXT conformational stabilities based on their potential energy surfaces (PESs) have been completed by DFT calculations. The 2:1 β-CD–PXT complex with the greater presence of dispersion interactions is more energetically favorable than the unimolar complex. Conversely, whereas free PXT, PXT (II) and PXT in complex with serotonin transporter are more energetically stable, PXT (I) is least stable and stabilized in the β-CD cavity. As SSRIs could lessen the COVID-19 severity, the CD inclusion complexation not only helps to improve the drug bioavailability, but also promotes the use of antidepressants and COVID-19 medicines concurrently. Full article
(This article belongs to the Special Issue Seeking New Antidepressant Agents)
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Article
Antimicrobial Activity and Degradation Ability Study on Nanoparticle-Enriched Formulations Specially Designed for the Neutralization of Real and Simulated Biological and Chemical Warfare Agents
Pharmaceuticals 2022, 15(1), 97; https://doi.org/10.3390/ph15010097 - 14 Jan 2022
Viewed by 755
Abstract
The present work reveals a comprehensive decontamination study on real and simulated biological and chemical warfare agents (BCWA). The emphasis was on evaluating the antimicrobial activity against real biological warfare agents, such as Bacillus anthracis, and also the capacity of neutralizing real [...] Read more.
The present work reveals a comprehensive decontamination study on real and simulated biological and chemical warfare agents (BCWA). The emphasis was on evaluating the antimicrobial activity against real biological warfare agents, such as Bacillus anthracis, and also the capacity of neutralizing real chemical warfare agents, such as mustard gas or soman, by employing three different types of organic solutions enriched with ZnO, TiO2, and zeolite nanoparticles, specially designed for decontamination applications. The capacity of decontaminating BCWA was evaluated through specific investigation tools, including surface monitoring with the swabs method, minimum inhibitory (MIC) and minimum bactericidal concentration (MBC) evaluations, time-kill tests for microorganisms, and GC-MS for monitoring chemical agents on different types of surfaces (glass, painted metal, rubber, and cotton butyl rubber). These tests revealed high decontamination factors for BCWA even after only 10 min, accomplishing the requirements imposed by NATO standards. At the completion of the decontamination process, the formulations reached 100% efficacy for Bacillus anthracis after 10–15 min, for soman after 20–30 min, and for mustard gas in an interval comprised between 5 and 24 h depending on the type of surface analyzed. Full article
(This article belongs to the Section Pharmaceutical Technology)
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Article
Radioiodination and Purification of [131I]β-CIT and [131I]FP-CIT with an Automated Radiosynthesizer
Pharmaceuticals 2022, 15(1), 96; https://doi.org/10.3390/ph15010096 - 14 Jan 2022
Cited by 1 | Viewed by 683
Abstract
Dopaminergic transporter (DAT) imaging with single photon emission computed tomography (SPECT) is used to diagnose Parkinson’s disease and to differentiate it from other neurodegenerative disorders without presynaptic dopaminergic dysfunction. The radioiodinated tropane alkaloids [123I]FP-CIT and [123I]β-CIT enable the evaluation [...] Read more.
Dopaminergic transporter (DAT) imaging with single photon emission computed tomography (SPECT) is used to diagnose Parkinson’s disease and to differentiate it from other neurodegenerative disorders without presynaptic dopaminergic dysfunction. The radioiodinated tropane alkaloids [123I]FP-CIT and [123I]β-CIT enable the evaluation of the integrity of DATs. Commonly, the labeling of these compounds is performed by electrophilic substitution of the alkylstannylated precursors with radioactive iodine and following purification by HPLC or solid phase extraction (SPE). This work presents the first radioiodination of β-CIT and FP-CIT with no carrier added [131I]NaI on a Scintomics GRP synthesis module. Free iodine-131 and impurities were removed by SPE over a C-18 Sep-Pak cartridge. We achieved a radiochemical yield of >75% and a radiochemical purity of >98% with both compounds. Our development of an automated synthesis on a commercially available synthesizer ensures robust and efficient labeling of [131I]FP-CIT and [131I]β-CIT starting with low concentrated radioiodine. Full article
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Article
Secukinumab Loss of Efficacy Is Perfectly Counteracted by the Introduction of Combination Therapy (Rescue Therapy): Data from a Multicenter Real-Life Study in a Cohort of Italian Psoriatic Patients That Avoided Secukinumab Switching
Pharmaceuticals 2022, 15(1), 95; https://doi.org/10.3390/ph15010095 - 14 Jan 2022
Cited by 5 | Viewed by 1166
Abstract
Since psoriasis (PsO) is a chronic inflammatory disease, patients may experience a drug failure also with very effective drugs (i.e., secukinumab) and, consequently, dermatologists have two therapeutic options: switching or perform a combination therapy (rescue therapy) to save the drug that had decreased [...] Read more.
Since psoriasis (PsO) is a chronic inflammatory disease, patients may experience a drug failure also with very effective drugs (i.e., secukinumab) and, consequently, dermatologists have two therapeutic options: switching or perform a combination therapy (rescue therapy) to save the drug that had decreased its efficacy. At the moment no studies focused on combination/rescue therapy of secukinumab, so we performed a 52-weeks multicenter retrospective observational study that involved 40 subjects with plaque psoriasis that experienced a secondary failure and were treated with combination therapy (ciclosporin (n = 11), MTX (n = 15), NB-UVB (n = 7) and apremilast (n = 7)). After 16 weeks of rescue/combination therapy, PASI and a DLQI varied respectively from 8 [7.0–9.0] and 13 [12.0–15.0], to 3 [2.8–4.0] and 3 [2.0–3.3]), suggesting a significant improvement of daily functionality and quality of life. Results were maintained at 52 weeks. No side effects were experienced during the study. Secukinumab remains a safety and effective drug for PsO patients also in the IL-23 and JAK inhibitors era. The rescue therapy is a valid therapeutic option in case of secukinumab secondary failure. Full article
(This article belongs to the Section Pharmacology)
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Article
How Molecular Topology Can Help in Amyotrophic Lateral Sclerosis (ALS) Drug Development: A Revolutionary Paradigm for a Merciless Disease
Pharmaceuticals 2022, 15(1), 94; https://doi.org/10.3390/ph15010094 - 14 Jan 2022
Cited by 1 | Viewed by 1194
Abstract
Even if amyotrophic lateral sclerosis is still considered an orphan disease to date, its prevalence among the population is growing fast. Despite the efforts made by researchers and pharmaceutical companies, the cryptic information related to the biological and physiological onset mechanisms, as well [...] Read more.
Even if amyotrophic lateral sclerosis is still considered an orphan disease to date, its prevalence among the population is growing fast. Despite the efforts made by researchers and pharmaceutical companies, the cryptic information related to the biological and physiological onset mechanisms, as well as the complexity in identifying specific pharmacological targets, make it almost impossible to find effective treatments. Furthermore, because of complex ethical and economic aspects, it is usually hard to find all the necessary resources when searching for drugs for new orphan diseases. In this context, computational methods, based either on receptors or ligands, share the capability to improve the success rate when searching and selecting potential candidates for further experimentation and, consequently, reduce the number of resources and time taken when delivering a new drug to the market. In the present work, a computational strategy based on Molecular Topology, a mathematical paradigm capable of relating the chemical structure of a molecule to a specific biological or pharmacological property by means of numbers, is presented. The result was the creation of a reliable and accessible tool to help during the early in silico stages in the identification and repositioning of potential hits for ALS treatment, which can also apply to other orphan diseases. Considering that further computational and experimental results will be required for the final identification of viable hits, three linear discriminant equations combined with molecular docking simulations on specific proteins involved in ALS are reported, along with virtual screening of the Drugbank database as a practical example. In this particular case, as reported, a clinical trial has been already started for one of the drugs proposed in the present study. Full article
(This article belongs to the Special Issue Therapeutic Agents for Neurological Disorders 2022)
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Article
Bcl-XL but Not Bcl-2 Is a Potential Target in Medulloblastoma Therapy
Pharmaceuticals 2022, 15(1), 91; https://doi.org/10.3390/ph15010091 - 14 Jan 2022
Cited by 2 | Viewed by 732
Abstract
Medulloblastoma (MB) is the most common solid tumour in children and, despite current treatment with a rather aggressive combination therapy, accounts for 10% of all deaths associated with paediatric cancer. Breaking the tumour cells’ intrinsic resistance to therapy-induced cell death should lead to [...] Read more.
Medulloblastoma (MB) is the most common solid tumour in children and, despite current treatment with a rather aggressive combination therapy, accounts for 10% of all deaths associated with paediatric cancer. Breaking the tumour cells’ intrinsic resistance to therapy-induced cell death should lead to less aggressive and more effective treatment options. In other tumour entities, this has been achieved by modulating the balance between the various pro- and anti-apoptotic members of the Bcl-2 family with small molecule inhibitors. To evaluate the therapeutic benefits of ABT-199 (Venetoclax), a Bcl-2 inhibitor, and ABT-263 (Navitoclax), a dual Bcl-XL/Bcl-2 inhibitor, increasingly more relevant model systems were investigated. Starting from established MB cell lines, progressing to primary patient-derived material and finally an experimental tumour system imbedded in an organic environment were chosen. Assessment of the metabolic activity (a surrogate readout for population viability), the induction of DNA fragmentation (apoptosis) and changes in cell number (the combined effect of alterations in proliferation and cell death induction) revealed that ABT-263, but not ABT-199, is a promising candidate for combination therapy, synergizing with cell death-inducing stimuli. Interestingly, in the experimental tumour setting, the sensitizing effect of ABT-263 seems to be predominantly mediated via an anti-proliferative and not a pro-apoptotic effect, opening a future line of investigation. Our data show that modulation of specific members of the Bcl-2 family might be a promising therapeutic addition for the treatment of MB. Full article
(This article belongs to the Section Pharmacology)
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Review
Discovering the Potential of Natural Antioxidants in Age-Related Macular Degeneration: A Review
Pharmaceuticals 2022, 15(1), 101; https://doi.org/10.3390/ph15010101 - 14 Jan 2022
Cited by 3 | Viewed by 1487
Abstract
Age-related macular degeneration (AMD) is a multifactorial disease associated with anatomical changes in the inner retina. Despite tremendous advances in clinical care, there is currently no cure for AMD. This review aims to evaluate the published literature on the therapeutic roles of natural [...] Read more.
Age-related macular degeneration (AMD) is a multifactorial disease associated with anatomical changes in the inner retina. Despite tremendous advances in clinical care, there is currently no cure for AMD. This review aims to evaluate the published literature on the therapeutic roles of natural antioxidants in AMD. A literature search of PubMed, Web of Science and Google Scholar for peer-reviewed articles published between 1 January 2011 and 31 October 2021 was undertaken. A total of 82 preclinical and 18 clinical studies were eligible for inclusion in this review. We identified active compounds, carotenoids, extracts and polysaccharides, flavonoids, formulations, vitamins and whole foods with potential therapeutic roles in AMD. We evaluated the integral cellular signaling pathways including the activation of antioxidant pathways and angiogenesis pathways orchestrating their mode of action. In conclusion, we examined the therapeutic roles of natural antioxidants in AMD which warrant further study for application in clinical practice. Our current understanding is that natural antioxidants have the potential to improve or halt the progression of AMD, and tailoring therapeutics to the specific disease stages may be the key to preventing irreversible vision loss. Full article
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Systematic Review
The Safety of Dronabinol and Nabilone: A Systematic Review and Meta-Analysis of Clinical Trials
Pharmaceuticals 2022, 15(1), 100; https://doi.org/10.3390/ph15010100 - 14 Jan 2022
Cited by 2 | Viewed by 1166
Abstract
Dronabinol, a natural cannabinoid, and its semi-synthetic derivative, nabilone, are marketed as medicines in several countries. The aim of our work was to systematically evaluate the frequency of adverse events related to dronabinol or nabilone treatment compared to placebo. Scientific databases were searched [...] Read more.
Dronabinol, a natural cannabinoid, and its semi-synthetic derivative, nabilone, are marketed as medicines in several countries. The aim of our work was to systematically evaluate the frequency of adverse events related to dronabinol or nabilone treatment compared to placebo. Scientific databases were searched for placebo-controlled clinical studies of patients receiving either dronabinol or nabilone therapy with placebo control groups. This meta-analysis was reported following the PRISMA guidelines using the PICO format, and it was registered with the PROSPERO register. There were 16 trials included in the meta-analysis. In the nabilone studies, drowsiness was more than 7 times as frequent in patients treated with nabilone than in the placebo group (OR: 7.25; 95% CI: 1.64–31.95), and the risk of dizziness (OR: 21.14; 95% CI: 2.92–152.75) and dry mouth was also higher (OR: 17.23; 95% CI: 4.33–68.55). The frequency of headache was not different in the two groups. In case of dronabinol, the frequency of dry mouth (OR: 5.58; 95% CI: 3.19–9.78), dizziness (OR: 4.60 95% CI: 2.39–8.83) and headache (OR: 2.90; 95% CI: 1.07–7.85) was significantly higher in the dronabinol groups, whereas in case of nausea, drowsiness and fatigue there was no difference. The severity of adverse events was typically mild-to-moderate and transient. In a risk-benefit assessment, these adverse effects are acceptable compared to the achievable benefit. However, considering the diversity of the adverse effects, more studies are needed to provide a more accurate assessment on the side effect profiles of these two compounds. Full article
(This article belongs to the Topic Advances in Cannabinoid Research)
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Article
Characterization of Drugs with Good Glass Formers in Loaded-Mesoporous Silica and Its Theoretical Value Relevance with Mesopores Surface and Pore-Filling Capacity
Pharmaceuticals 2022, 15(1), 93; https://doi.org/10.3390/ph15010093 - 13 Jan 2022
Cited by 3 | Viewed by 608
Abstract
The incorporation of a drug into mesoporous silica (MPS) is a promising strategy to stabilize its amorphous form. However, the drug within MPS has shown incomplete release, despite a supersaturated solution being generated. This indicates the determination of maximum drug loading in MPS [...] Read more.
The incorporation of a drug into mesoporous silica (MPS) is a promising strategy to stabilize its amorphous form. However, the drug within MPS has shown incomplete release, despite a supersaturated solution being generated. This indicates the determination of maximum drug loading in MPS below what is experimentally necessary to maximize the drug doses in the system. Therefore, this study aimed to characterize the drugs with good glass former loaded-mesoporous silica, determine the maximum drug loading, and compare its theoretical value relevance to monolayer covering the mesoporous (MCM) surface, as well as pore-filling capacity (PFC). Solvent evaporation and melt methods were used to load each drug into MPS. In addition, the glass transition of ritonavir (RTV) and cyclosporine A (CYP), as well as the melting peak of indomethacin (IDM) and saccharin (SAC) in mesoporous silica, were not discovered in the modulated differential scanning calorimetry (MDSC) curve, demonstrating that each drug was successfully incorporated into the mesopores. The amorphization of RTV-loaded MPS (RTV/MPS), CYP-loaded MPS (CYP/MPS), and IDM-loaded MPS (IDM/MPS) were confirmed as a halo pattern in powder X-ray diffraction measurements and a single glass transition event in the MDSC curve. Additionally, the good glass formers, nanoconfinement effect of MPS and silica surface interaction contributed to the amorphization of RTV, CYP and IDM within MPS. Meanwhile, the crystallization of SAC was observed in SAC-loaded MPS (SAC/MPS) due to its weak silica surface interaction and high recrystallization tendency. The maximum loading amount of RTV/MPS was experimentally close to the theoretical amount of MCM, showing monomolecular adsorption of RTV on the silica surface. On the other hand, the maximum loading amount of CYP/MPS and IDM/MPS was experimentally lower than the theoretical amount of MCM due to the lack of surface interaction. However, neither CYP or IDM occupied the entire silica surface, even though some drugs were adsorbed on the MPS surface. Moreover, the maximum loading amount of SAC/MPS was experimentally close to the theoretical amount of PFC, suggesting the multilayers of SAC within the MPS. Therefore, this study demonstrates that the characterization of drugs within MPS, such as molecular size and interaction of drug-silica surface, affects the loading efficiency of drugs within MPS that influence its relevance with the theoretical value of drugs. Full article
(This article belongs to the Section Pharmaceutical Technology)
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Article
Synthesis, Structural Characterization and Anticancer Activity of New 5-Trifluoromethyl-2-thioxo-thiazolo[4,5-d]pyrimidine Derivatives
Pharmaceuticals 2022, 15(1), 92; https://doi.org/10.3390/ph15010092 - 13 Jan 2022
Cited by 3 | Viewed by 710
Abstract
Thiazolo[4,5-d]pyrimidine derivatives are considered potential therapeutic agents, particularly in the development of anticancer drugs. In this study, new 7-oxo-(2a-e), 7-chloro-(3a-e) and also three 7-amino-(4a-c) 5-trifluoromethyl-2-thioxo-thiazolo[4,5-d]pyrimidine derivatives have been synthesized and evaluated for their [...] Read more.
Thiazolo[4,5-d]pyrimidine derivatives are considered potential therapeutic agents, particularly in the development of anticancer drugs. In this study, new 7-oxo-(2a-e), 7-chloro-(3a-e) and also three 7-amino-(4a-c) 5-trifluoromethyl-2-thioxo-thiazolo[4,5-d]pyrimidine derivatives have been synthesized and evaluated for their potential anticancer activity. These derivatives were characterized by spectroscopic methods and elemental analysis, and the single-crystal X-ray diffraction was further performed to confirm a 3D structure for compounds 2e and 4b. The antiproliferative activity evaluation of twelve new compounds was carried out on a variety of cell lines including four human cancer (A375, C32, DU145, MCF-7/WT) and two normal cell lines (CHO-K1 and HaCaT). Four of them (2b, 3b, 4b and 4c) were selected by the National Cancer Institute and evaluated for their in vitro anticancer activity using the NCI-60 screening program. 7-Chloro-3-phenyl-5-(trifluoromethyl)[1,3]thiazolo[4,5-d]pyrimidine-2(3H)-thione (3b) proved to be the most active among the newly synthesized compounds. Full article
(This article belongs to the Section Medicinal Chemistry)
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Review
Aptamer-Based Lateral Flow Assays: Current Trends in Clinical Diagnostic Rapid Tests
Pharmaceuticals 2022, 15(1), 90; https://doi.org/10.3390/ph15010090 - 13 Jan 2022
Cited by 8 | Viewed by 1600
Abstract
The lateral flow assay (LFA) is an extensively used paper-based platform for the rapid and on-site detection of different analytes. The method is user-friendly with no need for sophisticated operation and only includes adding sample. Generally, antibodies are employed as the biorecognition elements [...] Read more.
The lateral flow assay (LFA) is an extensively used paper-based platform for the rapid and on-site detection of different analytes. The method is user-friendly with no need for sophisticated operation and only includes adding sample. Generally, antibodies are employed as the biorecognition elements in the LFA. However, antibodies possess several disadvantages including poor stability, high batch-to-batch variation, long development time, high price and need for ethical approval and cold chain. Because of these limitations, aptamers screened by an in vitro process can be a good alternative to antibodies as biorecognition molecules in the LFA. In recent years, aptamer-based LFAs have been investigated for the detection of different analytes in point-of-care diagnostics. In this review, we summarize the applications of aptamer technology in LFAs in clinical diagnostic rapid tests for the detection of biomarkers, microbial analytes, hormones and antibiotics. Performance, advantages and drawbacks of the developed assays are also discussed. Full article
(This article belongs to the Special Issue Potential of the Aptamers to Fill Therapeutic and Diagnostic Gaps)
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Article
P2X7 Receptor Antagonist Reduces Fibrosis and Inflammation in a Mouse Model of Alpha-Sarcoglycan Muscular Dystrophy
Pharmaceuticals 2022, 15(1), 89; https://doi.org/10.3390/ph15010089 - 13 Jan 2022
Cited by 3 | Viewed by 756
Abstract
Limb-girdle muscular dystrophy R3, a rare genetic disorder affecting the limb proximal muscles, is caused by mutations in the α-sarcoglycan gene (Sgca) and aggravated by an immune-mediated damage, finely modulated by the extracellular (e)ATP/purinoceptors axis. Currently, no specific drugs are available. The aim [...] Read more.
Limb-girdle muscular dystrophy R3, a rare genetic disorder affecting the limb proximal muscles, is caused by mutations in the α-sarcoglycan gene (Sgca) and aggravated by an immune-mediated damage, finely modulated by the extracellular (e)ATP/purinoceptors axis. Currently, no specific drugs are available. The aim of this study was to evaluate the therapeutic effectiveness of a selective P2X7 purinoreceptor antagonist, A438079. Sgca knockout mice were treated with A438079 every two days at 3 mg/Kg for 24 weeks. The P2X7 antagonist improved clinical parameters by ameliorating mice motor function and decreasing serum creatine kinase levels. Histological analysis of muscle morphology indicated a significant reduction of the percentage of central nuclei, of fiber size variability and of the extent of local fibrosis and inflammation. A cytometric characterization of the muscle inflammatory infiltrates showed that A438079 significantly decreased innate immune cells and upregulated the immunosuppressive regulatory T cell subpopulation. In α-sarcoglycan null mice, the selective P2X7 antagonist A438079 has been shown to be effective to counteract the progression of the dystrophic phenotype and to reduce the inflammatory response. P2X7 antagonism via selective inhibitors could be included in the immunosuppressant strategies aimed to dampen the basal immune-mediated damage and to favor a better engraftment of gene-cell therapies. Full article
(This article belongs to the Special Issue Development of Medicines for Rare Pediatric Diseases)
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Article
Mirogabalin Decreases Pain-like Behaviours and Improves Opioid and Ketamine Antinociception in a Mouse Model of Neuropathic Pain
Pharmaceuticals 2022, 15(1), 88; https://doi.org/10.3390/ph15010088 - 13 Jan 2022
Viewed by 956
Abstract
Neuropathic pain remains a difficult clinical challenge due to its diverse aetiology and complex pathomechanisms, which are yet to be fully understood. Despite the variety of available therapies, many patients suffer from ineffective pain relief; hence, the search for more efficacious treatments continues. [...] Read more.
Neuropathic pain remains a difficult clinical challenge due to its diverse aetiology and complex pathomechanisms, which are yet to be fully understood. Despite the variety of available therapies, many patients suffer from ineffective pain relief; hence, the search for more efficacious treatments continues. The new gabapentinoid, mirogabalin has recently been approved for clinical use. Although its main mechanism of action occurs at the α2σ-1 and α2σ-2 subunits of calcium channels and is well documented, how the drug affects the disturbed neuropathic interactions at the spinal cord level has not been clarified, which is crucial information from a clinical perspective. The findings of our study suggest that several indirect mechanisms may be responsible for the beneficial analgesic effect of mirogabalin. This is the first study to report that mirogabalin enhances the mRNA expression of spinal antinociceptive factors, such as IL-10 and IL-18BP, and reduces the concentration of the pronociceptive substance P. Importantly, mirogabalin improves the morphine-, buprenorphine-, oxycodone-, and ketamine-induced antinociceptive effects in a neuropathic pain model. Our findings support the hypothesis that enhancing opioid and ketamine analgesia by combining these drugs with mirogabalin may represent a new strategy for the effective pharmacotherapy of neuropathic pain. Full article
(This article belongs to the Section Pharmacology)
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Article
Extraction and Fractionation of Bioactives from Dipsacus fullonum L. Leaves and Evaluation of Their Anti-Borrelia Activity
Pharmaceuticals 2022, 15(1), 87; https://doi.org/10.3390/ph15010087 - 12 Jan 2022
Cited by 2 | Viewed by 1211
Abstract
Lyme disease (LD) is a tick-borne bacterial disease that is caused by Borrelia burgdorferi. Although acute LD is treated with antibiotics, it can develop into relapsing chronic form caused by latent forms of B. burgdorferi. This leads to the search for [...] Read more.
Lyme disease (LD) is a tick-borne bacterial disease that is caused by Borrelia burgdorferi. Although acute LD is treated with antibiotics, it can develop into relapsing chronic form caused by latent forms of B. burgdorferi. This leads to the search for phytochemicals against resistant LD. Therefore, this study aimed to evaluate the activity of Dipsacus fullonum L. leaves extract (DE) and its fractions against stationary phase B. burgdorferi in vitro. DE showed high activity against stationary phase B. burgdorferi (residual viability 19.8 ± 4.7%); however, it exhibited a noticeable cytotoxicity on NIH cells (viability 20.2 ± 5.2%). The iridoid-glycoside fraction showed a remarkable anti-Borrelia effect and reduced cytotoxicity. The iridoid-glycoside fraction was, therefore, further purified and showed to contain two main bioactives—sylvestrosides III and IV, that showed a considerable anti-Borrelia activity being the least toxic to murine fibroblast NIH/3T3 cells. Moreover, the concentration of sylvestrosides was about 15% of DE, endorsing the feasibility of purification of the compounds from D. fullonum L. leaves. Full article
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Article
In Silico-Based Discovery of Natural Anthraquinones with Potential against Multidrug-Resistant E. coli
Pharmaceuticals 2022, 15(1), 86; https://doi.org/10.3390/ph15010086 - 11 Jan 2022
Cited by 1 | Viewed by 795
Abstract
E. coli is a Gram-negative bacterium that causes different human infections. Additionally, it resists common antibiotics due to its outer protective membrane. Natural products have been proven to be efficient antibiotics. However, plant natural products are far less explored in this regard. Accordingly, [...] Read more.
E. coli is a Gram-negative bacterium that causes different human infections. Additionally, it resists common antibiotics due to its outer protective membrane. Natural products have been proven to be efficient antibiotics. However, plant natural products are far less explored in this regard. Accordingly, over 16,000 structures covering almost all African medicinal plants in AfroDb in a structural-based virtual screening were used to find efficient anti-E. coli candidates. These drug-like structures were docked into the active sites of two important molecular targets (i.e., E. coli’s Ddl-B and Gyr-B). The top-scoring hits (i.e., got docking scores < −10 kcal/mol) produced in the initial virtual screening (0.15% of the database structures for Ddl-B and 0.17% of the database structures for Gyr-B in the database) were further refined using molecular dynamic simulation-based binding free energy (ΔG) calculation. Anthraquinones were found to prevail among the retrieved hits. Accordingly, readily available anthraquinone derivatives (10 hits) were selected, prepared, and tested in vitro against Ddl-B, Gyr-B, multidrug-resistant (MDR) E. coli, MRSA, and VRSA. A number of the tested derivatives demonstrated strong micromolar enzyme inhibition and antibacterial activity against E. coli, MRSA, and VRSA, with MIC values ranging from 2 to 64 µg/mL. Moreover, both E. coli’s Ddl-B and Gyr-B were inhibited by emodin and chrysophanol with IC50 values comparable to the reference inhibitors (IC50 = 216 ± 5.6, 236 ± 8.9 and 0.81 ± 0.3, 1.5 ± 0.5 µM for Ddl-B and Gyr-B, respectively). All of the active antibacterial anthraquinone hits showed low to moderate cellular cytotoxicity (CC50 > 50 µM) against human normal fibroblasts (WI-38). Furthermore, molecular dynamic simulation (MDS) experiments were carried out to reveal the binding modes of these inhibitors inside the active site of each enzyme. The findings presented in this study are regarded as a significant step toward developing novel antibacterial agents against MDR strains. Full article
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Article
New IMB16-4 Nanoparticles Improved Oral Bioavailability and Enhanced Anti-Hepatic Fibrosis on Rats
Pharmaceuticals 2022, 15(1), 85; https://doi.org/10.3390/ph15010085 - 11 Jan 2022
Cited by 2 | Viewed by 638
Abstract
Liver fibrosis is challenging to treat because of the lack of effective agents worldwide. Recently, we have developed a novel compound, N-(3,4,5-trichlorophenyl)-2(3-nitrobenzenesulfonamido) benzamide referred to as IMB16-4. However, its poor aqueous solubility and poor oral bioavailability obstruct the drug discovery programs. To increase [...] Read more.
Liver fibrosis is challenging to treat because of the lack of effective agents worldwide. Recently, we have developed a novel compound, N-(3,4,5-trichlorophenyl)-2(3-nitrobenzenesulfonamido) benzamide referred to as IMB16-4. However, its poor aqueous solubility and poor oral bioavailability obstruct the drug discovery programs. To increase the dissolution, improve the oral bioavailability and enhance the antifibrotic activity of IMB16-4, PVPK30 was selected to establish the IMB16-4 nanoparticles. Drug release behavior, oral bioavailability, and anti-hepatic fibrosis effects of IMB16-4 nanoparticles were evaluated. The results showed that IMB16-4 nanoparticles greatly increased the dissolution rate of IMB16-4. The oral bioavailability of IMB16-4 nanoparticles was improved 26-fold compared with that of pure IMB16-4. In bile duct ligation rats, IMB16-4 nanoparticles significantly repressed hepatic fibrogenesis and improved the liver function. These findings indicate that IMB16-4 nanoparticles will provide information to expand a novel anti-hepatic fibrosis agent. Full article
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Article
Mangostanin, a Xanthone Derived from Garcinia mangostana Fruit, Exerts Protective and Reparative Effects on Oxidative Damage in Human Keratinocytes
Pharmaceuticals 2022, 15(1), 84; https://doi.org/10.3390/ph15010084 - 11 Jan 2022
Cited by 5 | Viewed by 1118
Abstract
The fruit of Garcinia mangostana (mangosteen) is known in ancient traditional Asian medicine for its antioxidant, anti-inflammatory, immunomodulatory and anticancer activities. These effects are mainly due to the action of polyphenols known as xanthones, which are contained in the pericarp of the fruit. [...] Read more.
The fruit of Garcinia mangostana (mangosteen) is known in ancient traditional Asian medicine for its antioxidant, anti-inflammatory, immunomodulatory and anticancer activities. These effects are mainly due to the action of polyphenols known as xanthones, which are contained in the pericarp of the fruit. In recent years, there has been a growing interest from pharmaceutical companies in formulating new topicals based on mangosteen full extracts to prevent skin aging. However, the molecules responsible for these effects and the mechanisms involved have not been investigated so far. Here, the arils and shells of Garcinia mangostana were extracted with chloroform and methanol, and the extracts were further purified to yield 12 xanthone derivatives. Their effects were evaluated using in vitro cultures of human epidermal keratinocytes. After confirming the absence of cytotoxicity, we evaluated the antioxidant potential of these compounds, identifying mangostanin as capable of both protecting and restoring oxidative damage induced by H2O2. We showed how mangostanin, by reducing the generation of intracellular reactive oxygen species (ROS), prevents the activation of AKT (protein kinase B), ERK (extracellular signal-regulated kinase), p53, and other cellular pathways underlying cell damage and apoptosis activation. In conclusion, our study is the first to demonstrate that mangostanin is effective in protecting the skin from the action of free radicals, thus preventing skin aging, confirming a potential toward its development in the nutraceutical and cosmeceutical fields. Full article
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Article
Extracellular Vesicle Delivery of Neferine for the Attenuation of Neurodegenerative Disease Proteins and Motor Deficit in an Alzheimer’s Disease Mouse Model
Pharmaceuticals 2022, 15(1), 83; https://doi.org/10.3390/ph15010083 - 10 Jan 2022
Cited by 2 | Viewed by 1370
Abstract
Exosomes are nano-extracellular vesicles with diameters ranging from 30 to 150 nm, which are secreted by the cell. With their role in drug cargo loading, exosomes have been applied to carry compounds across the blood–brain barrier in order to target the central nervous [...] Read more.
Exosomes are nano-extracellular vesicles with diameters ranging from 30 to 150 nm, which are secreted by the cell. With their role in drug cargo loading, exosomes have been applied to carry compounds across the blood–brain barrier in order to target the central nervous system (CNS). In this study, high-purity exosomes isolated by the ultra-high-speed separation method were applied as the natural compound carrier, with the loading efficiency confirmed by UHPLC-MS analysis. Through the optimization of various cargo loading methods using exosomes, this study compared the efficiency of different ways for the separation of exosomes and the exosome encapsulation of natural compounds with increasing molecular weights via extensive in vitro and in vivo efficacy studies. In a pharmacokinetic study, our data suggested that the efficiency of compound’s loading into exosomes is positively correlated to its molecular weight. However, with a molecular weight of greater than 1109 Da, the exosome-encapsulated natural compounds were not able to pass through the blood–brain barrier (BBB). In vitro cellular models confirmed that three of the selected exosome-encapsulated natural compounds—baicalin, hederagenin and neferine—could reduce the level of neurodegenerative disease mutant proteins—including huntingtin 74 (HTT74), P301L tau and A53T α-synuclein (A53T α-syn)—more effectively than the compounds alone. With the traditional pharmacological role of the herbal plant Nelumbo nucifera in mitigating anxiety, exosome-encapsulated-neferine was, for the first time, reported to improve the motor deficits of APP/PS1 (amyloid precursor protein/ presenilin1) double transgenic mice, and to reduce the level of β-amyloid (Aβ) in the brain when compared with the same concentration of neferine alone. With the current trend in advocating medicine–food homology and green healthcare, this study has provided a rationale from in vitro to in vivo for the encapsulation of natural compounds using exosomes for the targeting of BBB permeability and neurodegenerative diseases in the future. Full article
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Article
In Silico Design, Synthesis, and Biological Evaluation of Anticancer Arylsulfonamide Endowed with Anti-Telomerase Activity
Pharmaceuticals 2022, 15(1), 82; https://doi.org/10.3390/ph15010082 - 10 Jan 2022
Cited by 2 | Viewed by 776
Abstract
Telomerase, a reverse transcriptase enzyme involved in DNA synthesis, has a tangible role in tumor progression. Several studies have evidenced telomerase as a promising target for developing cancer therapeutics. The main reason is due to the overexpression of telomerase in cancer cells (85–90%) [...] Read more.
Telomerase, a reverse transcriptase enzyme involved in DNA synthesis, has a tangible role in tumor progression. Several studies have evidenced telomerase as a promising target for developing cancer therapeutics. The main reason is due to the overexpression of telomerase in cancer cells (85–90%) compared with normal cells where it is almost unexpressed. In this paper, we used a structure-based approach to design potential inhibitors of the telomerase active site. The MYSHAPE (Molecular dYnamics SHared PharmacophorE) approach and docking were used to screen an in-house library of 126 arylsulfonamide derivatives. Promising compounds were synthesized using classical and green methods. Compound 2C revealed an interesting IC50 (33 ± 4 µM) against the K-562 cell line compared with the known telomerase inhibitor BIBR1532 IC50 (208 ± 11 µM) with an SI ~10 compared to the BALB/3-T3 cell line. A 100 ns MD simulation of 2C in the telomerase active site evidenced Phe494 as the key residue as well as in BIBR1532. Each moiety of compound 2C was involved in key interactions with some residues of the active site: Arg557, Ile550, and Gly553. Compound 2C, as an arylsulfonamide derivative, is an interesting hit compound that deserves further investigation in terms of optimization of its structure to obtain more active telomerase inhibitors Full article
(This article belongs to the Special Issue In Silico Approaches in Drug Design)
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Review
Pharmacological Modulation and (Patho)Physiological Roles of TRPM4 Channel—Part 1: Modulation of TRPM4
Pharmaceuticals 2022, 15(1), 81; https://doi.org/10.3390/ph15010081 - 10 Jan 2022
Viewed by 899
Abstract
Transient receptor potential melastatin 4 is a unique member of the TRPM protein family and, similarly to TRPM5, is Ca2+-sensitive and permeable to monovalent but not divalent cations. It is widely expressed in many organs and is involved in several functions [...] Read more.
Transient receptor potential melastatin 4 is a unique member of the TRPM protein family and, similarly to TRPM5, is Ca2+-sensitive and permeable to monovalent but not divalent cations. It is widely expressed in many organs and is involved in several functions by regulating the membrane potential and Ca2+ homeostasis in both excitable and non-excitable cells. This part of the review discusses the pharmacological modulation of TRPM4 by listing, comparing, and describing both endogenous and exogenous activators and inhibitors of the ion channel. Moreover, other strategies used to study TRPM4 functions are listed and described. These strategies include siRNA-mediated silencing of TRPM4, dominant-negative TRPM4 variants, and anti-TRPM4 antibodies. TRPM4 is receiving more and more attention and is likely to be the topic of research in the future. Full article
(This article belongs to the Special Issue Ion Channels: Current Pharmacological Challenges)
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Review
Histone Deacetylase (HDAC) Inhibitors for the Treatment of Schistosomiasis
Pharmaceuticals 2022, 15(1), 80; https://doi.org/10.3390/ph15010080 - 10 Jan 2022
Cited by 5 | Viewed by 1009
Abstract
Schistosomiasis is a major neglected parasitic disease that affects more than 240 million people worldwide and for which the control strategy consists of mass treatment with the only available drug, praziquantel. Schistosomes display morphologically distinct stages during their life cycle and the transformations [...] Read more.
Schistosomiasis is a major neglected parasitic disease that affects more than 240 million people worldwide and for which the control strategy consists of mass treatment with the only available drug, praziquantel. Schistosomes display morphologically distinct stages during their life cycle and the transformations between stages are controlled by epigenetic mechanisms. The targeting of epigenetic actors might therefore represent the parasites’ Achilles’ heel. Specifically, histone deacetylases have been recently characterized as drug targets for the treatment of schistosomiasis. This review focuses on the recent development of inhibitors for schistosome histone deacetylases. In particular, advances in the development of inhibitors of Schistosoma mansoni histone deacetylase 8 have indicated that targeting this enzyme is a promising approach for the treatment of this infection. Full article
(This article belongs to the Special Issue Drug Discovery and Development for Tropical Diseases (TDs))
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Article
The Statin Target HMG-Coenzyme a Reductase (Hmgcr) Regulates Sleep Homeostasis in Drosophila
Pharmaceuticals 2022, 15(1), 79; https://doi.org/10.3390/ph15010079 - 10 Jan 2022
Cited by 1 | Viewed by 1097
Abstract
Statins, HMG Coenzyme A Reductase (HMGCR) inhibitors, are a first-line therapy, used to reduce hypercholesterolemia and the risk for cardiovascular events. While sleep disturbances are recognized as a side-effect of statin treatment, the impact of statins on sleep is under debate. Using Drosophila, [...] Read more.
Statins, HMG Coenzyme A Reductase (HMGCR) inhibitors, are a first-line therapy, used to reduce hypercholesterolemia and the risk for cardiovascular events. While sleep disturbances are recognized as a side-effect of statin treatment, the impact of statins on sleep is under debate. Using Drosophila, we discovered a novel role for Hmgcr in sleep modulation. Loss of pan-neuronal Hmgcr expression affects fly sleep behavior, causing a decrease in sleep latency and an increase in sleep episode duration. We localized the pars intercerebralis (PI), equivalent to the mammalian hypothalamus, as the region within the fly brain requiring Hmgcr activity for proper sleep maintenance. Lack of Hmgcr expression in the PI insulin-producing cells recapitulates the sleep effects of pan-neuronal Hmgcr knockdown. Conversely, loss of Hmgcr in a different PI subpopulation, the corticotropin releasing factor (CRF) homologue-expressing neurons (DH44 neurons), increases sleep latency and decreases sleep duration. The requirement for Hmgcr activity in different neurons signifies its importance in sleep regulation. Interestingly, loss of Hmgcr in the PI does not affect circadian rhythm, suggesting that Hmgcr regulates sleep by pathways distinct from the circadian clock. Taken together, these findings suggest that Hmgcr activity in the PI is essential for proper sleep homeostasis in flies. Full article
(This article belongs to the Section Pharmacology)
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