Next Issue
Volume 14, October
Previous Issue
Volume 14, August

Pharmaceuticals, Volume 14, Issue 9 (September 2021) – 113 articles

Cover Story (view full-size image): An indole alkaloid, isolated from the African medicinal plant Tabernaemontana elegans, was derivatized yielding nineteen azines and eleven semicarbazones. Through a functional assay, in a human ABCB1-transfected mouse T-lymphoma cell model overexpressing P-glycoprotein, a significant increase in P-gp inhibitory activity was observed for most derivatives, those with trimethoxyphenyl or naphthyl motifs being among the most active. In chemosensitivity assays, they interacted synergistically with doxorubicin. Most of them showed MDR-selective activity toward resistant cells, having a collateral sensitivity effect. In the ATPase assay, selected compounds behaved as inhibitors. A QSAR model allowed us to deduce that compounds bearing bulky and lipophilic substituents were stronger P-gp inhibitors. View this paper.
  • Issues are regarded as officially published after their release is announced to the table of contents alert mailing list.
  • You may sign up for e-mail alerts to receive table of contents of newly released issues.
  • PDF is the official format for papers published in both, html and pdf forms. To view the papers in pdf format, click on the "PDF Full-text" link, and use the free Adobe Readerexternal link to open them.
Order results
Result details
Select all
Export citation of selected articles as:
Article
A Comparative Survey of Anti-Melanoma and Anti-Inflammatory Potential of Usnic Acid Enantiomers—A Comprehensive In Vitro Approach
Pharmaceuticals 2021, 14(9), 945; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14090945 - 21 Sep 2021
Viewed by 617
Abstract
Usnic acid (UA) is a chiral lichen metabolite with an interesting pharmacological profile. The aim of this study was to compare the anti-melanoma effect of (+)-UA and (−)-UA in an in vitro model by studying their impact on the cells as well as [...] Read more.
Usnic acid (UA) is a chiral lichen metabolite with an interesting pharmacological profile. The aim of this study was to compare the anti-melanoma effect of (+)-UA and (−)-UA in an in vitro model by studying their impact on the cells as well as the processes associated with cancer progression. The effect of UA enantiomers on the viability, proliferation, and invasive potential of three melanoma cell lines (HTB140, A375, WM793) was evaluated. Their interaction with a chemotherapeutic drug—doxorubicin was assessed by isobolographic analysis. Anti-inflammatory and anti-tyrosinase properties of (+)-UA and (−)-UA were also examined. Both UA enantiomers dose- and time-dependently decreased the viability of all three melanoma cell lines. Their synergistic effect with doxorubicin was observed on A375 cells. (+)-Usnic acid at a sub-cytotoxic dose strongly inhibited melanoma cells migration. Both UA enantiomers decreased the release of pro-inflammatory mediators. The cytotoxic effect of (+)-UA and (−)-UA depends greatly on the melanoma cell type; however, the overall anti-melanoma potential is perspective. Our results indicate that the strategy of combining usnic acid enantiomers with cytostatic drugs may be an interesting option to consider in combating melanoma; however, further studies are required. Full article
Show Figures

Figure 1

Article
Less Polar Compounds and Targeted Antioxidant Potential (In Vitro and In Vivo) of Codium adhaerens C. Agardh 1822
Pharmaceuticals 2021, 14(9), 944; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14090944 - 21 Sep 2021
Viewed by 437
Abstract
Codium adhaerens from the Adriatic Sea (Croatia) was comprehensively investigated regarding less polar compounds for the first time. Although there are several phytochemical studies on C. adhaerens from other regions, this is the first report on volatile organic compounds (VOCs) from fresh (FrCa) [...] Read more.
Codium adhaerens from the Adriatic Sea (Croatia) was comprehensively investigated regarding less polar compounds for the first time. Although there are several phytochemical studies on C. adhaerens from other regions, this is the first report on volatile organic compounds (VOCs) from fresh (FrCa) and air-dried (DrCa) samples. The novelty is also related to its targeted antioxidant potential in vitro and in vivo. The main aims were to: (a) identify and compare VOCs of FrCa and DrCa obtained by headspace solid-phase microextraction (HS-SPME) and hydrodistillation (HD); (b) determine fatty acid (FA) composition of freeze-dried sample (FdCa); (c) determine the composition of less polar fractions of FdCa by high-performance liquid chromatography–high-resolution mass spectrometry with electrospray ionisation (UHPLC-ESI-HRMS); and (d) comprehensively evaluate the antioxidant activity of the fractions by four in vitro assays and in vivo zebrafish model (including embryotoxicity). Significant changes of VOCs were found after air drying. ω6 FAs were present in higher content than ω3 FAs indicating C. adhaerens as a good source of dietary polyunsaturated FAs. The results obtained in vivo correlate well with in vitro methods and both fractions exerted similar antioxidative responses which is in agreement with the high abundance of present biomolecules with known antioxidant properties (e.g., fucoxanthin, pheophytin a, and pheophorbide a). These results suggest that C. adhaerens might be a potent source of natural antioxidants that could be further used in the research of oxidative stress-related diseases. Full article
(This article belongs to the Special Issue Chemistry and Biomedical Potential of Marine Natural Products)
Show Figures

Graphical abstract

Article
Development and Validation of a New Storage Procedure to Extend the In-Use Stability of Azacitidine in Pharmaceutical Formulations
Pharmaceuticals 2021, 14(9), 943; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14090943 - 21 Sep 2021
Viewed by 401
Abstract
Stability studies performed by the pharmaceutical industry are principally designed to fulfill licensing requirements. Thus, post-dilution or post-reconstitution stability data are frequently limited to 24 h only for bacteriological reasons, regardless of the true physicochemical stability which could, in many cases, be longer. [...] Read more.
Stability studies performed by the pharmaceutical industry are principally designed to fulfill licensing requirements. Thus, post-dilution or post-reconstitution stability data are frequently limited to 24 h only for bacteriological reasons, regardless of the true physicochemical stability which could, in many cases, be longer. In practice, the pharmacy-based centralized preparation may require preparation in advance for administration, for example, on weekends, holidays, or in general when pharmacies may be closed. We report an innovative strategy for storing resuspended solutions of azacitidine, a well-known chemotherapic agent, for which the manufacturer lists maximum stability of 22 h. By placing the syringe with the azacitidine reconstituted suspension between two refrigerant gel packs and storing it at 4 °C, we found that the concentration of azacitidine remained above 98% of the initial concentration for 48 h, and no change in color nor the physicochemical properties of the suspension were observed throughout the study period. The physicochemical and microbiological properties were evaluated by HPLC–UV and UHPLC-HRMS analysis, FTIR spectroscopy, pH determination, visual and subvisual examination, and sterility assay. The HPLC-UV method used for evaluating the chemical stability of azacitidine was validated according to ICH. Precise control of storage temperature was obtained by a digital data logger. Our study indicates that by changing the storage procedure of azacitidine reconstituted suspension, the usage window of the drug can be significantly extended to a time frame that better copes with its use in the clinical environment. Full article
(This article belongs to the Section Pharmaceutical Technology)
Show Figures

Figure 1

Article
The Synthetic Curcumin Analog HO-3867 Rescues Suppression of PLAC1 Expression in Ovarian Cancer Cells
Pharmaceuticals 2021, 14(9), 942; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14090942 - 21 Sep 2021
Viewed by 566
Abstract
Elevated expression of placenta-specific protein 1 (PLAC1) is associated with the increased proliferation and invasiveness of a variety of human cancers, including ovarian cancer. Recent studies have shown that the tumor suppressor p53 directly suppresses PLAC1 transcription. However, mutations in p53 lead to [...] Read more.
Elevated expression of placenta-specific protein 1 (PLAC1) is associated with the increased proliferation and invasiveness of a variety of human cancers, including ovarian cancer. Recent studies have shown that the tumor suppressor p53 directly suppresses PLAC1 transcription. However, mutations in p53 lead to the loss of PLAC1 transcriptional suppression. Small molecules that structurally convert mutant p53 proteins to wild-type conformations are emerging. Our objective was to determine whether the restoration of the wild-type function of mutated p53 could rescue PLAC1 transcriptional suppression in tumors harboring certain TP53 mutations. Ovarian cancer cells OVCAR3 and ES-2, both harboring TP53 missense mutations, were treated with the p53 reactivator HO-3867. Treatment with HO-3867 successfully rescued PLAC1 transcriptional suppression. In addition, cell proliferation was inhibited and cell death through apoptosis was increased in both cell lines. We conclude that the use of HO-3867 as an adjuvant to conventional therapeutics in ovarian cancers harboring TP53 missense mutations could improve patient outcomes. Validation of this conclusion must, however, come from an appropriately designed clinical trial. Full article
(This article belongs to the Section Pharmacology)
Show Figures

Figure 1

Article
Chicory Extracts and Sesquiterpene Lactones Show Potent Activity against Bacterial and Fungal Pathogens
Pharmaceuticals 2021, 14(9), 941; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14090941 - 20 Sep 2021
Viewed by 919
Abstract
Chicory (Cichorium intybus L.) is an important industrial crop cultivated mainly to extract the dietary fiber inulin. However, chicory also contains bioactive compounds such as sesquiterpene lactones and certain polyphenols, which are currently discarded as waste. Plants are an important source of [...] Read more.
Chicory (Cichorium intybus L.) is an important industrial crop cultivated mainly to extract the dietary fiber inulin. However, chicory also contains bioactive compounds such as sesquiterpene lactones and certain polyphenols, which are currently discarded as waste. Plants are an important source of active pharmaceutical ingredients, including novel antimicrobials that are urgently needed due to the global spread of drug-resistant bacteria and fungi. Here, we tested different extracts of chicory for a range of bioactivities, including antimicrobial, antifungal and cytotoxicity assays. Antibacterial and antifungal activities were generally more potent in ethyl acetate extracts compared to water extracts, whereas supercritical fluid extracts showed the broadest range of bioactivities in our assays. Remarkably, the chicory supercritical fluid extract and a purified fraction thereof inhibited both methicillin-resistant Staphylococcus aureus (MRSA) and ampicillin-resistant Pseudomonas aeruginosa IBRS P001. Chicory extracts also showed higher antibiofilm activity against the yeast Candida albicans than standard sesquiterpene lactone compounds. The cytotoxicity of the extracts was generally low. Our results may thus lead to the development of novel antibacterial and antifungal preparations that are both effective and safe for human use. Full article
(This article belongs to the Special Issue Natural Pharmacons: Biologically Active Plant Based Pharmaceuticals)
Show Figures

Graphical abstract

Article
Antioxidant and Anti-Inflammatory Potential of Thymoquinone and Lycopene Mitigate the Chlorpyrifos-Induced Toxic Neuropathy
Pharmaceuticals 2021, 14(9), 940; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14090940 - 20 Sep 2021
Viewed by 568
Abstract
CPF (chlorpyrifos) is an organophosphate pesticide used in agricultural and veterinary applications. Our experiment aimed to explore the effects of thymoquinone (TQ) and/or lycopene (LP) against CPF-induced neurotoxicity. Wistar rats were categorized into seven groups: first group served as a control (corn oil [...] Read more.
CPF (chlorpyrifos) is an organophosphate pesticide used in agricultural and veterinary applications. Our experiment aimed to explore the effects of thymoquinone (TQ) and/or lycopene (LP) against CPF-induced neurotoxicity. Wistar rats were categorized into seven groups: first group served as a control (corn oil only); second group, TQ (10 mg/kg); third group, LP (10 mg/kg); fourth group, CPF (10 mg/kg) and deemed as CPF toxic control; fifth group, TQ + CPF; sixth group, (LP + CPF); and seventh group, (TQ + LP + CPF). CPF intoxication inhibited acetylcholinesterase (AchE), decreased glutathione (GSH) content, and increased levels of malondialdehyde (MDA), an oxidative stress biomarker. Furthermore, CPF impaired the activity of antioxidant enzymes including superoxide dismutase (SOD) and catalase (CAT) along with enhancement of the level of inflammatory mediators such as tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-1β. CPF evoked apoptosis in brain tissue. TQ or LP treatment of CPF-intoxicated rats greatly improved AchE activity, oxidative state, inflammatory responses, and cell death. Co-administration of TQ and LP showed better restoration than their sole treatment. In conclusion, TQ or LP supplementation may alleviate CPF-induced neuronal injury, most likely due to TQ or LPs’ antioxidant, anti-inflammatory, and anti-apoptotic effects. Full article
Show Figures

Figure 1

Article
Preparation of Soluble Complex of Curcumin for the Potential Antagonistic Effects on Human Colorectal Adenocarcinoma Cells
Pharmaceuticals 2021, 14(9), 939; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14090939 - 19 Sep 2021
Viewed by 676
Abstract
This study was designed to investigate the effects of curcumin (CMN) soluble complex (SC) prepared by melt casting (HM) and hot-melt extrusion (HME) technology. Phase solubility (PS) study, in silico molecular modeling, aqueous solubility, drug release, and physicochemical investigation including a novel dyeing [...] Read more.
This study was designed to investigate the effects of curcumin (CMN) soluble complex (SC) prepared by melt casting (HM) and hot-melt extrusion (HME) technology. Phase solubility (PS) study, in silico molecular modeling, aqueous solubility, drug release, and physicochemical investigation including a novel dyeing test was performed to obtain an optimized complex by a central composite design (CCD). The results show that the HME-SC produces better improvements towards solubility (0.852 ± 0.02), dissolution (91.87 ± 0.21% at 30 min), with an ideal stability constant (309 and 377 M−1 at 25 and 37 °C, respectively) and exhibits AL type of isotherm indicating 1:1 stoichiometry. Intermolecular hydrogen bonding involves the formation of SC, which does not undergo any chemical modification, followed by the complete conversion of the amorphous form which was identified by XRD. The in vitro cytotoxicity showed that IC50 was achieved in the SW480 (72 µM.mL−1) and Caco-2 (40 µM.mL−1) cells while that of pure CMN ranged from 146 to 116 µM/mL−1. Apoptosis studies showed that cell death is primarily due to apoptosis, with a low rate of necrosis. In vivo toxicity, confirmed by the zebrafish model, exhibited the safety of the HME-SC. In conclusion, the HME-SC potentially enhances the solubility and cytotoxicity to the treatment of colorectal cancer (CRC). Full article
(This article belongs to the Topic Compounds with Medicinal Value)
Show Figures

Graphical abstract

Article
Asymmetric Total Syntheses of Both Enantiomers of Plymuthipyranone B and Its Unnatural Analogues: Evaluation of anti-MRSA Activity and Its Chiral Discrimination
Pharmaceuticals 2021, 14(9), 938; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14090938 - 19 Sep 2021
Viewed by 683
Abstract
Chiral total syntheses of both enantiomers of the anti-MRSA active plymuthipyranone B and all of the both enantiomers of three unnatural and synthetic analogues were performed. These two pairs of four chiral compounds are composed of the same 3-acyl-5,6-dihydro-2H-pyran-2-one structure. [...] Read more.
Chiral total syntheses of both enantiomers of the anti-MRSA active plymuthipyranone B and all of the both enantiomers of three unnatural and synthetic analogues were performed. These two pairs of four chiral compounds are composed of the same 3-acyl-5,6-dihydro-2H-pyran-2-one structure. The starting synthetic step utilized a privileged asymmetric Mukaiyama aldol addition using Ti(OiPr)4/(S)-BINOL or Ti(OiPr)4/(R)-BINOL catalysis to afford the corresponding (R)- and (S)-δ-hydroxy-β-ketoesters, respectively, with highly enantiomeric excess (>98%). Conventional lactone formation and successive EDCI-mediated C-acylation produced the desired products, (R)- and (S)-plymuthipyranones B and three (R)- and (S)- synthetic analogues, with an overall yield of 42–56% with a highly enantiomeric excess (95–99%). A bioassay of the anti-MRSA activity against ATCC 43300 and 33591 revealed that (i) the MICs of the synthetic analogues against ATCC 43300 and ATCC 33591 were between 2 and 16 and 4 and 16 μg/mL, respectively, and those of vancomycin (reference) were 1 μg/mL. (ii) The natural (S)-plymuthipyranone B exhibited significantly higher activity than the unnatural (R)-antipode against both AACCs. (iii) The natural (R)-plymuthipyranone B and (R)-undecyl synthetic analogue at the C6 position exhibited the highest activity. The present work is the first investigation of the SAR between chiral R and S forms of this chemical class. Full article
(This article belongs to the Special Issue Chirality in Drug Discovery)
Show Figures

Figure 1

Article
High-Throughput Screening and Molecular Dynamics Simulation of Natural Product-like Compounds against Alzheimer’s Disease through Multitarget Approach
Pharmaceuticals 2021, 14(9), 937; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14090937 - 18 Sep 2021
Viewed by 530
Abstract
Alzheimer’s disease (AD) is a progressive neurological disorder that affects 50 million people. Despite this, only two classes of medication have been approved by the FDA. Therefore, we have planned to develop therapeutics by multitarget approach. We have explored the library of 2029 [...] Read more.
Alzheimer’s disease (AD) is a progressive neurological disorder that affects 50 million people. Despite this, only two classes of medication have been approved by the FDA. Therefore, we have planned to develop therapeutics by multitarget approach. We have explored the library of 2029 natural product-like compounds for their multi-targeting potential against AD by inhibiting AChE, BChE (cholinergic pathway) MAO-A, and MOA-B (oxidative stress pathway) through in silico high-throughput screening and molecular dynamics simulation. Based on the binding energy of these target enzymes, approximately 189 compounds exhibited a score of less than −10 kcal/mol against all targets. However, none of the control inhibitors exhibited a binding affinity of less than −10 kcal/mol. Among these, the top 10 hits of compounds against all four targets were selected for ADME-T analysis. As a result, only F0850-4777 exhibited an acceptable range of physicochemical properties, drug-likeness, pharmacokinetics, and suitability for BBB permeation with high GI-A and non-toxic effects. The molecular dynamics study confirmed that F0850-4777 remained inside the binding cavity of targets in a stable conformation throughout the simulation and Prime-MM/GBSA study revealed that van der Waals’ energy (ΔGvdW) and non-polar solvation or lipophilic energy (ΔGSol_Lipo) contribute favorably towards the formation of a stable protein–ligand complex. Thus, F0850-4777 could be a potential candidate against multiple targets of two pathophysiological pathways of AD and opens the doors for further confirmation through in vitro and in vivo systems. Full article
(This article belongs to the Special Issue In Silico Approaches in Drug Design 2021)
Show Figures

Figure 1

Review
The Endocannabinoid System and Cannabidiol: Past, Present, and Prospective for Cardiovascular Diseases
Pharmaceuticals 2021, 14(9), 936; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14090936 - 17 Sep 2021
Viewed by 675
Abstract
In the past, cannabis was commonly associated with mysticism and illegality. Fortunately, in recent years perspectives and discourses have changed. More prominence has been given to the rigorous scientific effort that led to the discovery of cannabis’ many physiological actions and endogenous signalling [...] Read more.
In the past, cannabis was commonly associated with mysticism and illegality. Fortunately, in recent years perspectives and discourses have changed. More prominence has been given to the rigorous scientific effort that led to the discovery of cannabis’ many physiological actions and endogenous signalling mechanisms. The endocannabinoid system is a complex and heterogeneous pro-homeostatic network comprising different receptors with several endogenous ligands, numerous metabolic enzymes and regulatory proteins. Therefore, it is not surprising that alterations and dysfunctions of the endocannabinoid system are observed in almost every category of disease. Such high degree of pathophysiological involvement suggests the endocannabinoid system is a promising therapeutic target and prompted the translation of resurgent scientific findings into clinical therapies. Shifting attitudes toward cannabis also raised other matters such as increased patient awareness, prescription requests, self-medication, recreational use, recognition of new knowledge gaps, renewed scientific activity, and seemingly exponential growth of the cannabis industry. This review, following a general overview of cannabis and the endocannabinoid system, assiduously describes its role within the context of cardiovascular diseases, paying particular attention to the Janus influence that endocannabinoid system modulators can have on the cardiovascular system. Full article
Show Figures

Graphical abstract

Article
The Metabolomic Approach Reveals the Alteration in Human Serum and Cerebrospinal Fluid Composition in Parkinson’s Disease Patients
Pharmaceuticals 2021, 14(9), 935; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14090935 - 17 Sep 2021
Viewed by 586
Abstract
Parkinson’s disease (PD) is a major public health problem. Since currently there are no reliable diagnostic tools to reveal the early steps of PD, new methods should be developed, including those searching the variations in human metabolome. Alterations in human metabolites could help [...] Read more.
Parkinson’s disease (PD) is a major public health problem. Since currently there are no reliable diagnostic tools to reveal the early steps of PD, new methods should be developed, including those searching the variations in human metabolome. Alterations in human metabolites could help to establish an earlier and more accurate diagnosis. The presented research shows a targeted metabolomics study of both of the serum and CSF from PD patients, atypical parkinsonian disorders (APDs) patients, and the control. The use of the LC-MS/MS system enabled to quantitate 144 analytes in the serum and 51 in the CSF. This information about the concentration enabled for selection of the metabolites useful for differentiation between the studied group of patients, which should be further evaluated as candidates for markers of screening and differential diagnosis of PD and APDs. Among them, the four compounds observed to be altered in both the serum and CSF seem to be the most important: tyrosine, putrescine, trans-4-hydroxyproline, and total dimethylarginine. Furthermore, we indicated the metabolic pathways potentially related to neurodegeneration processes. Our studies present evidence that the proline metabolism might be related to neurodegeneration processes underlying PD and APDs. Further studies on the proposed metabolites and founded metabolic pathways may significantly contribute to understanding the molecular background of PD and improving the diagnostics and treatment in the future. Full article
(This article belongs to the Section Pharmacology)
Show Figures

Figure 1

Review
Manufacturing Bacteriophages (Part 1 of 2): Cell Line Development, Upstream, and Downstream Considerations
Pharmaceuticals 2021, 14(9), 934; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14090934 - 17 Sep 2021
Viewed by 641
Abstract
Within this first part of the two-part series on phage manufacturing, we will give an overview of the process leading to bacteriophages as a drug substance, before covering the formulation into a drug product in the second part. The principal goal is to [...] Read more.
Within this first part of the two-part series on phage manufacturing, we will give an overview of the process leading to bacteriophages as a drug substance, before covering the formulation into a drug product in the second part. The principal goal is to provide the reader with a comprehensive framework of the challenges and opportunities that present themselves when developing manufacturing processes for bacteriophage-based products. We will examine cell line development for manufacture, upstream and downstream processes, while also covering the additional opportunities that engineered bacteriophages present. Full article
(This article belongs to the Special Issue Bacteriophages as Therapeutic Delivery Vehicles)
Show Figures

Figure 1

Review
Neuropsychiatric Disorders and COVID-19: What We Know So Far
Pharmaceuticals 2021, 14(9), 933; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14090933 - 17 Sep 2021
Viewed by 722
Abstract
SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus-2) affects the central nervous system (CNS), which is shown in a significant number of patients with neurological events. In this study, an updated literature review was carried out regarding neurological disorders in COVID-19. Neurological symptoms are more [...] Read more.
SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus-2) affects the central nervous system (CNS), which is shown in a significant number of patients with neurological events. In this study, an updated literature review was carried out regarding neurological disorders in COVID-19. Neurological symptoms are more common in patients with severe infection according to their respiratory status and divided into three categories: (1) CNS manifestations; (2) cranial and peripheral nervous system manifestations; and (3) skeletal muscle injury manifestations. Patients with pre-existing cerebrovascular disease are at a higher risk of admission to the intensive care unit (ICU) and mortality. The neurological manifestations associated with COVID-19 are of great importance, but when life-threatening abnormal vital signs occur in severely ill COVID-19 patients, neurological problems are usually not considered. It is crucial to search for new treatments for brain damage, as well as for alternative therapies that recover the damaged brain and reduce the inflammatory response and its consequences for other organs. In addition, there is a need to diagnose these manifestations as early as possible to limit long-term consequences. Therefore, much research is needed to explain the involvement of SARS-CoV-2 causing these neurological symptoms because scientists know zero about it. Full article
(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)
Show Figures

Figure 1

Article
Engineering Mitochondriotropic Carbon Dots for Targeting Cancer Cells
Pharmaceuticals 2021, 14(9), 932; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14090932 - 16 Sep 2021
Viewed by 684
Abstract
Aiming to understand and enhance the capacity of carbon dots (CDs) to transport through cell membranes and target subcellular organelles—in particular, mitochondria—a series of nitrogen-doped CDs were prepared by the one-step microwave-assisted pyrolysis of citric acid and ethylenediamine. Following optimization of the reaction [...] Read more.
Aiming to understand and enhance the capacity of carbon dots (CDs) to transport through cell membranes and target subcellular organelles—in particular, mitochondria—a series of nitrogen-doped CDs were prepared by the one-step microwave-assisted pyrolysis of citric acid and ethylenediamine. Following optimization of the reaction conditions for maximum fluorescence, functionalization at various degrees with alkylated triphenylphosphonium functional groups of two different alkyl chain lengths afforded a series of functionalized CDs that exhibited either lysosome or mitochondria subcellular localization. Further functionalization with rhodamine B enabled enhanced fluorescence imaging capabilities in the visible spectrum and allowed the use of low quantities of CDs in relevant experiments. It was thus possible, by the appropriate selection of the alkyl chain length and degree of functionalization, to attain successful mitochondrial targeting, while preserving non-toxicity and biocompatibility. In vitro cell experiments performed on normal as well as cancer cell lines proved their non-cytotoxic character and imaging potential, even at very low concentrations, by fluorescence microscopy. Precise targeting of mitochondria is feasible with carefully designed CDs that, furthermore, are specifically internalized in cells and cell mitochondria of high transmembrane potential and thus exhibit selective uptake in malignant cells compared to normal cells. Full article
(This article belongs to the Special Issue Nano Drug Carriers 2021)
Show Figures

Graphical abstract

Article
Pilot Sub-Study of the Effect of Hepatitis C Cure by Glecaprevir/Pibrentasvir on the Gut Microbiome of Patients with Chronic Hepatitis C Genotypes 1 to 6 in the Mythen Study
Pharmaceuticals 2021, 14(9), 931; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14090931 - 16 Sep 2021
Viewed by 493
Abstract
In this small pilot sub-study, longitudinal gut microbiota composition changes, after successful treatment of hepatitis C virus (HCV) with the co-formulated glecaprevir/pibrentasvir (GLE/PIB), were analyzed before treatment (baseline) and 12 weeks post-treatment. Participating patients provided a fresh stool sample the week before their [...] Read more.
In this small pilot sub-study, longitudinal gut microbiota composition changes, after successful treatment of hepatitis C virus (HCV) with the co-formulated glecaprevir/pibrentasvir (GLE/PIB), were analyzed before treatment (baseline) and 12 weeks post-treatment. Participating patients provided a fresh stool sample the week before their study visit, from which microbial DNA was extracted and sequenced for the 16S rRNA region in an Illumina MiSeq2 platform. Microbial and statistical analyses were conducted to determine the alpha-diversity (number of different taxa within a sample) and beta-diversity (number of overlapping taxa between samples). Stool samples from 58 patients were eligible for analysis. There were 27 patients with HCV genotype 1, 10 with genotype 2, 16 with genotype 3, and 5 with genotype 4. No statistically significant differences in gut microbiota diversity, species richness, or microbial community pattern were found at baseline and at post-treatment Week 12. Lack of statistically significant differences remained consistent in further analysis by demographic and baseline disease characteristics. Surprisingly, no statistically significant changes in alpha- and beta-diversity were seen in the microbiota after GLE/PIB treatment, though there was a trend toward less richness over time. Further investigation is needed into this unexpected outcome to better understand the role of HCV treatment and the gut microbiota. Full article
(This article belongs to the Section Pharmacology)
Show Figures

Figure 1

Review
Antidepressants in Alzheimer’s Disease: A Focus on the Role of Mirtazapine
Pharmaceuticals 2021, 14(9), 930; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14090930 - 16 Sep 2021
Viewed by 564
Abstract
Mirtazapine belongs to the category of antidepressants clinically used mainly in major depressive disorder but also used in obsessive-compulsive disorders, generalized anxiety, and sleep disturbances. This drug acts mainly by antagonizing the adrenergic α2, and the serotonergic 5-HT2 and 5-HT3 receptors. Neuropsychiatric symptoms, [...] Read more.
Mirtazapine belongs to the category of antidepressants clinically used mainly in major depressive disorder but also used in obsessive-compulsive disorders, generalized anxiety, and sleep disturbances. This drug acts mainly by antagonizing the adrenergic α2, and the serotonergic 5-HT2 and 5-HT3 receptors. Neuropsychiatric symptoms, such as depression and agitation, are strongly associated with Alzheimer’s disease, reducing the life quality of these patients. Thus, it is crucial to control depression in Alzheimer’s patients. For this purpose, drugs such as mirtazapine are important in the control of anxiety, agitation, and other depressive symptoms in these patients. Indeed, despite some contradictory studies, evidence supports the role of mirtazapine in this regard. In this review, we will focus on depression in Alzheimer’s disease, highlighting the role of mirtazapine in this context. Full article
(This article belongs to the Special Issue Treatment of Alzheimer Disease)
Show Figures

Figure 1

Article
In Vitro and In Vivo Evaluation of Oral Controlled Release Formulation of BCS Class I Drug Using Polymer Matrix System
Pharmaceuticals 2021, 14(9), 929; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14090929 - 16 Sep 2021
Viewed by 671
Abstract
Diltiazem hydrochloride is a calcium channel blocker, which belongs to the family of benzothiazepines. It is commonly used to treat hypertension and atrial fibrillation. Even though the drug has high solubility, its high permeability and rapid metabolism in the liver can limit the [...] Read more.
Diltiazem hydrochloride is a calcium channel blocker, which belongs to the family of benzothiazepines. It is commonly used to treat hypertension and atrial fibrillation. Even though the drug has high solubility, its high permeability and rapid metabolism in the liver can limit the bioavailability and increase the dose frequencies for up to four times per day. This study focused on a polymer matrix system not only to control the drug release but also to prolong the duration of bioavailability. The polymer matrices were prepared using different ratios of poloxamer-188, hydroxypropyl methylcellulose, and stearyl alcohol. In vitro and in vivo assessments took place using 24 rabbits and the results were compared to commercially available product Tildiem® (60 mg tablet) as reference. Overall, the rate of drug release was sustained with the gradual increase of poloxamer-188 incorporated with hydroxypropyl methylcellulose and stearyl alcohol in the matrix system, achieving a maximum release period of 10 h. The oral bioavailability and pharmacokinetic parameters of diltiazem hydrochloride incorporated in polymer matrix system were similar to commercial reference Tildiem®. In conclusion, the combination of polymers can have a substantial effect on controlling and prolonging the drug release pattern. The outcomes showed that poloxamer-188 combined with hydroxypropyl methylcellulose and stearyl alcohol is a powerful matrix system for controlling release of diltiazem hydrochloride. Full article
(This article belongs to the Section Pharmaceutical Technology)
Show Figures

Figure 1

Review
State of the Art on Approved Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Modulators and Triple-Combination Therapy
Pharmaceuticals 2021, 14(9), 928; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14090928 - 15 Sep 2021
Viewed by 559
Abstract
Cystic fibrosis (CF) is the most common life-limiting inherited disease in Caucasian populations, affecting approximately 80,000 people worldwide. CF is a complex multi-organ monogenic autosomal recessive disorder caused by a mutation in cystic fibrosis transmembrane conductance regulator (CFTR) gene. Since the [...] Read more.
Cystic fibrosis (CF) is the most common life-limiting inherited disease in Caucasian populations, affecting approximately 80,000 people worldwide. CF is a complex multi-organ monogenic autosomal recessive disorder caused by a mutation in cystic fibrosis transmembrane conductance regulator (CFTR) gene. Since the discovery of the CFTR gene in 1989, more than 2000 mutations have been identified so far and about 240 can cause CF. Until recently, the treatment for CF was aimed to prevent and manage the manifestations of CFTR dysfunction, primarily recurrent pulmonary infections and pancreatic exocrine failure. Over the past few decades, the therapeutic approach to CF has been revolutionized by the development of a new class of small molecules called CFTR modulators that target specific defects caused by mutations in the CFTR gene. CFTR modulators have been shown to change profoundly the clinical course of the CF, leading to meaningful improvements in the lives of a large proportion of people of CF heterozygous for F508del, especially if started in young children. Further studies are needed to extend the use of triple CFTR modulation therapy also for young children in order to prevent the irreversible effects of the disease and for patients with very rare mutations with a personalized approach to treatment. Full article
(This article belongs to the Special Issue Prevention, Diagnosis and Treatment of Pediatric Diseases)
Show Figures

Figure 1

Article
Population Pharmacokinetic Analysis of Pazopanib in Patients and Determination of Target AUC
Pharmaceuticals 2021, 14(9), 927; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14090927 - 15 Sep 2021
Viewed by 487
Abstract
Pazopanib is a potent multi-targeted kinase inhibitor approved for the treatment of advanced renal cell carcinoma and soft tissue sarcoma. The pharmacokinetics of pazopanib is characterized by a significant inter- and intra-patient variability and a target through plasma concentration of 20.5 mg·L−1 [...] Read more.
Pazopanib is a potent multi-targeted kinase inhibitor approved for the treatment of advanced renal cell carcinoma and soft tissue sarcoma. The pharmacokinetics of pazopanib is characterized by a significant inter- and intra-patient variability and a target through plasma concentration of 20.5 mg·L−1. However, routine monitoring of trough plasma concentrations at fixed hours is difficult in daily practice. Herein, we aimed to characterize the pharmacokinetic (PK) profile of pazopanib and to identify a target area under the curve (AUC) more easily extrapolated from blood samples obtained at various timings after drug intake. A population pharmacokinetic (popPK) model was constructed to analyze pazopanib PK and to estimate the pazopanib clearance of a patient regardless of the time of sampling. Data from the therapeutic drug monitoring (TDM) of patients with cancer at Institute Gustave Roussy and a clinical study (phase I/II) that evaluates the tolerance to pazopanib were used. From the individual clearance, it is then possible to obtain the patient’s AUC. A target AUC for maximum efficacy and minimum side effects of 750 mg·h·L−1 was determined. The comparison of the estimated AUC with the target AUC would enable us to determine whether plasma exposure is adequate or whether it would be necessary to propose therapeutic adjustments. Full article
Show Figures

Figure 1

Review
New Strategies for the Treatment of Atrial Fibrillation
Pharmaceuticals 2021, 14(9), 926; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14090926 - 15 Sep 2021
Viewed by 561
Abstract
Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia in the clinical practice. It significantly contributes to the morbidity and mortality of the elderly population. Over the past 25–30 years intense effort in basic research has advanced the understanding of the relationship between [...] Read more.
Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia in the clinical practice. It significantly contributes to the morbidity and mortality of the elderly population. Over the past 25–30 years intense effort in basic research has advanced the understanding of the relationship between the pathophysiology of AF and atrial remodelling. Nowadays it is clear that the various forms of atrial remodelling (electrical, contractile and structural) play crucial role in initiating and maintaining the persistent and permanent types of AF. Unlike in ventricular fibrillation, in AF rapid ectopic firing originating from pulmonary veins and re-entry mechanism may induce and maintain (due to atrial remodelling) this complex cardiac arrhythmia. The present review presents and discusses in detail the latest knowledge on the role of remodelling in AF. Special attention is paid to novel concepts and pharmacological targets presumably relevant to the drug treatment of atrial fibrillation. Full article
(This article belongs to the Special Issue Ion Channels: Current Pharmacological Challenges)
Show Figures

Figure 1

Article
Incident Type 2 Diabetes Risk of Selective Estrogen Receptor Modulators in Female Patients with Breast Cancer
Pharmaceuticals 2021, 14(9), 925; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14090925 - 14 Sep 2021
Viewed by 751
Abstract
Accumulating evidence indicates a link between diabetes and cancer. Selective estrogen receptor modulators (SERMs) may increase diabetes risk via antiestrogen effects. This study investigated incident diabetes risk of SERM treatment and its effects on metastatic cancer and death prevention in breast cancer survivors. [...] Read more.
Accumulating evidence indicates a link between diabetes and cancer. Selective estrogen receptor modulators (SERMs) may increase diabetes risk via antiestrogen effects. This study investigated incident diabetes risk of SERM treatment and its effects on metastatic cancer and death prevention in breast cancer survivors. This retrospective cohort study included female patients with early-stage breast cancer, treated with or without SERMs, between 2008 and 2020 in a tertiary care hospital in Korea. Four propensity score-matched comparison pairs were designed: SERM use versus non-use, long-term use (≥1500 days) versus non-use, tamoxifen use versus non-use, and toremifene use versus non-use; then, logistic regression analysis was performed for risk analysis. SERMs in general were not associated with an elevated risk of diabetes; however, when used for ≥1500 days, SERMs—especially toremifene—substantially increased diabetes risk in breast cancer patients (OR 1.63, p = 0.048). Meanwhile, long-term SERM treatment was effective at preventing metastatic cancer (OR 0.20, p < 0.001) and death (OR 0.13, p < 0.001). SERM treatment, albeit generally safe and effective, may increase diabetes risk with its long-term use in women with breast cancer. Further studies are required to verify the association between toremifene treatment and incident diabetes. Full article
(This article belongs to the Special Issue Adverse Drug Reactions and Gender Differences)
Show Figures

Figure 1

Perspective
Progress in the Treatment of Migraine Attacks: From Traditional Approaches to Eptinezumab
Pharmaceuticals 2021, 14(9), 924; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14090924 - 13 Sep 2021
Viewed by 564
Abstract
Migraine is the second cause of disability and of lost years of healthy life worldwide. Migraine is characterized by recurrent headache attacks and accompanying disabling symptoms lasting 4–48 h. In episodic migraine, attacks occur in less than 15 days per month and in [...] Read more.
Migraine is the second cause of disability and of lost years of healthy life worldwide. Migraine is characterized by recurrent headache attacks and accompanying disabling symptoms lasting 4–48 h. In episodic migraine, attacks occur in less than 15 days per month and in chronic migraine, in more than 15 monthly days. Whilst successful translation of pharmacological discoveries into efficacious therapeutics has been achieved in the preventative therapy of chronic migraine, treatment of acute migraine suffers the lack of effective advancements. An effective treatment affords complete freedom from pain two hours after therapy and provides the absence of the most bothersome symptom (MBS) associated with migraine after 2 h. However, available anti-migraine abortive treatments for acute attacks do not represent an effective and safe treatment for all the populations treated. In particular, the most used specific treatment is represented by triptans that offer 2-h sustained freedom from pain achieved in 18–50% of patients but they are contraindicated in coronary artery disease, stroke and peripheral vascular disease due to the vasoconstriction at the basis of their pharmacologic action. The most novel therapies, i.e., gepants and ditans, are without sufficient post-marketing data for secure use. Here, an attempt is proposed to analyse the rational basis and evidence in favour of investigating the efficacy and safety in acute migraine attacks of eptinezumab, i.e., monoclonal antibody (mAb) directed towards calcitonin gene-related peptide (CGRP) unique for intravenous infusion administration. Full article
(This article belongs to the Special Issue Monoclonal Antibodies for Migraine Prevention)
Show Figures

Figure 1

Review
Osteosarcoma in Children: Not Only Chemotherapy
Pharmaceuticals 2021, 14(9), 923; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14090923 - 13 Sep 2021
Viewed by 510
Abstract
Osteosarcoma (OS) is the most severe bone malignant tumor, responsible for altered osteoid deposition and with a high rate of metastasis. It is characterized by heterogeneity, chemoresistance and its interaction with bone microenvironment. The 5-year survival rate is about 67% for patients with [...] Read more.
Osteosarcoma (OS) is the most severe bone malignant tumor, responsible for altered osteoid deposition and with a high rate of metastasis. It is characterized by heterogeneity, chemoresistance and its interaction with bone microenvironment. The 5-year survival rate is about 67% for patients with localized OS, while it remains at 20% in case of metastases. The standard therapy for OS patients is represented by neoadjuvant chemotherapy, surgical resection, and adjuvant chemotherapy. The most used chemotherapy regimen for children is the combination of high-dose methotrexate, doxorubicin, and cisplatin. Considered that the necessary administration of high-dose chemotherapy is responsible for a lot of acute and chronic side effects, the identification of novel therapeutic strategies to ameliorate OS outcome and the patients’ life expectancy is necessary. In this review we provide an overview on new possible innovative therapeutic strategies in OS. Full article
(This article belongs to the Special Issue Osteosarcomas: Treatment Strategies)
Show Figures

Graphical abstract

Article
Development and Characterisation of Antibody-Based Optical Imaging Probes for Inflammatory Bowel Disease
Pharmaceuticals 2021, 14(9), 922; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14090922 - 13 Sep 2021
Viewed by 568
Abstract
Monoclonal antibodies are an important addition to the medicinal treatment paradigm for IBD patients. While effective, these agents show a high degree of primary and secondary non-response, and methods to predict response are highly desired. Information on drug distribution at the target level [...] Read more.
Monoclonal antibodies are an important addition to the medicinal treatment paradigm for IBD patients. While effective, these agents show a high degree of primary and secondary non-response, and methods to predict response are highly desired. Information on drug distribution at the target level is often lacking. Fluorescent endoscopic imaging using labelled antibody drugs may provide insight regarding drug distribution, target engagement and drug response, but these assessments require stable and functional fluorescently-conjugated probes. Infliximab, vedolizumab, adalimumab and ustekinumab were conjugated to IRDye 800CW, IRDye 680LT and ZW800-1. The resulting 12 tracer candidates were analysed and characterised on SE-HPLC, SDS-PAGE, iso-electric focussing (IEF) and ELISA in order to evaluate their feasibility as candidate clinical tracers for cGMP development. Major differences in the conjugation results could be seen for each conjugated drug. For Infliximab, 2 conjugates (800CW and 680LT) showed formation of aggregates, while conjugates of all drugs with ZW800-1 showed reduced fluorescent brightness, reduced purification yield and formation of fragments. All 6 of these candidates were considered unfeasible. From the remaining 6, ustekinumab-680LT showed reduced binding to IL23, and was therefore considered unfeasible. Out of 12 potential tracer candidates, 5 were considered feasible for further development: vedolizumab-800CW, vedolizumab-680LT, adalimumab-800CW, adalimumab-680LT and ustekinumab-800CW. Infliximab-680LT and ustekinumab-680LT failed to meet the standards for this panel, but may be rendered feasible if tracer production methods were further optimized. Full article
(This article belongs to the Special Issue Hybrid Agents for Multimodal Imaging)
Show Figures

Figure 1

Article
Use of 3D Printing for the Development of Biodegradable Antiplatelet Materials for Cardiovascular Applications
Pharmaceuticals 2021, 14(9), 921; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14090921 - 11 Sep 2021
Viewed by 776
Abstract
Small-diameter synthetic vascular grafts are required for surgical bypass grafting when there is a lack of suitable autologous vessels due to different reasons, such as previous operations. Thrombosis is the main cause of failure of small-diameter synthetic vascular grafts when used for this [...] Read more.
Small-diameter synthetic vascular grafts are required for surgical bypass grafting when there is a lack of suitable autologous vessels due to different reasons, such as previous operations. Thrombosis is the main cause of failure of small-diameter synthetic vascular grafts when used for this revascularization technique. Therefore, the development of biodegradable vascular grafts capable of providing a localized and sustained antithrombotic drug release mark a major step forward in the fight against cardiovascular diseases, which are the leading cause of death globally. The present paper describes the use of an extrusion-based 3D printing technology for the production of biodegradable antiplatelet tubular grafts for cardiovascular applications. For this purpose, acetylsalicylic acid (ASA) was chosen as a model molecule due to its antiplatelet activity. Poly(caprolactone) and ASA were combined for the fabrication and characterization of ASA-loaded tubular grafts. Moreover, rifampicin (RIF) was added to the formulation containing the higher ASA loading, as a model molecule that can be used to prevent vascular prosthesis infections. The produced tubular grafts were fully characterized through multiple techniques and the last step was to evaluate their drug release, antiplatelet and antimicrobial activity and cytocompatibility. The results suggested that these materials were capable of providing a sustained ASA release for periods of up to 2 weeks. Tubular grafts containing 10% (w/w) of ASA showed lower platelet adhesion onto the surface than the blank and grafts containing 5% (w/w) of ASA. Moreover, tubular grafts scaffolds containing 1% (w/w) of RIF were capable of inhibiting the growth of Staphylococcus aureus. Finally, the evaluation of the cytocompatibility of the scaffold samples revealed that the incorporation of ASA or RIF into the composition did not compromise cell viability and proliferation at short incubation periods (24 h). Full article
Show Figures

Graphical abstract

Opinion
The Mediterranean Diet as a Source of Natural Compounds: Does It Represent a Protective Choice against Cancer?
Pharmaceuticals 2021, 14(9), 920; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14090920 - 11 Sep 2021
Viewed by 538
Abstract
The Mediterranean diet (MD), characterized by a high intake of fruits, vegetables, legumes, nuts and grains, a moderate intake of red wine and a reduced consumption of meat, has been considered one of the healthiest dietary patterns worldwide. Growing evidence suggests an inverse [...] Read more.
The Mediterranean diet (MD), characterized by a high intake of fruits, vegetables, legumes, nuts and grains, a moderate intake of red wine and a reduced consumption of meat, has been considered one of the healthiest dietary patterns worldwide. Growing evidence suggests an inverse relationship between high adherence to the MD and cancer, as well as other chronic degenerative diseases. The beneficial effects elicited by the MD pattern on cancer are due to the high contents of bioactive compounds contained in many foods of MD, which protect cells by oxidative and inflammatory processes and inhibit carcinogenesis by targeting the various hallmarks of cancer with different mechanisms of action. Although over the past decades numerous dietary and phytochemical compounds from Mediterranean food that have anticancer potential have been identified, a clear association between the MD eating pattern and cancer needs to be established. While we wait for answers to this question from well-conducted research, the empowering of the MD as a protective choice against cancer should represent the priority for public health policies. Full article
(This article belongs to the Special Issue Anticancer Compounds in Medicinal Plants)
Show Figures

Figure 1

Communication
Testing the Stability of Drug Resistance on Cryopreserved, Gene-Engineered Human Induced Pluripotent Stem Cells
Pharmaceuticals 2021, 14(9), 919; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14090919 - 11 Sep 2021
Viewed by 668
Abstract
Human induced pluripotent stem cells (hiPSCs) have emerged as a powerful tool for in vitro modelling of diseases with broad application in drug development or toxicology testing. These assays usually require large quantities of hiPSC, which can entail long-term storage via cryopreservation of [...] Read more.
Human induced pluripotent stem cells (hiPSCs) have emerged as a powerful tool for in vitro modelling of diseases with broad application in drug development or toxicology testing. These assays usually require large quantities of hiPSC, which can entail long-term storage via cryopreservation of the same cell charges. However, it is essential that cryopreservation does not oppose durable changes on the cells. In this project, we characterize one parameter of functionality of one that is well established in the field, in a different research context, an applied hiPSC line (iPS11), namely their resistance to a medium size library of chemo interventions (>160 drugs). We demonstrate that cells, before and after cryopreservation, do not change their relative overall drug response phenotypes, as defined by identification of the top 20 interventions causing dose-dependent reduction of cell growth. Importantly, also frozen cells that are exogenously enforced for stable overexpression of oncogenes myelocytomatosis (cMYC) or tumor protein 53 mutation (TP53R175H), respectively, are not changed in their relative top 20 drugs response compared to their non-frozen counterparts. Taken together, our results support iPSCs as a reliable in vitro platform for in vitro pharmacology, further raising hopes that this technology supports biomarker-associated drug development. Given the general debate on ethical and economic problems associated with the reproducibly crisis in biomedicine, our results may be of interest to a wider audience beyond stem cell research. Full article
(This article belongs to the Special Issue Drug Screening or Drug Designing Based on Stem Cell Models)
Show Figures

Graphical abstract

Article
Gene Dosage Analysis on the Single-Cell Transcriptomes Linking Cotranslational Protein Targeting to Metastatic Triple-Negative Breast Cancer
Pharmaceuticals 2021, 14(9), 918; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14090918 - 10 Sep 2021
Viewed by 469
Abstract
Many recent efforts have been put into the association between expression heterogeneity and different cell types and states using single-cell RNA transcriptome analysis. There is only limited understanding of gene dosage effects for the genetic heterogeneity at the single-cell level. By focusing on [...] Read more.
Many recent efforts have been put into the association between expression heterogeneity and different cell types and states using single-cell RNA transcriptome analysis. There is only limited understanding of gene dosage effects for the genetic heterogeneity at the single-cell level. By focusing on concordant copy number variation (CNV) and expression, we presented a computational framework to explore dosage effect for aggressive metastatic triple-negative breast cancer (TNBC) at the single-cell level. In practice, we collected CNV and single-cell expression data from the same patients with independent technologies. By focusing on 47,198 consistent copy number gains (CNG) and gene up-regulation from 1145 single cells, ribosome proteins with important roles in protein targeting were enriched. Independent validation in another metastatic TNBC dataset further prioritized signal recognition particle-dependent protein targeting as the top functional module. More interesting, the increased ribosome gene copies in TNBC may associate with their enhanced stemness and metastatic potential. Indeed, the prioritization of a well-upregulated functional module confirmed by high copy numbers at the single-cell level and contributing to patient survival may indicate the possibility of targeted therapy based on ribosome proteins for TNBC. Full article
Show Figures

Figure 1

Article
Antifungal Activity of Extracts, Fractions, and Constituents from Coccoloba cowellii Leaves
Pharmaceuticals 2021, 14(9), 917; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14090917 - 10 Sep 2021
Viewed by 625
Abstract
Coccoloba cowellii Britton (Polygonaceae, order Caryophyllales) is an endemic and critically endangered plant species that only grows in the municipality of Camagüey, a province of Cuba. A preliminary investigation of its total methanolic extract led to the discovery of promising antifungal activity. In [...] Read more.
Coccoloba cowellii Britton (Polygonaceae, order Caryophyllales) is an endemic and critically endangered plant species that only grows in the municipality of Camagüey, a province of Cuba. A preliminary investigation of its total methanolic extract led to the discovery of promising antifungal activity. In this study, a bioassay-guided fractionation allowed the isolation of quercetin and four methoxyflavonoids: 3-O-methylquercetin, myricetin 3,3′,4′-trimethyl ether, 6-methoxymyricetin 3,4′-dimethyl ether, and 6-methoxymyricetin 3,3′,4′-trimethyl ether. The leaf extract, fractions, and compounds were tested against various fungi and showed strong in vitro antifungal activity against Cryptococcus neoformans and various Candida spp. with no cytotoxicity (CC50 > 64.0 µg/mL) on MRC-5 SV2 cells, determined by a resazurin assay. A Candida albicans SC5314 antibiofilm assay indicated that the antifungal activity of C. cowellii extracts and constituents is mainly targeted to planktonic cells. The total methanolic extract showed higher and broader activity compared with the fractions and mixture of compounds. Full article
(This article belongs to the Special Issue Natural Pharmacons: Biologically Active Plant Based Pharmaceuticals)
Show Figures

Graphical abstract

Article
Chemoreversal Agents from Taiwanofungus Genus and Their More Potent Methyl Derivatives Targeting Signal Transducer and Activator of Transcription 3 (STAT3) Phosphorylation
Pharmaceuticals 2021, 14(9), 916; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14090916 - 10 Sep 2021
Viewed by 475
Abstract
Multidrug resistance (MDR), for which the mechanisms are not yet fully clear, is one of the major obstacles to cancer treatment. In recent years, signal transducer and activator of transcription 3 (STAT3) were found to be one of the important MDR mechanism pathways. [...] Read more.
Multidrug resistance (MDR), for which the mechanisms are not yet fully clear, is one of the major obstacles to cancer treatment. In recent years, signal transducer and activator of transcription 3 (STAT3) were found to be one of the important MDR mechanism pathways. Based on the previous research, zhankuic acid A, B, and C were found to have collateral sensitivity effects on MDR cancer cells, and MDR inhibitory activity of zhankuic acid methyl ester was found to be better than that of its acid. Therefore, we executed a systematic examination of the structure–activity relationship of zhankuic acid methyl ester derivatives to collateral sensitivity in MDR cancer cells. The results showed that compound 12 is the best in terms of chemoreversal activity, where the reversal fold was 692, and the IC50 value of paclitaxel combined with 10 μM compound 12 treatment was 1.69 nM in MDR KBvin cells. Among all the derivatives, methyl ester compounds were found to be better than their acids, and a detailed discussion of the structure–activity relationships of all of the derivatives is provided in this work. In addition, compounds 8, 12, and 26 were shown to influence the activation of STAT3 in KBvin cells, accounting for part of their chemoreversal effects. Our results may provide a new combined therapy with paclitaxel to treat multidrug-resistant cancers and provide a new therapy option for patients. Full article
Show Figures

Graphical abstract

Previous Issue
Next Issue
Back to TopTop