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Pharmaceuticals, Volume 13, Issue 5 (May 2020) – 26 articles

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Open AccessArticle
Anticancer Activity of Amb4269951, a Choline Transporter-Like Protein 1 Inhibitor, in Human Glioma Cells
Pharmaceuticals 2020, 13(5), 104; https://doi.org/10.3390/ph13050104 - 25 May 2020
Viewed by 188
Abstract
Choline transporter-like protein 1 (CTL1) is highly expressed in glioma cells, and inhibition of CTL1 function induces apoptotic cell death. Therefore, CTL1 is a potential target molecule for glioma therapy. Here, we investigated the therapeutic mechanism underlying the antitumor effects of Amb4269951, a [...] Read more.
Choline transporter-like protein 1 (CTL1) is highly expressed in glioma cells, and inhibition of CTL1 function induces apoptotic cell death. Therefore, CTL1 is a potential target molecule for glioma therapy. Here, we investigated the therapeutic mechanism underlying the antitumor effects of Amb4269951, a recently discovered novel CTL1 inhibitor, in the human glioma cell line U251MG, and evaluated its in vivo effects in a mouse xenograft model. Amb4269951 inhibited choline uptake and cell viability and increased caspase-3/7 activity. CTL1-mediated choline uptake is associated with cell viability, and the functional inhibition of CTL1 by Amb4269951 may promote apoptotic cell death via ceramide-induced suppression of the expression of survivin, an apoptotic inhibitory factor. Finally, Amb4269951 demonstrated an antitumor effect in a mice xenograft model by significantly inhibiting tumor growth without any weight loss. Amb4269951 is the lead compound in the treatment of glioma and exhibits a novel therapeutic mechanism. These results may lead to the development of novel anticancer drugs targeting the choline transporter CTL1, which has a different mechanism of action than conventional anticancer drugs against gliomas. Full article
(This article belongs to the Special Issue Novel Therapeutic Targets in Cancer)
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Open AccessArticle
Constructing Auxin-Inducible Degron Mutants Using an All-in-One Vector
Pharmaceuticals 2020, 13(5), 103; https://doi.org/10.3390/ph13050103 - 23 May 2020
Viewed by 208
Abstract
Conditional degron-based methods are powerful for studying protein function because a degron-fused protein can be rapidly and efficiently depleted by adding a defined ligand. Auxin-inducible degron (AID) is a popular technology by which a degron-fused protein can be degraded by adding an auxin. [...] Read more.
Conditional degron-based methods are powerful for studying protein function because a degron-fused protein can be rapidly and efficiently depleted by adding a defined ligand. Auxin-inducible degron (AID) is a popular technology by which a degron-fused protein can be degraded by adding an auxin. However, compared with other technologies such as dTAG and HaloPROTAC, AID is complicated because of its two protein components: OsTIR1 and mAID (degron). To simplify the use of AID in mammalian cells, we constructed bicistronic all-in-one plasmids that express OsTIR1 and a mAID-fused protein using a P2A self-cleavage sequence. To generate a HeLa mutant line for the essential replication factor MCM10, we transfected a CRISPR-knockout plasmid together with a bicistronic plasmid containing mAID-fused MCM10 cDNA. After drug selection and colony isolation, we successfully isolated HeLa mutant lines, in which mAID–MCM10 was depleted by the addition of indole-3-acetic acid, a natural auxin. The bicistronic all-in-one plasmids described in this report are useful for controlling degradation of a transgene-derived protein fused with mAID. These plasmids can be used for the construction of conditional mutants by combining them with a CRISPR-based gene knockout. Full article
(This article belongs to the Special Issue Targeted Protein Degradation: From Chemical Biology to Drug Discovery)
Open AccessCommunication
Actaea racemosa L. Is More Effective in Combination with Rhodiola rosea L. for Relief of Menopausal Symptoms: A Randomized, Double-Blind, Placebo-Controlled Study
Pharmaceuticals 2020, 13(5), 102; https://doi.org/10.3390/ph13050102 - 21 May 2020
Viewed by 295
Abstract
Background: The aim of this study was to assess the efficacy and safety of a new herbal preparation (Menopause Relief EP®), the hybrid combination of Actaea racemosa L. (black cohosh, BC) and Rhodiola rosea L. (RR) root extracts, compared with [...] Read more.
Background: The aim of this study was to assess the efficacy and safety of a new herbal preparation (Menopause Relief EP®), the hybrid combination of Actaea racemosa L. (black cohosh, BC) and Rhodiola rosea L. (RR) root extracts, compared with the most effective dose of BC extract in women with menopausal complaints. Methods: A total of 220 women were randomly assigned to receive two capsules either BC (6.5 mg), BC500 (500 mg), Menopause Relief EP® (206,5), or placebo once per day for 12 weeks. The efficacy endpoints were relief of menopausal symptoms, measured using the Kupperman Menopausal Index (KMI), Menopause Relief Score (MRS), and menopause Utian Quality of Life (UQOL) index. Results: The menopause symptom relief effects of RR-BC were significantly superior in all tests to the effects of BC and placebo after their repeated administration for 6 and 12 weeks. There was no statistically significant difference between the effects of BC and BC500 over time. RR-BC significantly improved the QOL index in patients, compared to BC, BC500, and placebo, mainly due to the beneficial effects on the emotional and health domains. Conclusions: BC is more effective in combination with RR in relief of menopausal symptoms, particularly psychological symptoms. Full article
(This article belongs to the Special Issue Medicinal Plants 2020)
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Open AccessCommunication
A Brief Report on an Implantation of Small-Caliber Biodegradable Vascular Grafts in a Carotid Artery of the Sheep
Pharmaceuticals 2020, 13(5), 101; https://doi.org/10.3390/ph13050101 - 21 May 2020
Viewed by 196
Abstract
The development of novel biodegradable vascular grafts of a small diameter (<6 mm) is an unmet clinical need for patients requiring arterial replacement. Here we performed a pre-clinical study of new small-caliber biodegradable vascular grafts using a sheep model of carotid artery implantation. [...] Read more.
The development of novel biodegradable vascular grafts of a small diameter (<6 mm) is an unmet clinical need for patients requiring arterial replacement. Here we performed a pre-clinical study of new small-caliber biodegradable vascular grafts using a sheep model of carotid artery implantation. The 4 mm diameter vascular grafts were manufactured using a mix of polyhydroxybutyrate/valerate and polycaprolactone supplemented with growth factors VEGF, bFGF and SDF-1α (PHBV/PCL-GFmix) and additionally modified by a polymer hydrogel coating with incorporation of drugs heparin and iloprost (PHBV/PCL-GFmixHep/Ilo). Animals with carotid artery autograft implantation and those implanted with clinically used GORE-TEX® grafts were used as control groups. We observed that 24 h following surgery, animals with carotid artery autograft implantation showed 87.5% patency, while all the PHBV/PCL-GFmix and GORE-TEX® grafts displayed thrombosis. PHBV/PCL-GFmixHep/Ilo grafts demonstrated 62.5% patency 24 h following surgery and it had remained at 50% 1 year post-operation. All the PHBV/PCL grafts completely degraded less than 1 year following surgery and were replaced by de novo vasculature without evidence of calcification. On the other hand, GORE-TEX® grafts displayed substantial amounts of calcium deposits throughout graft tissues. Thus, here we report a potential clinical usefulness of PHBV/PCL grafts upon their additional modification by growth factors and drugs to promote endothelialization and reduce thrombogenicity. Full article
Open AccessArticle
Upregulated and Hyperactivated Thalamic Connexin 43 Plays Important Roles in Pathomechanisms of Cognitive Impairment and Seizure of Autosomal Dominant Sleep-Related Hypermotor Epilepsy with S284L-Mutant α4 Subunit of Nicotinic ACh Receptor
Pharmaceuticals 2020, 13(5), 99; https://doi.org/10.3390/ph13050099 - 18 May 2020
Viewed by 291
Abstract
To understand the pathomechanism and pathophysiology of autosomal dominant sleep-related hypermotor epilepsy (ADSHE), we studied functional abnormalities of glutamatergic transmission in thalamocortical pathway from reticular thalamic nucleus (RTN), mediodorsal thalamic nucleus (MDTN) to orbitofrontal cortex (OFC) associated with S286L-mutant α4β2-nicotinic acetylcholine receptor (nAChR), [...] Read more.
To understand the pathomechanism and pathophysiology of autosomal dominant sleep-related hypermotor epilepsy (ADSHE), we studied functional abnormalities of glutamatergic transmission in thalamocortical pathway from reticular thalamic nucleus (RTN), mediodorsal thalamic nucleus (MDTN) to orbitofrontal cortex (OFC) associated with S286L-mutant α4β2-nicotinic acetylcholine receptor (nAChR), and connexin43 (Cx43) hemichannel of transgenic rats bearing rat S286L-mutant Chrna4 gene (S286L-TG), corresponding to the human S284L-mutant CHRNA4 gene using simple Western analysis and multiprobe microdialysis. Cx43 expression in the thalamic plasma membrane fraction of S286L-TG was upregulated compared with that of wild-type. Subchronic administrations of therapeutic-relevant doses of zonisamide (ZNS) and carbamazepine (CBZ) decreased and did not affect Cx43 expression of S286L-TG, respectively. Upregulated Cx43 enhanced glutamatergic transmission during both resting and hyperexcitable stages in S286L-TG. Furthermore, activation of GABAergic transmission RTN–MDTN pathway conversely enhanced, but not inhibited, l-glutamate release in the MDTN via upregulated/activated Cx43. Local administration of therapeutic-relevant concentration of ZNS and CBZ acutely supressed and did not affect glutamatergic transmission in the thalamocortical pathway, respectively. These results suggest that pathomechanisms of ADSHE seizure and its cognitive deficit comorbidity, as well as pathophysiology of CBZ-resistant/ZNS-sensitive ADSHE seizures of patients with S284L-mutation. Full article
(This article belongs to the Special Issue Therapeutic Agents for Neurological Disorders)
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Open AccessArticle
Formulation and Evaluation of Loperamide HCl Oro Dispersible Tablets
Pharmaceuticals 2020, 13(5), 100; https://doi.org/10.3390/ph13050100 - 18 May 2020
Viewed by 291
Abstract
This work proposes the design of novel oral disintegrating tablets (ODTs) of loperamide HCl with special emphasis on disintegration and dissolution studies. The main goal was augmenting the adherence to treatment of diseases which happen with diarrhea in soldiers who are exposed to [...] Read more.
This work proposes the design of novel oral disintegrating tablets (ODTs) of loperamide HCl with special emphasis on disintegration and dissolution studies. The main goal was augmenting the adherence to treatment of diseases which happen with diarrhea in soldiers who are exposed to diverse kinds of hostile environments. Optimized orally disintegrating tablets were prepared by the direct compression method from galenic development to the industrial scale technique, thanks to strategic and support actions between the Spanish Army Force Lab and the Department of Biomedical Sciences (UAH). The results show that loperamide HCl ODT offers a rapid beginning of action and improvement in the bioavailability of poorly absorbed drugs. The manufactured ODTs complied with the pharmacopeia guidelines regarding hardness, weight variation, thickness, friability, drug content, wetting time, percentage of water absorption, disintegration time, and in vitro dissolution profile. Drug compatibility with excipients was checked by DSC, FTIR, and SEM studies. Full article
(This article belongs to the Section Pharmaceutical Technology)
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Open AccessOpinion
COVID-19: An Update About the Discovery Clinical Trial
Pharmaceuticals 2020, 13(5), 98; https://doi.org/10.3390/ph13050098 - 14 May 2020
Viewed by 864
Abstract
Finding efficacious and safe treatments for COVID-19 emerges as a crucial need in order to control the spread of the pandemic. Whereas plasma therapy attracts much interest, the European project Discovery focuses on the potentialities of small molecules like remdesivir, the combination of [...] Read more.
Finding efficacious and safe treatments for COVID-19 emerges as a crucial need in order to control the spread of the pandemic. Whereas plasma therapy attracts much interest, the European project Discovery focuses on the potentialities of small molecules like remdesivir, the combination of lopinavir/ritonavir, hydroxychloroquine, and chloroquine. Results recently published on the clinical evaluation of those drugs are compiled in this brief report, although complete data are still impatiently awaited. Full article
(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)
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Open AccessArticle
Mantonico and Pecorello Grape Seed Extracts: Chemical Characterization and Evaluation of In Vitro Wound-Healing and Anti-Inflammatory Activities
Pharmaceuticals 2020, 13(5), 97; https://doi.org/10.3390/ph13050097 - 14 May 2020
Viewed by 268
Abstract
The winemaking process produces a huge number of pomaces that generally are used for energy purposes. Further valuable applications such as health-promoting properties are still under investigation. The seeds of the white berries of Mantonico and Pecorello cv. were extracted in a Soxhlet [...] Read more.
The winemaking process produces a huge number of pomaces that generally are used for energy purposes. Further valuable applications such as health-promoting properties are still under investigation. The seeds of the white berries of Mantonico and Pecorello cv. were extracted in a Soxhlet apparatus, using n-hexane and chloroform as solvents. Extracts were characterized by NMR and GC-MS analyses. They were assayed in vitro as wound healing and anti-inflammatory agents in HaCaT and RAW 264.7 cell lines, respectively. n-hexane Mantonico extract resulted in the most interesting wound healing sample, while n-hexane Pecorello, containing a good number of carotenoids, resulted in a good anti-inflammatory candidate. These preliminary findings underlined the benefit of grape seed extracts valorization due to their health-promoting properties. Full article
(This article belongs to the Special Issue Medicinal Plants 2020)
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Open AccessReview
The Rationale for Potential Pharmacotherapy of COVID-19
Pharmaceuticals 2020, 13(5), 96; https://doi.org/10.3390/ph13050096 - 14 May 2020
Viewed by 599
Abstract
On 11 March 2020, the coronavirus disease (COVID-19) was defined by the World Health Organization as a pandemic. Severe acute respiratory syndrome-2 (SARS-CoV-2) is the newly evolving human coronavirus infection that causes COVID-19, and it first appeared in Wuhan, China in December 2019 [...] Read more.
On 11 March 2020, the coronavirus disease (COVID-19) was defined by the World Health Organization as a pandemic. Severe acute respiratory syndrome-2 (SARS-CoV-2) is the newly evolving human coronavirus infection that causes COVID-19, and it first appeared in Wuhan, China in December 2019 and spread rapidly all over the world. COVID-19 is being increasingly investigated through virology, epidemiology, and clinical management strategies. There is currently no established consensus on the standard of care in the pharmacological treatment of COVID-19 patients. However, certain medications suggested for other diseases have been shown to be potentially effective for treating this infection, though there has yet to be clear evidence. Therapies include new agents that are currently tested in several clinical trials, in addition to other medications that have been repurposed as antiviral and immune-modulating therapies. Previous high-morbidity human coronavirus epidemics such as the 2003 SARS-CoV and the 2012 Middle East respiratory syndrome coronavirus (MERS-CoV) prompted the identification of compounds that could theoretically be active against the emerging coronavirus SARS-CoV-2. Moreover, advances in molecular biology techniques and computational analysis have allowed for the better recognition of the virus structure and the quicker screening of chemical libraries to suggest potential therapies. This review aims to summarize rationalized pharmacotherapy considerations in COVID-19 patients in order to serve as a tool for health care professionals at the forefront of clinical care during this pandemic. All the reviewed therapies require either additional drug development or randomized large-scale clinical trials to be justified for clinical use. Full article
(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)
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Open AccessReview
Molecular Mechanisms of the Teratogenic Effects of Thalidomide
Pharmaceuticals 2020, 13(5), 95; https://doi.org/10.3390/ph13050095 - 13 May 2020
Viewed by 427
Abstract
Thalidomide was sold worldwide as a sedative over 60 years ago, but it was quickly withdrawn from the market due to its teratogenic effects. Thalidomide was later found to have therapeutic effects in several diseases, although the molecular mechanisms remained unclear. The discovery [...] Read more.
Thalidomide was sold worldwide as a sedative over 60 years ago, but it was quickly withdrawn from the market due to its teratogenic effects. Thalidomide was later found to have therapeutic effects in several diseases, although the molecular mechanisms remained unclear. The discovery of cereblon (CRBN), the direct target of thalidomide, a decade ago greatly improved our understanding of its mechanism of action. Accumulating evidence has shown that CRBN functions as a substrate of Cullin RING E3 ligase (CRL4CRBN), whose specificity is controlled by ligands such as thalidomide. For example, lenalidomide and pomalidomide, well-known thalidomide derivatives, degrade the neosubstrates Ikaros and Aiolos, resulting in anti-proliferative effects in multiple myeloma. Recently, novel CRBN-binding drugs have been developed. However, for the safe handling of thalidomide and its derivatives, a greater understanding of the mechanisms of its adverse effects is required. The teratogenic effects of thalidomide occur in multiple tissues in the developing fetus and vary in phenotype, making it difficult to clarify this issue. Recently, several CRBN neosubstrates (e.g., SALL4 (Spalt Like Transcription Factor 4) and p63 (Tumor Protein P63)) have been identified as candidate mediators of thalidomide teratogenicity. In this review, we describe the current understanding of molecular mechanisms of thalidomide, particularly in the context of its teratogenicity. Full article
(This article belongs to the Special Issue Targeted Protein Degradation: From Chemical Biology to Drug Discovery)
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Open AccessArticle
Antiproliferative and Carbonic Anhydrase II Inhibitory Potential of Chemical Constituents from Lycium shawii and Aloe vera: Evidence from In Silico Target Fishing and In Vitro Testing
Pharmaceuticals 2020, 13(5), 94; https://doi.org/10.3390/ph13050094 - 13 May 2020
Viewed by 336
Abstract
Lycium shawii Roem. & Schult and resin of Aloe vera (L.) BURM. F. are commonly used in Omani traditional medication against various ailments. Herein, their antiproliferative and antioxidant potential was explored. Bioassay-guided fractionation of the methanol extract of both plants led to the [...] Read more.
Lycium shawii Roem. & Schult and resin of Aloe vera (L.) BURM. F. are commonly used in Omani traditional medication against various ailments. Herein, their antiproliferative and antioxidant potential was explored. Bioassay-guided fractionation of the methanol extract of both plants led to the isolation of 14 known compounds, viz., 19 from L. shawii and 1020 from A. vera. Their structures were confirmed by combined spectroscopic techniques including 1D (1H and 13C) and 2D (HMBC, HSQC, COSY) nuclear magnetic resonance (NMR), and electrospray ionization-mass spectrometry (ESI-MS). The cytotoxic potential of isolates was tested against the triple-negative breast cancer cell line (MDA-MB-231). Compound 5 exhibited excellent antiproliferative activity in a range of 31 μM, followed by compounds 13, 7, and 12, which depicted IC50 values in the range of 35–60 μM, while 8, 6, and 9 also demonstrated IC50 values >72 μM. Subsequently, in silico target fishing was applied to predict the most potential cellular drug targets of the active compounds, using pharmacophore modeling and inverse molecular docking approach. The extensive in silico analysis suggests that our compounds may target carbonic anhydrase II (CA-II) to exert their anticancer activities. When tested on CA-II, compounds 5 (IC50 = 14.4 µM), 12 (IC50 = 23.3), and 2 (IC50 = 24.4 µM) showed excellent biological activities in vitro. Additionally, the ethyl acetate fraction of both plants showed promising antioxidant activity. Among the isolated compounds, 4 possesses the highest antioxidant (55 μM) activity followed by 14 (241 μM). The results indicated that compound 4 can be a promising candidate for antioxidant drugs, while compound 5 is a potential candidate for anticancer drugs. Full article
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Open AccessArticle
Cytokine-Induced Killer (CIK) Cells, In Vitro Expanded under Good Manufacturing Process (GMP) Conditions, Remain Stable over Time after Cryopreservation
Pharmaceuticals 2020, 13(5), 93; https://doi.org/10.3390/ph13050093 - 12 May 2020
Viewed by 303
Abstract
Cytokine-induced killer (CIK) cells are advanced therapy medicinal products, so their production and freezing process has to be validated before their clinical use, to verify their stability as a drug formulation according to the good manufacturing practice (GMP) guidelines. We designed a stability [...] Read more.
Cytokine-induced killer (CIK) cells are advanced therapy medicinal products, so their production and freezing process has to be validated before their clinical use, to verify their stability as a drug formulation according to the good manufacturing practice (GMP) guidelines. We designed a stability program for our GMP-manufactured CIK cells, evaluating the viability, identity and potency of cryopreserved CIK cells at varying time periods from freezing, and compared them with fresh CIK cells. We evaluated the effects of the cryopreservation method, transportation, and the length of time of different process phases (pre-freezing, freezing and post-thawing) on the stability of CIK cells. This included a worst case for each stage. The expanded CIK cells were viable for up to 30 min from the addition of the freezing solution, when transported on dry ice within 48 h once frozen, within 60 min from thawing and from 12 months of freezing while preserving their cytotoxic effects. The reference samples, cryopreserved simultaneously in tubes and following the same method, were considered representative of the batch and useful in the case of further analysis. Data obtained from this drug stability program can inform the accurate use of CIK cells in clinical settings. Full article
(This article belongs to the Section Pharmacology)
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Open AccessReview
The Association Between Vascular Inflammation and Depressive Disorder. Causality, Biomarkers and Targeted Treatment
Pharmaceuticals 2020, 13(5), 92; https://doi.org/10.3390/ph13050092 - 12 May 2020
Viewed by 368
Abstract
Diabetes, obesity, atherosclerosis, and myocardial infarction are frequently co-morbid with major depressive disorder. In the current review, it is argued that vascular inflammation is a factor that is common to all disorders and that an endothelial dysfunction of the blood-brain barrier could be [...] Read more.
Diabetes, obesity, atherosclerosis, and myocardial infarction are frequently co-morbid with major depressive disorder. In the current review, it is argued that vascular inflammation is a factor that is common to all disorders and that an endothelial dysfunction of the blood-brain barrier could be involved in the induction of depression symptoms. Biomarkers for vascular inflammation include a high plasma level of C-reactive protein, soluble cell-adhesion molecules, von Willebrand factor, aldosterone, and proinflammatory cytokines like interleukin-6 or tumor necrosis factor α. A further possible biomarker is flow-mediated dilation of the brachial artery. Treatment of vascular inflammation is expected to prevent or to reduce symptoms of depression. Several tentative treatments for this form of depression can be envisioned: eicosapentaenoic acid (EPA), valproate, Vagus-nerve stimulation, nicotinic α7 agonists, and agonists of the cannabinoid CB2-receptor. Full article
(This article belongs to the Section Pharmacology)
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Open AccessArticle
Is the Way to Fight Cancer Paved with Gold? Metal-Based Carbene Complexes with Multiple and Fascinating Biological Features
Pharmaceuticals 2020, 13(5), 91; https://doi.org/10.3390/ph13050091 - 11 May 2020
Viewed by 291
Abstract
Herein, we report the synthesis and the multiple anti-tumor properties of new gold and silver carbene complexes. The chemical modifications, grounded on our previous studies, led us to identify a good lead complex, gold-based, whose biological features are very exciting and promising in [...] Read more.
Herein, we report the synthesis and the multiple anti-tumor properties of new gold and silver carbene complexes. The chemical modifications, grounded on our previous studies, led us to identify a good lead complex, gold-based, whose biological features are very exciting and promising in the anti-cancer research and could be further developed. Indeed, the bis-[4,5-dichloro-(N-methyl-N’(2-hydroxy-2-phenyl)ethyl-imidazole-2-ylidene)gold(I)]+[dichloro-gold] (AuL7) complex possesses the ability to interfere with at least three important and different intracellular targets, namely the human topoisomerases I and II and tubulin, which are able to modulate metabolic processes not directly correlated each other. We proved that the modifications of the ligands structure in AuL7, with respect to another already published complex, i.e., bis-[4,5-dichloro-(N-methyl-N’(cyclopentane-2ol)-imidazole-2-ylidine)gold(I)]+[dichloro-gold] (AuL4), produce a different behavior toward tubulin-polymerization process, since AuL7 is a tubulin-polymerization inhibitor and AuL4 a stabilizer, with the final same result of hampering the tumor growth. Taken together, our outcomes designate AuL7 as a promising compound for the development of multi-targeted anti-cancer therapies. Full article
(This article belongs to the Section Medicinal Chemistry)
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Open AccessArticle
Therapeutic Targeting of Pancreatic Cancer via EphA2 Dimeric Agonistic Agents
Pharmaceuticals 2020, 13(5), 90; https://doi.org/10.3390/ph13050090 - 10 May 2020
Viewed by 448
Abstract
Recently, we reported on potent EphA2 targeting compounds and demonstrated that dimeric versions of such agents can exhibit remarkably increased agonistic activity in cellular assays compared to the monomers. Here we further characterize the activity of dimeric compounds at the structural, biochemical, and [...] Read more.
Recently, we reported on potent EphA2 targeting compounds and demonstrated that dimeric versions of such agents can exhibit remarkably increased agonistic activity in cellular assays compared to the monomers. Here we further characterize the activity of dimeric compounds at the structural, biochemical, and cellular level. In particular, we propose a structural model for the mechanism of receptor activation by dimeric agents and characterize the effect of most potent compounds in inducing EphA2 activation and degradation in a pancreatic cancer cell line. These cellular studies indicate that the pro-migratory effects induced by the receptor can be reversed in EphA2 knockout cells, by treatment with either a dimeric natural ligand (ephrinA1-Fc), or by our synthetic agonistic dimers. Based on these data we conclude that the proposed agents hold great potential as possible therapeutics in combination with standard of care, where these could help suppressing a major driver for cell migration and tumor metastases. Finally, we also found that, similar to ephrinA1-Fc, dimeric agents cause a sustained internalization of the EphA2 receptor, hence, with proper derivatizations, these could also be used to deliver chemotherapy selectively to pancreatic tumors. Full article
(This article belongs to the Special Issue Targeting the Eph–ephrin System)
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Open AccessCommunication
Exploring Kinase Inhibition Properties of 9H-pyrimido[5,4-b]- and [4,5-b]indol-4-amine Derivatives
Pharmaceuticals 2020, 13(5), 89; https://doi.org/10.3390/ph13050089 - 09 May 2020
Viewed by 354
Abstract
We previously highlighted the interest in 6,5,6-fused tricyclic analogues of 4-aminoquinazolines as kinase inhibitors in the micromolar to the nanomolar range of IC50 values. For the generation of chemical libraries, the formamide-mediated cyclization of the cyanoamidine precursors was carried out under microwave [...] Read more.
We previously highlighted the interest in 6,5,6-fused tricyclic analogues of 4-aminoquinazolines as kinase inhibitors in the micromolar to the nanomolar range of IC50 values. For the generation of chemical libraries, the formamide-mediated cyclization of the cyanoamidine precursors was carried out under microwave irradiation in an eco-friendly approach. In order to explore more in-depth the pharmacological interest in such tricyclic skeletons, the central five member ring, i.e., thiophène or furan, was replaced by a pyrrole to afford 9H-pyrimido[5,4-b]- and [4,5-b]indol-4-amine derivatives inspired from harmine. The inhibitory potency of the final products was determined against four protein kinases (CDK5/p25, CK1δ/ε, GSK3α/β and DYRK1A). As a result, we have identified promising compounds targeting CK1δ/ε and DYRK1A and displaying micromolar and submicromolar IC50 values. Full article
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Open AccessReview
Antibody Targeting of Eph Receptors in Cancer
Pharmaceuticals 2020, 13(5), 88; https://doi.org/10.3390/ph13050088 - 08 May 2020
Viewed by 348
Abstract
The Eph subfamily of receptor tyrosine kinases mediate cell-cell communication controlling cell and tissue patterning during development. While generally less active in adult tissues, they often re-emerge in cancers, particularly on undifferentiated or progenitor cells in tumors and the tumor microenvironment, associated with [...] Read more.
The Eph subfamily of receptor tyrosine kinases mediate cell-cell communication controlling cell and tissue patterning during development. While generally less active in adult tissues, they often re-emerge in cancers, particularly on undifferentiated or progenitor cells in tumors and the tumor microenvironment, associated with tumor initiation, angiogenesis and metastasis. Eph receptors are thus attractive therapeutic targets, and monoclonal antibodies have been commonly developed and tested for anti-cancer activity in preclinical models, and in some cases in the clinic. This review summarizes 20 years of research on various antibody-based approaches to target Eph receptors in tumors and the tumor microenvironment, including their mode of action, tumor specificity, and efficacy in pre-clinical and clinical testing. Full article
(This article belongs to the Special Issue Targeting the Eph–ephrin System)
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Open AccessArticle
Vasorelaxant Effects Induced by Red Wine and Pomace Extracts of Magliocco Dolce cv.
Pharmaceuticals 2020, 13(5), 87; https://doi.org/10.3390/ph13050087 - 03 May 2020
Viewed by 481
Abstract
Several epidemiological studies demonstrate that moderate (red) wine consumption may afford protection against cardiovascular diseases. Protection is ascribed to the biological activity of wine components, many of which, however, are discarded during winemaking. In vitro rat thoracic aorta rings contracted with phenylephrine or [...] Read more.
Several epidemiological studies demonstrate that moderate (red) wine consumption may afford protection against cardiovascular diseases. Protection is ascribed to the biological activity of wine components, many of which, however, are discarded during winemaking. In vitro rat thoracic aorta rings contracted with phenylephrine or KCl were used to assess the vasorelaxant activity of extracts from wine pomaces (seeds and skins) of the Calabrian autochthonous grape variety Magliocco dolce (Arvino). NMR spectroscopy was used to ascertain their chemical composition. Data demonstrate that seed and skin, but not must, extracts are capable of relaxing vascular preparations in an endothelium-dependent manner, similarly to the red wine extract, due to the presence of comparable amounts of bioactive constituents. In rings pre-contracted with 20–30 mM KCl, only seed extracts showed a moderate relaxation. The most efficacious vasodilating extract (wine) showed a good antioxidant profile in both [(2,2-diphenyl-1-picrylhydrazyl)acid] radical (DPPH) and [2,2’-azino-bis (3-ethylbenzothiazoline-6-sulphonic acid)] radical (ABTS) assays. In conclusion, winemaking from Magliocco dolce grape can provide potentially health-promoting by-products useful in cardiovascular disease management. Full article
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Open AccessArticle
Crosslinked Fibroin Nanoparticles: Investigations on Biostability, Cytotoxicity, and Cellular Internalization
Pharmaceuticals 2020, 13(5), 86; https://doi.org/10.3390/ph13050086 - 30 Apr 2020
Viewed by 377
Abstract
Recently, crosslinked fibroin nanoparticles (FNP) using the crosslinker 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) or the polymer poly(ethylenimine) (PEI) have been developed and showed potentials as novel drug delivery systems. Thus, this study further investigated the biological properties of these crosslinked FNP by labeling them [...] Read more.
Recently, crosslinked fibroin nanoparticles (FNP) using the crosslinker 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) or the polymer poly(ethylenimine) (PEI) have been developed and showed potentials as novel drug delivery systems. Thus, this study further investigated the biological properties of these crosslinked FNP by labeling them with fluorescein isothiocyanate (FITC) for in vitro studies. All formulations possessed a mean particle size of approximately 300 nm and a tunable zeta potential (−20 to + 30 mV) dependent on the amount/type of crosslinkers. The FITC-bound FNP showed no significant difference in physical properties compared to the blank FNP. They possessed a binding efficacy of 3.3% w/w, and no FITC was released in sink condition up to 8 h. All formulations were colloidal stable in the sheep whole blood. The degradation rate of these FNP in blood could be controlled depending on their crosslink degree. Moreover, no potential toxicity in erythrocytes, Caco-2, HepG2, and 9L cells was noted for all formulations at particle concentrations of < 1 mg/mL. Finally, all FNP were internalized into the Caco-2 cells after 3 h incubation. The uptake rate of the positively charged particles was significantly higher than the negatively charged ones. In summary, the crosslinked FNP were safe and showed high potentials as versatile systems for biomedical applications. Full article
(This article belongs to the Section Pharmaceutical Technology)
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Open AccessArticle
The Impact of Iron Supplementation for Treating Anemia in Patients with Chronic Kidney Disease: Results from Pairwise and Network Meta-Analyses of Randomized Controlled Trials
Pharmaceuticals 2020, 13(5), 85; https://doi.org/10.3390/ph13050085 - 30 Apr 2020
Viewed by 531
Abstract
After relative erythropoietin deficiency, iron deficiency is the second most important contributing factor for anemia in chronic kidney disease (CKD) patients. Iron supplementation is a crucial part of the treatment of anemia in CKD patients, and intravenous (IV) iron supplementation is considered to [...] Read more.
After relative erythropoietin deficiency, iron deficiency is the second most important contributing factor for anemia in chronic kidney disease (CKD) patients. Iron supplementation is a crucial part of the treatment of anemia in CKD patients, and intravenous (IV) iron supplementation is considered to be superior to per os (PO) iron supplementation. The differences between the available formulations are poorly characterized. This report presents results from pairwise and network meta-analyses carried out after a comprehensive search in sources of published and unpublished studies, according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) recommendations (International prospective register of systematic reviews PROSPERO reference ID: CRD42020148155). Meta-analytic calculations were performed for the outcome of non-response to iron supplementation (i.e., hemoglobin (Hgb) increase of <0.5–1.0 g/dL, or initiation/intensification of erythropoiesis-stimulating agent (ESA) therapy, or increase/change of iron supplement, or requirements of blood transfusion). A total of 34 randomized controlled trials (RCT) were identified, providing numerical data for analyses covering 93.7% (n = 10.097) of the total study population. At the network level, iron supplementation seems to have a more protective effect against the outcome of non-response before the start of dialysis than once dialysis is initiated, and some preparations seem to be more potent (e.g., ferumoxytol, ferric carboxymaltose), compared to the rest of iron supplements assessed (surface under the cumulative ranking area (SUCRA) > 0.8). This study provides parameters for adequately following-up patients requiring iron supplementation, by presenting the most performing preparations, and, indirectly, by making it possible to identify good responders among all patients treated with these medicines. Full article
(This article belongs to the Special Issue Metal-Based Drugs: Updates and Perspectives)
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Open AccessArticle
A Polyphenol-Rich Fraction from Eugenia uniflora Exhibits Antioxidant and Hepatoprotective Activities In Vivo
Pharmaceuticals 2020, 13(5), 84; https://doi.org/10.3390/ph13050084 - 29 Apr 2020
Viewed by 477
Abstract
Leaves from Eugenia uniflora, the red Brazilian cherry, have a high content of flavonoids that possess several biological effects such as anti-inflammatory, antioxidant, and antidiabetic activities. However, their influence on carbon tetrachloride (CCl4)-induced acute liver injury in rats has not [...] Read more.
Leaves from Eugenia uniflora, the red Brazilian cherry, have a high content of flavonoids that possess several biological effects such as anti-inflammatory, antioxidant, and antidiabetic activities. However, their influence on carbon tetrachloride (CCl4)-induced acute liver injury in rats has not been investigated. In the current study, a bioguided fractionation assay revealed that the ethyl acetate fraction (EAF) of Eugenia uniflora is the safest and most active fraction. LC-MS analysis of the ethyl acetate fraction revealed 22 secondary metabolites, mainly myricetin and quercetin derivatives. EAF did not show toxicity up to 2000 mg/kg, and exhibited antioxidant activities in vitro in DPPH assay with IC50 of 3.35 µg/mL. Additionally, EAF exhibited substantial antioxidant activities in vivo by counteracting the oxidative damage of the prooxidant juglone [80 µM] in Caenorhabditis elegans model organism and increased its survival rate in a dose-dependent fashion through the DAF-16/Foxo pathway. Furthermore, the hepatoprotective activity of EAF (200 mg/kg against carbon tetrachloride (CCl4) intoxicated male Wistar rats was assessed. EAF significantly inhibited CCl4-induced elevation of alanine aminotransferase (ALT), aspartate transaminase (AST), total bilirubin (TB), total cholesterol (TC), and triglycerides (TG), in the blood serum and prevented lipid peroxidation and restored superoxide dismutase (SOD) activity and glutathione (GSH) content in liver tissues. The observed hepatoprotective effects of EAF, which were supported by histopathological observations as pretreatment with EAF, effectively attenuated the CCl4-induced histopathological changes. In conclusion, EAF of Eugenia uniflora leaves has substantial hepatoprotective activities against CCl4 induced acute liver injury in rats due to its antioxidant activity. Full article
(This article belongs to the Special Issue Medicinal Plants 2020)
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Open AccessReview
Polymyxin Delivery Systems: Recent Advances and Challenges
Pharmaceuticals 2020, 13(5), 83; https://doi.org/10.3390/ph13050083 - 29 Apr 2020
Viewed by 399
Abstract
Polymyxins are vital antibiotics for the treatment of multiresistant Gram-negative ESKAPE pathogen infections. However, their clinical value is limited by their high nephrotoxicity and neurotoxicity, as well as their poor permeability and absorption in the gastrointestinal tract. This review focuses on various polymyxin [...] Read more.
Polymyxins are vital antibiotics for the treatment of multiresistant Gram-negative ESKAPE pathogen infections. However, their clinical value is limited by their high nephrotoxicity and neurotoxicity, as well as their poor permeability and absorption in the gastrointestinal tract. This review focuses on various polymyxin delivery systems that improve polymyxin bioavailability and reduce drug toxicity through targeted and controlled release. Currently, the most suitable systems for improving oral, inhalation, and parenteral polymyxin delivery are polymer particles, liposomes, and conjugates, while gels, polymer fibers, and membranes are attractive materials for topical administration of polymyxin for the treatment of infected wounds and burns. In general, the application of these systems protects polymyxin molecules from the negative effects of both physiological and pathological factors while achieving higher concentrations at the target site and reducing dosage and toxicity. Improving the properties of polymyxin will be of great interest to researchers who are focused on developing antimicrobial drugs that show increased efficacy and safety. Full article
(This article belongs to the Special Issue Small Molecules as Antimicrobials)
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Open AccessArticle
Polyphenolic Profile and Varied Bioactivities of Processed Taiwanese Grown Broccoli: A Comparative Study of Edible and Non-Edible Parts
Pharmaceuticals 2020, 13(5), 82; https://doi.org/10.3390/ph13050082 - 28 Apr 2020
Viewed by 410
Abstract
Broccoli contains a substantial amount of bioactive compounds such as glucosinolates, phenolics, and essential nutrients, which are positively linked to health-promoting effects. This work aimed to evaluate whether both edible and non-edible parts of broccoli could be effective by examining in vitro antioxidant, [...] Read more.
Broccoli contains a substantial amount of bioactive compounds such as glucosinolates, phenolics, and essential nutrients, which are positively linked to health-promoting effects. This work aimed to evaluate whether both edible and non-edible parts of broccoli could be effective by examining in vitro antioxidant, cytotoxic, apoptotic, and antibacterial properties of its floret, leaf, and seed extracts (FE, LE, and SE, correspondingly). High-performance liquid chromatography (HPLC) and various assays exhibited strong antioxidant activities of all samples. LE obtained the highest capacity, correlated to its polyphenolic contents. SE exerted significant cytotoxicity against A549, Caco-2, and HepG2 cancer cell lines at low inhibitory concentration (IC)50 values (0.134, 0.209, and 0.238 mg/mL, respectively), as tested by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Flow cytometry confirmed apoptosis induction of extracts in Caco-2 cells by revealing an increased subG1 population and a decreased mitochondrial membrane potential. The considerable antibacterial efficacy was observed in either LE and SE against Bacillus subtilis and Salmonella typhimurium (0.39–0.78 mg/mL) using well-agar diffusion and minimum inhibitory concentration (MIC) techniques, along with the weak activity against Staphylococcus aureus and Escherichia coli (1.56–3.13 mg/mL). The findings suggest that broccoli and its byproducts might serve as a promising source for further development of food or pharmaceutical products. Full article
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Open AccessArticle
Experimental Evaluation of Anticancer Efficiency and Acute Toxicity of Anthrafuran for Oral Administration
Pharmaceuticals 2020, 13(5), 81; https://doi.org/10.3390/ph13050081 - 28 Apr 2020
Viewed by 354
Abstract
The new antitumor agent anthrafuran has demonstrated a consistent effect in murine tumor models when administered parenterally due to the simultaneous inhibition of multiple cellular targets such as topoisomerases I/II and protein kinases. In this study, we assessed the anticancer efficiency and acute [...] Read more.
The new antitumor agent anthrafuran has demonstrated a consistent effect in murine tumor models when administered parenterally due to the simultaneous inhibition of multiple cellular targets such as topoisomerases I/II and protein kinases. In this study, we assessed the anticancer efficiency and acute toxicity of anthrafuran administered orally. The action of anthrafuran was studied on transplanted tumor models which included P388 leukemia, Ca755 mammary adenocarcinoma, LLC lung carcinoma, and T47D human breast cancer xenografts on Balb/c nude mice. A significant antitumor efficacy of oral anthrafuran was revealed for all tested tumor models as follows: T/Cmax = 219% for P388, TGImax = 91% for Ca755, TGImax = 84% with CRmax = 54% for LLC, and T/C = 38% for T47D. The optimal treatment schedule of orally administered anthrafuran was 70–100 mg/kg given daily for five days. The LD50 value of orally administered anthrafuran (306.7 mg/kg) in mice was six times higher than that for i.p. administration (52.5 mg/kg). The rates of antitumor efficacy and acute toxicity indicate the high potential for further research on anthrafuran as a new original oral anticancer multitarget agent with an expected satisfactory tolerability and bioavailability. Full article
(This article belongs to the Section Pharmacology)
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Open AccessArticle
Paradoxical Anticonvulsant Effect of Cefepime in the Pentylenetetrazole Model of Seizures in Rats
Pharmaceuticals 2020, 13(5), 80; https://doi.org/10.3390/ph13050080 - 26 Apr 2020
Viewed by 350
Abstract
Many β-lactam antibiotics, including cephalosporins, may cause neurotoxic and proconvulsant effects. The main molecular mechanism of such effects is considered to be γ-aminobutyric acid type a (GABAa) receptor blockade, leading to the suppression of GABAergic inhibition and subsequent overexcitation. We found that cefepime [...] Read more.
Many β-lactam antibiotics, including cephalosporins, may cause neurotoxic and proconvulsant effects. The main molecular mechanism of such effects is considered to be γ-aminobutyric acid type a (GABAa) receptor blockade, leading to the suppression of GABAergic inhibition and subsequent overexcitation. We found that cefepime (CFP), a cephalosporin, has a pronounced antiepileptic effect in the pentylenetetrazole (PTZ)-induced seizure model by decreasing the duration and severity of the seizure and animal mortality. This effect was specific to the PTZ model. In line with findings of previous studies, CFP exhibited a proconvulsant effect in other models, including the maximal electroshock model and 4-aminopyridine model of epileptiform activity, in vitro. To determine the antiepileptic mechanism of CFP in the PTZ model, we used whole-cell patch-clamp recordings. We demonstrated that CFP or PTZ decreased the amplitude of GABAa receptor-mediated postsynaptic currents. PTZ also decreased the current decay time constant and temporal summation of synaptic responses. In contrast, CFP slightly increased the decay time constant and did not affect summation. When applied together, CFP prevented alterations to the summation of responses by PTZ, strongly reducing the effects of PTZ on repetitive inhibitory synaptic transmission. The latter may explain the antiepileptic effect of CFP in the PTZ model. Full article
(This article belongs to the Section Pharmacology)
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Open AccessArticle
Multitarget Activities of Kleeb Bua Daeng, a Thai Traditional Herbal Formula, Against Alzheimer’s Disease
Pharmaceuticals 2020, 13(5), 79; https://doi.org/10.3390/ph13050079 - 25 Apr 2020
Viewed by 629
Abstract
The Kleeb Bua Daeng formula (KBD) is a Thai traditional medicine for brain health promotion. On the basis of the activities of its individual components, the KBD could have good potential for the treatment of Alzheimer’s disease (AD). Herein, we investigated the KBD [...] Read more.
The Kleeb Bua Daeng formula (KBD) is a Thai traditional medicine for brain health promotion. On the basis of the activities of its individual components, the KBD could have good potential for the treatment of Alzheimer’s disease (AD). Herein, we investigated the KBD as an AD treatment. The ethanol extracts of KBD and its components, i.e., Nelumbo nucifera (NN), Piper nigrum fruits (BP), and the aerial part of Centella asiatica (CA) exhibited antioxidant activity, as determined by both ABTS and DPPH assays. The Ellman’s assay revealed that the KBD, NN, and BP showed an ability to inhibit acetylcholinesterase. The thioflavin T assay indicated that the KBD, NN, BP, and CA inhibited beta-amyloid aggregation. The neuroprotection and Western blot analysis revealed that the KBD reduced H2O2-induced neuronal cell death by inhibiting the expression of pro-apoptotic factors, i.e., cleaved caspase-9 and -3, p-P65, p-JNK, and p-GSK-3β, as well as by inducing expression of anti-apoptotic factors, i.e., MCl1, BClxl, and survivin. Furthermore, the KBD could improve scopolamine induced memory deficit in mice. Our results illustrate that the KBD with multimode action has the potential to be employed in AD treatment. Thus, the KBD could be used as an alternative novel choice for the prevention and treatment of patients with AD. Full article
(This article belongs to the Section Natural Products)
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