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Pharmaceuticals, Volume 14, Issue 7 (July 2021) – 105 articles

Cover Story (view full-size image): Cell-Penetrating Peptides (CPPs) and nanobodies could combine into powerful targeting tools, if we optimize their synergy. Nanobodies are low molecular weight antigen-specific binders that show good tissue penetration. However, their fast clearance narrows the time window in which nanobodies distribute into the target tissue. CPPs could increase tissue accumulation of nanobodies, by enhancing their cellular uptake. Several CPPs enhance the uptake of the epidermal growth factor receptor-targeting nanobody 7D12 in monolayer cultures and cell spheroids. The physicochemical properties of each CPP influence those of the whole conjugate. Differences between CPPs suggest that future research should focus on understanding which and how physicochemical properties of CPP conjugates drive optimal biodistribution. View this paper
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Review
Recent Advances in the Clinical Translation of Silicon Fluoride Acceptor (SiFA) 18F-Radiopharmaceuticals
Pharmaceuticals 2021, 14(7), 701; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14070701 - 20 Jul 2021
Viewed by 575
Abstract
The incorporation of silicon fluoride acceptor (SiFA) moieties into a variety of molecules, such as peptides, proteins and biologically relevant small molecules, has improved the generation of 18F-radiopharmaceuticals for medical imaging. The efficient isotopic exchange radiofluorination process, in combination with the enhanced [...] Read more.
The incorporation of silicon fluoride acceptor (SiFA) moieties into a variety of molecules, such as peptides, proteins and biologically relevant small molecules, has improved the generation of 18F-radiopharmaceuticals for medical imaging. The efficient isotopic exchange radiofluorination process, in combination with the enhanced [18F]SiFA in vivo stability, make it a suitable strategy for fluorine-18 incorporation. This review will highlight the clinical applicability of [18F]SiFA-labeled compounds and discuss the significant radiotracers currently in clinical use. Full article
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Review
Monoclonal Antibodies Targeting CGRP: From Clinical Studies to Real-World Evidence—What Do We Know So Far?
Pharmaceuticals 2021, 14(7), 700; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14070700 - 20 Jul 2021
Viewed by 684
Abstract
Now more than ever is the time of monoclonal antibody use in neurology. In headaches, disease-specific and mechanism-based treatments existed only for symptomatic management of migraines (i.e., triptans), while the standard prophylactic anti-migraine treatments consist of non-specific and repurposed drugs that share limited [...] Read more.
Now more than ever is the time of monoclonal antibody use in neurology. In headaches, disease-specific and mechanism-based treatments existed only for symptomatic management of migraines (i.e., triptans), while the standard prophylactic anti-migraine treatments consist of non-specific and repurposed drugs that share limited safety profiles and high risk for interactions with other medications, resulting in rundown adherence rates. Recent advances in headache science have increased our understanding of the role of calcitonin gene relate peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP) pathways in cephalic pain neurotransmission and peripheral or central sensitization, leading to the development of monoclonal antibodies (mAbs) or small molecules targeting these neuropeptides or their receptors. Large scale randomized clinical trials confirmed that inhibition of the CGRP system attenuates migraine, while the PACAP mediated nociception is still under scientific and clinical investigation. In this review, we provide the latest clinical evidence for the use of anti-CGRP in migraine prevention with emphasis on efficacy and safety outcomes from Phase III and real-world studies. Full article
(This article belongs to the Special Issue Monoclonal Antibodies for Migraine Prevention)
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Article
Development of Machine Learning Models for Accurately Predicting and Ranking the Activity of Lead Molecules to Inhibit PRC2 Dependent Cancer
Pharmaceuticals 2021, 14(7), 699; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14070699 - 20 Jul 2021
Viewed by 390
Abstract
Disruption of epigenetic processes to eradicate tumor cells is among the most promising interventions for cancer control. EZH2 (Enhancer of zeste homolog 2), a catalytic component of polycomb repressive complex 2 (PRC2), methylates lysine 27 of histone H3 to promote transcriptional silencing and [...] Read more.
Disruption of epigenetic processes to eradicate tumor cells is among the most promising interventions for cancer control. EZH2 (Enhancer of zeste homolog 2), a catalytic component of polycomb repressive complex 2 (PRC2), methylates lysine 27 of histone H3 to promote transcriptional silencing and is an important drug target for controlling cancer via epigenetic processes. In the present study, we have developed various predictive models for modeling the inhibitory activity of EZH2. Binary and multiclass models were built using SVM, random forest and XGBoost methods. Rigorous validation approaches including predictiveness curve, Y-randomization and applicability domain (AD) were employed for evaluation of the developed models. Eighteen descriptors selected from Boruta methods have been used for modeling. For binary classification, random forest and XGBoost achieved an accuracy of 0.80 and 0.82, respectively, on external test set. Contrastingly, for multiclass models, random forest and XGBoost achieved an accuracy of 0.73 and 0.75, respectively. 500 Y-randomization runs demonstrate that the models were robust and the correlations were not by chance. Evaluation metrics from predictiveness curve show that the selected eighteen descriptors predict active compounds with total gain (TG) of 0.79 and 0.59 for XGBoost and random forest, respectively. Validated models were further used for virtual screening and molecular docking in search of potential hits. A total of 221 compounds were commonly predicted as active with above the set probability threshold and also under the AD of training set. Molecular docking revealed that three compounds have reasonable binding energy and favorable interactions with critical residues in the active site of EZH2. In conclusion, we highlighted the potential of rigorously validated models for accurately predicting and ranking the activities of lead molecules against cancer epigenetic targets. The models presented in this study represent the platform for development of EZH2 inhibitors. Full article
(This article belongs to the Section Medicinal Chemistry)
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Article
Functional Characterization of the Oxantel-Sensitive Acetylcholine Receptor from Trichuris muris
Pharmaceuticals 2021, 14(7), 698; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14070698 - 20 Jul 2021
Viewed by 440
Abstract
The human whipworm, Trichuris trichiura, is estimated to infect 289.6 million people globally. Control of human trichuriasis is a particular challenge, as most anthelmintics have a limited single-dose efficacy, with the striking exception of the narrow-spectrum anthelmintic, oxantel. We recently identified a [...] Read more.
The human whipworm, Trichuris trichiura, is estimated to infect 289.6 million people globally. Control of human trichuriasis is a particular challenge, as most anthelmintics have a limited single-dose efficacy, with the striking exception of the narrow-spectrum anthelmintic, oxantel. We recently identified a novel ACR-16-like subunit from the pig whipworm, T. suis which gave rise to a functional acetylcholine receptor (nAChR) preferentially activated by oxantel. However, there is no ion channel described in the mouse model parasite T. muris so far. Here, we have identified the ACR-16-like and ACR-19 subunits from T. muris, and performed the functional characterization of the receptors in Xenopus laevis oocytes using two-electrode voltage-clamp electrophysiology. We found that the ACR-16-like subunit from T. muris formed a homomeric receptor gated by acetylcholine whereas the ACR-19 failed to create a functional channel. The subsequent pharmacological analysis of the Tmu-ACR-16-like receptor revealed that acetylcholine and oxantel were equally potent. The Tmu-ACR-16-like was more responsive to the toxic agonist epibatidine, but insensitive to pyrantel, in contrast to the Tsu-ACR-16-like receptor. These findings confirm that the ACR-16-like nAChR from Trichuris spp. is a preferential drug target for oxantel, and highlights the pharmacological difference between Trichuris species. Full article
(This article belongs to the Special Issue Antiparasitics)
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Article
Albumin Nanoparticle Formulation for Heart-Targeted Drug Delivery: In Vivo Assessment of Congestive Heart Failure
Pharmaceuticals 2021, 14(7), 697; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14070697 - 19 Jul 2021
Viewed by 426
Abstract
Congestive heart failure is a fatal cardiovascular disease resulting in tissue necrosis and loss of cardiac contractile function. Inotropic drugs such as milrinone are commonly used to improve the myocardial contractility and heart function. However, milrinone is associated with severe side effects and [...] Read more.
Congestive heart failure is a fatal cardiovascular disease resulting in tissue necrosis and loss of cardiac contractile function. Inotropic drugs such as milrinone are commonly used to improve the myocardial contractility and heart function. However, milrinone is associated with severe side effects and lower circulation time. In this article, a novel protein nanoparticle formulation for heart-targeted delivery of milrinone has been designed and tested. The formulation was prepared using albumin protein conjugated with the targeting ligand, angiotensin II peptide to form nanoparticles following the ethanol desolvation method. The formulation was characterized for size, charge, and morphology and tested in a rat model of congestive heart failure to study pharmacokinetics, biodistribution, and efficacy. The overall cardiac output parameters were evaluated comparing the formulation with the control non-targeted drug, milrinone lactate. This formulation exhibited improved pharmacokinetics with a mean retention time of 123.7 min, half-life of 101.3 min, and clearance rate of 0.24 L/(kg*h). The targeted formulation also significantly improved ejection fraction and fractional shortening parameters thus improving cardiac function. This study demonstrates a new approach in delivering inotropic drugs such as milrinone for superior treatment of congestive heart failure. Full article
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Article
Development and Characterization of n-Propyl Gallate Encapsulated Solid Lipid Nanoparticles-Loaded Hydrogel for Intranasal Delivery
Pharmaceuticals 2021, 14(7), 696; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14070696 - 19 Jul 2021
Viewed by 457
Abstract
The objective of the present study was to develop n-propyl gallate-loaded solid lipid nanoparticles (PG-SLNs) in a hydrogel (HG) formulation using Transcutol-P (TC-P) as a permeation enhancer. Modified solvent injection technique was applied to produce optimized PG-SLNs via the Quality by Design [...] Read more.
The objective of the present study was to develop n-propyl gallate-loaded solid lipid nanoparticles (PG-SLNs) in a hydrogel (HG) formulation using Transcutol-P (TC-P) as a permeation enhancer. Modified solvent injection technique was applied to produce optimized PG-SLNs via the Quality by Design approach and central composite design. The in vitro mucoadhesion, scavenging activity, drug release, permeation studies of PG from PG-SLNs-loaded HG were evaluated under simulated nasal conditions. Compared with in vitro release behavior of PG from SLNs, the drug release from the PG-SLNs-loaded HG showed a lower burst effect and sustained release profile. The cumulative permeation of PG from PG-SLNs-loaded HG with TC-P was 600 μg/cm2 within 60 min, which is 3–60-fold higher than PG-SLNs and native PG, respectively. Raman mapping showed that the distribution of PG-SLNs was more concentrated in HG having lower concentrations of hyaluronic acid. The scavenging assay demonstrated increased antioxidant activity at higher concentrations of HG. Due to enhanced stability and mucoadhesive properties, the developed HG-based SLNs can improve nasal absorption by increasing residence time on nasal mucosa. This study provides in vitro proof of the potential of combining the advantages of SLNs and HG for the intranasal delivery of antioxidants. Full article
(This article belongs to the Special Issue Current Insights on Lipid-Based Nanosystems)
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Article
Soluble Angiotensin Converting Enzyme 2 (ACE2) Is Upregulated and Soluble Endothelial Nitric Oxide Synthase (eNOS) Is Downregulated in COVID-19-induced Acute Respiratory Distress Syndrome (ARDS)
Pharmaceuticals 2021, 14(7), 695; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14070695 - 19 Jul 2021
Viewed by 460
Abstract
A damaged endothelium is an underlying condition of the many complications of COVID-19 patients. The increased mortality risk associated with diseases that have underlying endothelial dysfunction, such as acute respiratory distress syndrome (ARDS), suggests that endothelial (e) nitric oxide synthase (NOS)-derived nitric oxide [...] Read more.
A damaged endothelium is an underlying condition of the many complications of COVID-19 patients. The increased mortality risk associated with diseases that have underlying endothelial dysfunction, such as acute respiratory distress syndrome (ARDS), suggests that endothelial (e) nitric oxide synthase (NOS)-derived nitric oxide could be an important defense mechanism. Additionally, intravenous recombinant angiotensin converting enzyme 2 (ACE2) was recently reported as an effective therapy in severe COVID-19, by blocking viral entry, and thus reducing lung injury. Very few studies exist on the prognostic value of endothelium-related protective molecules in severe COVID-19 disease. To this end, serum levels of eNOS, inducible (i) NOS, adrenomedullin (ADM), soluble (s) ACE2 levels, and serum (s) ACE activity were measured on hospital admission in 89 COVID-19 patients, hospitalized either in a ward or ICU, of whom 68 had ARDS, while 21 did not. In our cohort, the COVID-19-ARDS patients had considerably lower eNOS levels compared to the COVID-19 non-ARDS patients. On the other hand, sACE2 was significantly higher in the ARDS patients. iNOS, ADM and sACE activity did not differ. Our results might support the notion of two distinct defense mechanisms in COVID-19-derived ARDS; eNOS-derived nitric oxide could be one of them, while the dramatic rise in sACE2 may also represent an endogenous mechanism involved in severe COVID-19 complications, such as ARDS. These results could provide insight to therapeutical applications in COVID-19. Full article
(This article belongs to the Special Issue Lung Injury and Repair)
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Article
The Effect of Cyanine Dye NK-4 on Photoreceptor Degeneration in a Rat Model of Early-Stage Retinitis Pigmentosa
Pharmaceuticals 2021, 14(7), 694; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14070694 - 19 Jul 2021
Viewed by 444
Abstract
The present study aimed to evaluate the effects of NK-4 on the apoptosis of photoreceptors in a rat model of retinitis pigmentosa and explore the mechanism underlying anti-apoptosis activity. The Royal College of Surgeons (RCS) rats received an intravitreous injection of NK-4 solution [...] Read more.
The present study aimed to evaluate the effects of NK-4 on the apoptosis of photoreceptors in a rat model of retinitis pigmentosa and explore the mechanism underlying anti-apoptosis activity. The Royal College of Surgeons (RCS) rats received an intravitreous injection of NK-4 solution in the left eye and vehicle control in the right eye. Apoptosis was detected by TUNEL method in frozen sections of the eyes. The retinal tissues of the rats were dissected for RNA-seq analysis. Functional and pathway enrichment analyses of differentially expressed genes (DEGs) were performed by using Metascape and DAVID software. The expression levels of DEGs were confirmed by real-time quantitative PCR (RT-qPCR). The number of apoptotic cells decreased in the outer nuclear layer (ONL) and the thickness of the ONL was significantly thicker in the retina of NK-4-injected eyes, compared with control eyes. Five DEGs were identified by RNA-seq analysis, and Hmox1, Mt1, Atf5, Slc7a11, and Bdh2 were confirmed to be up-regulated by RT-qPCR. Functional and pathway enrichment analysis of the up-regulated genes showed that anti-apoptosis effects of NK-4 in the retina of RCS rats may be related to the pathways of metal ion homeostasis, negative regulation of neuron death, response to toxic substance, and pigment metabolic process. We found a potential mechanism of NK-4, providing a new viewpoint for the development of more therapeutic uses of NK-4 in the future. Full article
(This article belongs to the Special Issue Advances in Ocular Pharmacology)
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Article
Synthesis and Human Carbonic Anhydrase I, II, IX, and XII Inhibition Studies of Sulphonamides Incorporating Mono-, Bi- and Tricyclic Imide Moieties
Pharmaceuticals 2021, 14(7), 693; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14070693 - 19 Jul 2021
Viewed by 340
Abstract
New derivatives were synthesised by reaction of amino-containing aromatic sulphonamides with mono-, bi-, and tricyclic anhydrides. These sulphonamides were investigated as human carbonic anhydrases (hCAs, EC 4.2.1.1) I, II, IX, and XII inhibitors. hCA I was inhibited with inhibition constants (Kis) ranging from [...] Read more.
New derivatives were synthesised by reaction of amino-containing aromatic sulphonamides with mono-, bi-, and tricyclic anhydrides. These sulphonamides were investigated as human carbonic anhydrases (hCAs, EC 4.2.1.1) I, II, IX, and XII inhibitors. hCA I was inhibited with inhibition constants (Kis) ranging from 49 to >10,000 nM. The physiologically dominant hCA II was significantly inhibited by most of the sulphonamide with the Kis ranging between 2.4 and 4515 nM. hCA IX and hCA XII were inhibited by these sulphonamides in the range of 9.7 to 7766 nM and 14 to 316 nM, respectively. The structure–activity relationships (SAR) are rationalised with the help of molecular docking studies. Full article
(This article belongs to the Section Medicinal Chemistry)
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Review
Thiophene-Based Compounds with Potential Anti-Inflammatory Activity
Pharmaceuticals 2021, 14(7), 692; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14070692 - 19 Jul 2021
Viewed by 304
Abstract
Rheumatoid arthritis, arthrosis and gout, among other chronic inflammatory diseases are public health problems and represent major therapeutic challenges. Non-steroidal anti-inflammatory drugs (NSAIDs) are the most prescribed clinical treatments, despite their severe side effects and their exclusive action in improving symptoms, without effectively [...] Read more.
Rheumatoid arthritis, arthrosis and gout, among other chronic inflammatory diseases are public health problems and represent major therapeutic challenges. Non-steroidal anti-inflammatory drugs (NSAIDs) are the most prescribed clinical treatments, despite their severe side effects and their exclusive action in improving symptoms, without effectively promoting the cure. However, recent advances in the fields of pharmacology, medicinal chemistry, and chemoinformatics have provided valuable information and opportunities for development of new anti-inflammatory drug candidates. For drug design and discovery, thiophene derivatives are privileged structures. Thiophene-based compounds, like the commercial drugs Tinoridine and Tiaprofenic acid, are known for their anti-inflammatory properties. The present review provides an update on the role of thiophene-based derivatives in inflammation. Studies on mechanisms of action, interactions with receptors (especially against cyclooxygenase (COX) and lipoxygenase (LOX)), and structure-activity relationships are also presented and discussed. The results demonstrate the importance of thiophene-based compounds as privileged structures for the design and discovery of novel anti-inflammatory agents. The studies reveal important structural characteristics. The presence of carboxylic acids, esters, amines, and amides, as well as methyl and methoxy groups, has been frequently described, and highlights the importance of these groups for anti-inflammatory activity and biological target recognition, especially for inhibition of COX and LOX enzymes. Full article
(This article belongs to the Special Issue Privileged Structures as Leads in Medicinal Chemistry)
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Perspective
Update on Functional Inhibitors of Acid Sphingomyelinase (FIASMAs) in SARS-CoV-2 Infection
Pharmaceuticals 2021, 14(7), 691; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14070691 - 18 Jul 2021
Viewed by 478
Abstract
The SARS-CoV-2 outbreak is characterized by the need of the search for curative drugs for treatment. In this paper, we present an update of knowledge about the interest of the functional inhibitors of acid sphingomyelinase (FIASMAs) in SARS-CoV-2 infection. Forty-nine FIASMAs have been [...] Read more.
The SARS-CoV-2 outbreak is characterized by the need of the search for curative drugs for treatment. In this paper, we present an update of knowledge about the interest of the functional inhibitors of acid sphingomyelinase (FIASMAs) in SARS-CoV-2 infection. Forty-nine FIASMAs have been suggested in the treatment of SARS-CoV-2 infection using in silico, in vitro or in vivo studies. Further studies using large-sized, randomized and double-blinded controlled clinical trials are needed to evaluate FIASMAs in SARS-CoV-2 infection as off-label therapy. Full article
(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)
Review
Dietary Effects of Anthocyanins in Human Health: A Comprehensive Review
Pharmaceuticals 2021, 14(7), 690; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14070690 - 18 Jul 2021
Viewed by 544
Abstract
In recent years, the consumption of natural-based foods, including beans, fruits, legumes, nuts, oils, vegetables, spices, and whole grains, has been encouraged. This fact is essentially due to their content in bioactive phytochemicals, with the phenolic compounds standing out. Among them, anthocyanins have [...] Read more.
In recent years, the consumption of natural-based foods, including beans, fruits, legumes, nuts, oils, vegetables, spices, and whole grains, has been encouraged. This fact is essentially due to their content in bioactive phytochemicals, with the phenolic compounds standing out. Among them, anthocyanins have been a target of many studies due to the presence of catechol, pyrogallol, and methoxy groups in their chemical structure, which confer notable scavenging, anti-apoptotic, and anti-inflammatory activities, being already recommended as supplementation to mitigate or even attenuate certain disorders, such as diabetes, cancer, and cardiovascular and neurological pathologies. The most well-known anthocyanins are cyanidin 3-O-glucoside and cyanidin 3-O-rutinoside. They are widespread in nature, being present in considerable amounts in red fruits and red vegetables. Overall, the present review intends to discuss the most recent findings on the potential health benefits from the daily intake of anthocyanin-rich foods, as well as their possible pharmacological mechanisms of action. However, before that, some emphasis regarding their chemical structure, dietary sources, and bioavailability was done. Full article
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Article
Small Molecule–Peptide Conjugates as Dimerization Inhibitors of Leishmania infantum Trypanothione Disulfide Reductase
Pharmaceuticals 2021, 14(7), 689; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14070689 - 17 Jul 2021
Viewed by 429
Abstract
Trypanothione disulfide reductase (TryR) is an essential homodimeric enzyme of trypanosomatid parasites that has been validated as a drug target to fight human infections. Using peptides and peptidomimetics, we previously obtained proof of concept that disrupting protein–protein interactions at the dimer interface of [...] Read more.
Trypanothione disulfide reductase (TryR) is an essential homodimeric enzyme of trypanosomatid parasites that has been validated as a drug target to fight human infections. Using peptides and peptidomimetics, we previously obtained proof of concept that disrupting protein–protein interactions at the dimer interface of Leishmania infantum TryR (LiTryR) offered an innovative and so far unexploited opportunity for the development of novel antileishmanial agents. Now, we show that linking our previous peptide prototype TRL38 to selected hydrophobic moieties provides a novel series of small-molecule–peptide conjugates that behave as good inhibitors of both LiTryR activity and dimerization. Full article
(This article belongs to the Special Issue Drug Discovery and Development for Tropical Diseases (TDs))
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Article
Conjugation of Diclofenac with Novel Oleanolic Acid Derivatives Modulate Nrf2 and NF-κB Activity in Hepatic Cancer Cells and Normal Hepatocytes Leading to Enhancement of Its Therapeutic and Chemopreventive Potential
Pharmaceuticals 2021, 14(7), 688; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14070688 - 17 Jul 2021
Viewed by 593
Abstract
Combining NSAIDs with conventional therapeutics was recently explored as a new strategy in cancer therapy. Our earlier studies showed that novel oleanolic acid oximes (OAO) conjugated with aspirin or indomethacin may enhance their anti-cancer potential through modulation of the Nrf2 and NF-κB signaling [...] Read more.
Combining NSAIDs with conventional therapeutics was recently explored as a new strategy in cancer therapy. Our earlier studies showed that novel oleanolic acid oximes (OAO) conjugated with aspirin or indomethacin may enhance their anti-cancer potential through modulation of the Nrf2 and NF-κB signaling pathways. This study focused on the synthesis and biological evaluation of four diclofenac (DCL)–OAO derivative conjugates in the context of these pathways’ modification and hepatic cells survival. Treatment with the conjugates 4d, 3-diclofenacoxyiminoolean-12-en-28-oic acid morpholide, and 4c, 3-diclofenacoxyiminoolean-12-en-28-oic acid benzyl ester significantly reduced cell viability in comparison to the DCL alone. In THLE-2, immortalized normal hepatocytes treated with these conjugates resulted in the activation of Nrf2 and increased expression in SOD-1 and NQO1, while the opposite effect was observed in the HepG2 hepatoma cells. In both cell lines, reduced activation of the NF-κB and COX-2 expression was observed. In HepG2 cells, conjugates increased ROS production resulting from a reduced antioxidant defense, induced apoptosis, and inhibited cell proliferation. In addition, the OAO morpholide derivative and its DCL hybrid reduced the tumor volume in mice bearing xenografts. In conclusion, our study demonstrated that conjugating diclofenac with the OAO morpholide and a benzyl ester might enhance its anti-cancer activity in HCC. Full article
(This article belongs to the Collection Old Pharmaceuticals with New Applications)
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Review
Investigating Potential Applications of the Fish Anti-Microbial Peptide Pleurocidin: A Systematic Review
Pharmaceuticals 2021, 14(7), 687; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14070687 - 17 Jul 2021
Viewed by 498
Abstract
The anti-microbial peptide (AMP) pleurocidin is found in winter flounder (Pseudopleuronectes americanus), an Atlantic flounder species. There is promising evidence for clinical, aquaculture, and veterinary applications of pleurocidin. This review provides an overview of the current literature available on pleurocidin to [...] Read more.
The anti-microbial peptide (AMP) pleurocidin is found in winter flounder (Pseudopleuronectes americanus), an Atlantic flounder species. There is promising evidence for clinical, aquaculture, and veterinary applications of pleurocidin. This review provides an overview of the current literature available on pleurocidin to guide future research directions. By fully elucidating pleurocidin’s mechanism of action and developing novel treatments against pathogenic microbes, populations of flatfish and humans can be protected. This review consulted publications from PubMed and Environment Complete with search terms such as “pleurocidin”, “winter flounder”, and “antimicrobial”. The fish immune system includes AMPs as a component of the innate immune system. Pleurocidin, one of these AMPs, has been found to be effective against various Gram-positive and Gram-negative bacteria. More investigations are required to determine pleurocidin’s suitability as a treatment against antibiotic-resistant pathogens. There is promising evidence for pleurocidin as a novel anti-cancer therapy. The peptide has been found to display potent anti-cancer effects against human cancer cells. Research efforts focused on pleurocidin may result in novel treatment strategies against antibiotic-resistant bacteria and cancer. More research is required to determine if the peptide is a suitable candidate to be developed into a novel anti-microbial treatment. Some of the microbes susceptible to the peptide are also pathogens of fish, suggesting its suitability as a therapeutic treatment for fish species. Full article
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Article
Antiparasitic Properties of Cardiovascular Agents against Human Intravascular Parasite Schistosoma mansoni
Pharmaceuticals 2021, 14(7), 686; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14070686 - 16 Jul 2021
Viewed by 475
Abstract
The intravascular parasitic worm Schistosoma mansoni is a causative agent of schistosomiasis, a disease of great global public health significance. Praziquantel is the only drug available to treat schistosomiasis and there is an urgent demand for new anthelmintic agents. Adopting a phenotypic drug [...] Read more.
The intravascular parasitic worm Schistosoma mansoni is a causative agent of schistosomiasis, a disease of great global public health significance. Praziquantel is the only drug available to treat schistosomiasis and there is an urgent demand for new anthelmintic agents. Adopting a phenotypic drug screening strategy, here, we evaluated the antiparasitic properties of 46 commercially available cardiovascular drugs against S. mansoni. From these screenings, we found that amiodarone, telmisartan, propafenone, methyldopa, and doxazosin affected the viability of schistosomes in vitro, with effective concentrations of 50% (EC50) and 90% (EC90) values ranging from 8 to 50 µM. These results were further supported by scanning electron microscopy analysis. Subsequently, the most effective drug (amiodarone) was further tested in a murine model of schistosomiasis for both early and chronic S. mansoni infections using a single oral dose of 400 mg/kg or 100 mg/kg daily for five consecutive days. Amiodarone had a low efficacy in chronic infection, with the worm and egg burden reduction ranging from 10 to 30%. In contrast, amiodarone caused a significant reduction in worm and egg burden in early infection (>50%). Comparatively, treatment with amiodarone is more effective in early infection than praziquantel, demonstrating the potential role of this cardiovascular drug as an antischistosomal agent. Full article
(This article belongs to the Special Issue Antiparasitics)
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Article
Interaction between DNA, Albumin and Apo-Transferrin and Iridium(III) Complexes with Phosphines Derived from Fluoroquinolones as a Potent Anticancer Drug
Pharmaceuticals 2021, 14(7), 685; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14070685 - 16 Jul 2021
Viewed by 455
Abstract
A group of cytotoxic half-sandwich iridium(III) complexes with aminomethyl(diphenyl)phosphine derived from fluoroquinolone antibiotics exhibit the ability to (i) accumulate in the nucleus, (ii) induce apoptosis, (iii) activate caspase-3/7 activity, (iv) induce the changes in cell cycle leading to G2/M phase arrest, and (v) [...] Read more.
A group of cytotoxic half-sandwich iridium(III) complexes with aminomethyl(diphenyl)phosphine derived from fluoroquinolone antibiotics exhibit the ability to (i) accumulate in the nucleus, (ii) induce apoptosis, (iii) activate caspase-3/7 activity, (iv) induce the changes in cell cycle leading to G2/M phase arrest, and (v) radicals generation. Herein, to elucidate the cytotoxic effects, we investigated the interaction of these complexes with DNA and serum proteins by gel electrophoresis, fluorescence spectroscopy, circular dichroism, and molecular docking studies. DNA binding experiments established that the complexes interact with DNA by moderate intercalation and predominance of minor groove binding without the capability to cause a double-strand cleavage. The molecular docking study confirmed two binding modes: minor groove binding and threading intercalation with the fluoroquinolone part of the molecule involved in pi stacking interactions and the Ir(III)-containing region positioned within the major or minor groove. Fluorescence spectroscopic data (HSA and apo-Tf titration), together with molecular docking, provided evidence that Ir(III) complexes can bind to the proteins in order to be transferred. All the compounds considered herein were found to bind to the tryptophan residues of HSA within site I (subdomain II A). Furthermore, Ir(III) complexes were found to dock within the apo-Tf binding site, including nearby tyrosine residues. Full article
(This article belongs to the Special Issue Privileged Structures as Leads in Medicinal Chemistry)
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Article
Delaying Effects of Prolactin and Growth Hormone on Aging Processes in Bovine Oocytes Matured In Vitro
Pharmaceuticals 2021, 14(7), 684; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14070684 - 16 Jul 2021
Viewed by 470
Abstract
Aging processes accelerate dramatically in oocytes that have reached the metaphase-II (M-II) stage. The present work aimed to study the patterns and intracellular pathways of actions of prolactin (PRL) and growth hormone (GH) on age-associated changes in bovine M-II oocytes aging in vitro. [...] Read more.
Aging processes accelerate dramatically in oocytes that have reached the metaphase-II (M-II) stage. The present work aimed to study the patterns and intracellular pathways of actions of prolactin (PRL) and growth hormone (GH) on age-associated changes in bovine M-II oocytes aging in vitro. To this end, we analyzed spontaneous parthenogenetic activation (cytogenetic assay), apoptosis (TUNEL assay), and the developmental capacity (IVF/IVC) of in vitro-matured oocytes after prolonged culturing. Both PRL and GH reduced the activation rate of aging cumulus-enclosed oocytes (CEOs) and denuded oocytes (DOs), and their respective hormone receptors were revealed in the ova. The inhibitor of Src-family tyrosine kinases PP2 eliminated the effects of PRL and GH on meiotic arrest in DOs, whereas the MEK inhibitor U0126 only abolished the PRL effect. Furthermore, PRL was able to maintain the apoptosis resistance and developmental competence of aging CEOs. The protein kinase C inhibitor calphostin C suppressed both the actions of PRL. Thus, PRL and GH can directly support meiotic arrest in aging M-II oocytes by activating MAP kinases and/or Src-family kinases. The effect of PRL in maintaining the developmental capacity of aging oocytes is cumulus-dependent and related to the pro-survival action of the protein kinase C-mediated signal pathway. Full article
(This article belongs to the Special Issue Novel Regulators of Female Reproduction)
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Article
Efficacy of an Anti-Cellulite Herbal Emgel: A Randomized Clinical Trial
Pharmaceuticals 2021, 14(7), 683; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14070683 - 16 Jul 2021
Viewed by 598
Abstract
Cellulite describes unsightly skin overlying subcutaneous fat around thighs and buttocks of post-pubescent females. A herbal ‘emgel’ containing volatile oils and extracts of A traditional Thai herbal compress was tested in a double-blind, placebo-controlled trial with 18 women aged 20–50 year with severe [...] Read more.
Cellulite describes unsightly skin overlying subcutaneous fat around thighs and buttocks of post-pubescent females. A herbal ‘emgel’ containing volatile oils and extracts of A traditional Thai herbal compress was tested in a double-blind, placebo-controlled trial with 18 women aged 20–50 year with severe cellulite. Appearance of cellulite (primary outcome), thigh circumferences, skin firmness, and cutaneous blood flow (secondary outcomes) were assessed at baseline, 2, 4, 8 and 12 weeks with a 2-week follow-up. Herbal emgel applied onto the thigh skin twice daily reduced cellulite severity scores in every time point. The score was reduced from 13.4 ± 0.3 (baseline) to 12.1 ± 0.3 (week 2) and 9.9 ± 0.6 (week 12). All secondary outcomes improved with both placebo and herbal emgels suggesting that ingredients in the base-formulation might be responsible. Querying of participants, analysis of their diaries, and physical monthly inspections found no adverse events. The herbal emgel safely improved the appearance of cellulite, while the base emgel may play a role for other endpoints. Further studies on the active constituents and their mechanism of action are needed to further explore these factors. Full article
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Article
Advantages of Tyrosine Kinase Anti-Angiogenic Cediranib over Bevacizumab: Cell Cycle Abrogation and Synergy with Chemotherapy
Pharmaceuticals 2021, 14(7), 682; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14070682 - 16 Jul 2021
Viewed by 412
Abstract
Angiogenesis plays a crucial role in tumor development and metastasis. Both bevacizumab and cediranib have demonstrated activity as single anti-angiogenic agents in endometrial cancer, though subsequent studies of bevacizumab combined with chemotherapy failed to improve outcomes compared to chemotherapy alone. Our objective was [...] Read more.
Angiogenesis plays a crucial role in tumor development and metastasis. Both bevacizumab and cediranib have demonstrated activity as single anti-angiogenic agents in endometrial cancer, though subsequent studies of bevacizumab combined with chemotherapy failed to improve outcomes compared to chemotherapy alone. Our objective was to compare the efficacy of cediranib and bevacizumab in endometrial cancer models. The cellular effects of bevacizumab and cediranib were examined in endometrial cancer cell lines using extracellular signal-related kinase (ERK) phosphorylation, ligand shedding, cell viability, and cell cycle progression as readouts. Cellular viability was also tested in eight patient-derived organoid models of endometrial cancer. Finally, we performed a phosphoproteomic array of 875 phosphoproteins to define the signaling changes related to bevacizumab versus cediranib. Cediranib but not bevacizumab blocked ligand-mediated ERK activation in endometrial cancer cells. In both cell lines and patient-derived organoids, neither bevacizumab nor cediranib alone had a notable effect on cell viability. Cediranib but not bevacizumab promoted marked cell death when combined with chemotherapy. Cell cycle analysis demonstrated an accumulation in mitosis after treatment with cediranib + chemotherapy, consistent with the abrogation of the G2/M checkpoint and subsequent mitotic catastrophe. Molecular analysis of key controllers of the G2/M cell cycle checkpoint confirmed its abrogation. Phosphoproteomic analysis revealed that bevacizumab and cediranib had both similar and unique effects on cell signaling that underlie their shared versus individual actions as anti-angiogenic agents. An anti-angiogenic tyrosine kinase inhibitor such as cediranib has the potential to be superior to bevacizumab in combination with chemotherapy. Full article
(This article belongs to the Special Issue TP53 Tumor Suppressor in Gynecologic Cancers)
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Article
Comprehensive Analysis of Chemotherapeutic Agents That Induce Infectious Neutropenia
Pharmaceuticals 2021, 14(7), 681; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14070681 - 15 Jul 2021
Viewed by 332
Abstract
Chemotherapy-induced neutropenia (CIN) has been associated with a risk of infections and chemotherapy dose reductions and delays. The chemotherapy regimen remains one of the primary determinants of the risk of neutropenia, with some regimens being more myelotoxic than others. Although a number of [...] Read more.
Chemotherapy-induced neutropenia (CIN) has been associated with a risk of infections and chemotherapy dose reductions and delays. The chemotherapy regimen remains one of the primary determinants of the risk of neutropenia, with some regimens being more myelotoxic than others. Although a number of clinical trials have currently highlighted the risk of CIN with each chemotherapy regimen, only a few ones have comprehensively examined the risk associated with all chemotherapeutic agents. Therefore, this study aimed to investigate the risk factors and characteristics of CIN caused by each neoplastic agent using data from the large voluntary reporting Food and Drug Administration Adverse Event Reporting System database. Initially, univariate analysis showed that an age ≥ 65 years, the female sex, and treatment with chemotherapeutic agents were factors that caused CIN. Then, cluster and component analyses showed that cytotoxic agents (i.e., alkylating agents, antimetabolic agents, antineoplastic antibiotics, platinating agents, and plant-derived alkaloids) were associated with infection following neutropenia. This comprehensive analysis comparing CIN risk suggests that elderly or underweight patients treated with cytotoxic drugs require particularly careful monitoring. Full article
(This article belongs to the Special Issue Anti-cancer Drugs Induced Toxicity and Interventions 2021)
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Review
Current Status of Baricitinib as a Repurposed Therapy for COVID-19
Pharmaceuticals 2021, 14(7), 680; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14070680 - 15 Jul 2021
Viewed by 570
Abstract
The emergence of the COVID-19 pandemic has mandated the instant (re)search for potential drug candidates. In response to the unprecedented situation, it was recognized early that repurposing of available drugs in the market could timely save lives, by skipping the lengthy phases of [...] Read more.
The emergence of the COVID-19 pandemic has mandated the instant (re)search for potential drug candidates. In response to the unprecedented situation, it was recognized early that repurposing of available drugs in the market could timely save lives, by skipping the lengthy phases of preclinical and initial safety studies. BenevolentAI’s large knowledge graph repository of structured medical information suggested baricitinib, a Janus-associated kinase inhibitor, as a potential repurposed medicine with a dual mechanism; hindering SARS-CoV2 entry and combatting the cytokine storm; the leading cause of mortality in COVID-19. However, the recently-published Adaptive COVID-19 Treatment Trial-2 (ACTT-2) positioned baricitinib only in combination with remdesivir for treatment of a specific category of COVID-19 patients, whereas the drug is not recommended to be used alone except in clinical trials. The increased pace of data output in all life sciences fields has changed our understanding of data processing and manipulation. For the purpose of drug design, development, or repurposing, the integration of different disciplines of life sciences is highly recommended to achieve the ultimate benefit of using new technologies to mine BIG data, however, the final say remains to be concluded after the drug is used in clinical practice. This review demonstrates different bioinformatics, chemical, pharmacological, and clinical aspects of baricitinib to highlight the repurposing journey of the drug and evaluates its placement in the current guidelines for COVID-19 treatment. Full article
(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)
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Article
Suppression of Intracellular Reactive Oxygen Species in Human Corneal Epithelial Cells via the Combination of Quercetin Nanoparticles and Epigallocatechin Gallate and In Situ Thermosensitive Gel Formulation for Ocular Drug Delivery
Pharmaceuticals 2021, 14(7), 679; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14070679 - 15 Jul 2021
Viewed by 445
Abstract
Oxidative stress can cause several severe ophthalmological diseases. In this study, we developed a thermosensitive gel as a delivery system for two antioxidant substances, namely, quercetin and epigallocatechin gallate. The quercetin was loaded in the PLGA nanoparticles using a solvent displacement method. The [...] Read more.
Oxidative stress can cause several severe ophthalmological diseases. In this study, we developed a thermosensitive gel as a delivery system for two antioxidant substances, namely, quercetin and epigallocatechin gallate. The quercetin was loaded in the PLGA nanoparticles using a solvent displacement method. The physical and chemical stability of the quercetin nanoparticles were evaluated, and the degradation kinetics of the quercetin in the nanoparticles was investigated. The in vitro antioxidant and intracellular reactive oxygen species inhibition of the quercetin nanoparticles, combined with the epigallocatechin gallate (EGCG), were determined using a 2,2-diphenyl-1-picrylhydrazyl radical scavenging assay and a 2,7-dichlorodihydrofluorescein fluorescent probes, respectively. The thermosensitive gel loaded with the quercetin nanoparticles and EGCG was formulated. We confirmed that quercetin nanoparticles displayed the desired physical characteristics, release kinetics, and stability. The combination of quercetin nanoparticles and EGCG suggested the additive effect of antioxidant activity. We also demonstrated the superior intracellular ROS inhibition activity of the quercetin nanoparticles and EGCG with n-acetyl cysteine. The thermosensitive gel showed an appropriate gelation temperature and time for ocular drug delivery. Our results provide promising prospects for applying the thermosensitive gel loaded with quercetin nanoparticles and EGCG as an efficient drug delivery system for antioxidant activity in human corneal epithelial cells. Full article
(This article belongs to the Section Pharmaceutical Technology)
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Article
Risk of Hospitalization for Adverse Drug Events in Women and Men: A Post Hoc Analysis of an Active Pharmacovigilance Study in Italian Emergency Departments
Pharmaceuticals 2021, 14(7), 678; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14070678 - 15 Jul 2021
Viewed by 453
Abstract
This post hoc analysis of an Italian active pharmacovigilance study describes pharmacological differences of ADEs leading to emergency department (ED) visits and hospitalization in women and men. During the study period (January 2007–December 2018), 61,855 reports of ADEs leading to ED visits were [...] Read more.
This post hoc analysis of an Italian active pharmacovigilance study describes pharmacological differences of ADEs leading to emergency department (ED) visits and hospitalization in women and men. During the study period (January 2007–December 2018), 61,855 reports of ADEs leading to ED visits were collected. Overall, 30.6% of ADEs resulted in hospitalization (30% in women and 31% in men). Multivariate logistic regression showed that, among women, drug classes significantly associated with an increased risk of hospitalization were heparins (ROR 1.41, CI 1.13–176), antidepressants (ROR 1.12, CI 1.03–1.23) and antidiabetics (ROR 1.13, CI 1.02–1.24). Among men, only vitamin K antagonists (ROR 1.28, CI 1.09–1.50), opioids (ROR 1.30, CI 1.06–1.60) and digitalis glycosides (ROR 1.32, CI 1.09–1.59) were associated with a higher risk of hospitalization. Overall, older age, multiple suspected drugs and the presence of comorbidities were significantly associated with a higher risk of hospitalization. A significantly reduced risk of hospitalization was observed in both women and men experiencing an adverse event following immunization (ROR 0.36, CI 0.27–0.48 and 0.83, 0.42–0.74, respectively) compared to drugs. Results obtained from this real-world analysis highlight important aspects of drug safety between sexes. Full article
(This article belongs to the Special Issue Adverse Drug Reactions and Gender Differences)
Review
Hacking Pancreatic Cancer: Present and Future of Personalized Medicine
Pharmaceuticals 2021, 14(7), 677; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14070677 - 15 Jul 2021
Viewed by 469
Abstract
Pancreatic cancer (PC) is a recalcitrant disease characterized by high incidence and poor prognosis. The extremely complex genomic landscape of PC has a deep influence on cultivating a tumor microenvironment, resulting in the promotion of tumor growth, drug resistance, and immune escape mechanisms. [...] Read more.
Pancreatic cancer (PC) is a recalcitrant disease characterized by high incidence and poor prognosis. The extremely complex genomic landscape of PC has a deep influence on cultivating a tumor microenvironment, resulting in the promotion of tumor growth, drug resistance, and immune escape mechanisms. Despite outstanding progress in personalized medicine achieved for many types of cancer, chemotherapy still represents the mainstay of treatment for PC. Olaparib was the first agent to demonstrate a significant benefit in a biomarker-selected population, opening the doors for a personalized approach. Despite the failure of a large number of studies testing targeted agents or immunotherapy to demonstrate benefits over standard chemotherapy regimens, some interesting agents, alone or in combination with other drugs, have achieved promising results. A wide spectrum of therapeutic strategies, including immune-checkpoint inhibitors tyrosine kinase inhibitors and agents targeting metabolic pathways or the tumor microenvironment, is currently under investigation. In this review, we aim to provide a comprehensive overview of the current landscape and future directions of personalized medicine for patients affected by PC. Full article
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Review
Phytomedicines Targeting Cancer Stem Cells: Therapeutic Opportunities and Prospects for Pharmaceutical Development
Pharmaceuticals 2021, 14(7), 676; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14070676 - 15 Jul 2021
Viewed by 647
Abstract
The presence of small subpopulations of cells within tumor cells are known as cancer stem cells (CSCs). These cells have been the reason for metastasis, resistance with chemotherapy or radiotherapy, and tumor relapse in several types of cancers. CSCs underwent to epithelial–mesenchymal transition [...] Read more.
The presence of small subpopulations of cells within tumor cells are known as cancer stem cells (CSCs). These cells have been the reason for metastasis, resistance with chemotherapy or radiotherapy, and tumor relapse in several types of cancers. CSCs underwent to epithelial–mesenchymal transition (EMT) and resulted in the development of aggressive tumors. CSCs have potential to modulate numerous signaling pathways including Wnt, Hh, and Notch, therefore increasing the stem-like characteristics of cancer cells. The raised expression of drug efflux pump and suppression of apoptosis has shown increased resistance with anti-cancer drugs. Among many agents which were shown to modulate these, the plant-derived bioactive agents appear to modulate these key regulators and were shown to remove CSCs. This review aims to comprehensively scrutinize the preclinical and clinical studies demonstrating the effects of phytocompounds on CSCs isolated from various tumors. Based on the available convincing literature from preclinical studies, with some clinical data, it is apparent that selective targeting of CSCs with plants, plant preparations, and plant-derived bioactive compounds, termed phytochemicals, may be a promising strategy for the treatment of relapsed cancers. Full article
(This article belongs to the Topic Compounds with Medicinal Value)
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Article
An Adenovirus Vector Expressing FMDV RNA Polymerase Combined with a Chimeric VLP Harboring a Neutralizing Epitope as a Prime Boost Strategy to Induce FMDV-Specific Humoral and Cellular Responses
Pharmaceuticals 2021, 14(7), 675; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14070675 - 15 Jul 2021
Viewed by 500
Abstract
Foot and mouth disease is a highly contagious disease affecting cattle, sheep, and swine among other cloven-hoofed animals that imposes serious economic burden by its direct effects on farm productivity as well as on commerce of farmed produce. Vaccination using inactivated viral strains [...] Read more.
Foot and mouth disease is a highly contagious disease affecting cattle, sheep, and swine among other cloven-hoofed animals that imposes serious economic burden by its direct effects on farm productivity as well as on commerce of farmed produce. Vaccination using inactivated viral strains of the different serotypes is an effective protective measure, but has several drawbacks including a lack of cross protection and the perils associated with the large-scale growth of infectious virus. We have previously developed chimeric virus-like particles (VLPs) bearing an FMDV epitope which induced strong specific humoral responses in vaccinated pigs but conferred only partial protection against homologous challenge. While this and other FMD vaccines under development mostly rely on the induction of neutralizing responses, it is thought that induction of specific T-cell responses might improve both cross protective efficacy as well as duration of immunity. Therefore, we here describe the development of a recombinant adenovirus expressing the highly conserved nonstructural FMDV 3D protein as well as its capacity to induce specific T-cell responses in a murine model. We further describe the generation of an FMDV serotype C-specific chimeric VLP and analyze the immunogenicity of two different prime-boost strategies combining both elements in mice. This combination can effectively induce both humoral and cellular FMDV-specific responses eliciting high titers of ELISA and neutralizing antibodies anti-FMDV as well as a high frequency of IFNγ-secreting cells. These results provide the basis for further testing of this anti FMD vaccination strategy in cattle or pig, two of the most relevant natural host of this pathogen. Full article
(This article belongs to the Special Issue Current Trends in RNA Virus Vaccines)
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Review
Impact of Endocytosis Mechanisms for the Receptors Targeted by the Currently Approved Antibody-Drug Conjugates (ADCs)—A Necessity for Future ADC Research and Development
Pharmaceuticals 2021, 14(7), 674; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14070674 - 15 Jul 2021
Viewed by 543
Abstract
Biologically-based therapies increasingly rely on the endocytic cycle of internalization and exocytosis of target receptors for cancer therapies. However, receptor trafficking pathways (endosomal sorting (recycling, lysosome localization) and lateral membrane movement) are often dysfunctional in cancer. Antibody-drug conjugates (ADCs) have revitalized the concept [...] Read more.
Biologically-based therapies increasingly rely on the endocytic cycle of internalization and exocytosis of target receptors for cancer therapies. However, receptor trafficking pathways (endosomal sorting (recycling, lysosome localization) and lateral membrane movement) are often dysfunctional in cancer. Antibody-drug conjugates (ADCs) have revitalized the concept of targeted chemotherapy by coupling inhibitory antibodies to cytotoxic payloads. Significant advances in ADC technology and format, and target biology have hastened the FDA approval of nine ADCs (four since 2019). Although the links between aberrant endocytic machinery and cancer are emerging, the impact of dysregulated internalization processes of ADC targets and response rates or resistance have not been well studied. This is despite the reliance on ADC uptake and trafficking to lysosomes for linker cleavage and payload release. In this review, we describe what is known about all the target antigens for the currently approved ADCs. Specifically, internalization efficiency and relevant intracellular sorting activities are described for each receptor under normal processes, and when complexed to an ADC. In addition, we discuss aberrant endocytic processes that have been directly linked to preclinical ADC resistance mechanisms. The implications of endocytosis in regard to therapeutic effectiveness in the clinic are also described. Unexpectedly, information on endocytosis is scarce (absent for two receptors). Moreover, much of what is known about endocytosis is not in the context of receptor-ADC/antibody complexes. This review provides a deeper understanding of the pertinent principles of receptor endocytosis for the currently approved ADCs. Full article
(This article belongs to the Special Issue Recent Insights of Antibody-Drug Conjugate Effectiveness)
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Use of Monoclonal Antibody to Treat COVID-19 in Children and Adolescents: Risk of Abuse of Prescription and Exacerbation of Health Inequalities
Pharmaceuticals 2021, 14(7), 673; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14070673 - 15 Jul 2021
Viewed by 522
Abstract
Monoclonal antibodies (mAbs) that neutralize SARS-CoV-2 in infected patients are a new class of antiviral agents approved as a type of passive immunotherapy. They should be administered to adults and children (≥12 years old, weighing ≥ 40 kg) with SARS-CoV-2 positivity, and who [...] Read more.
Monoclonal antibodies (mAbs) that neutralize SARS-CoV-2 in infected patients are a new class of antiviral agents approved as a type of passive immunotherapy. They should be administered to adults and children (≥12 years old, weighing ≥ 40 kg) with SARS-CoV-2 positivity, and who are suffering from a chronic underlying disease and are at risk of severe COVID-19 and/or hospitalization. The aim of this manuscript is to discuss the benefit-to-risk of mAb therapy to treat COVID-19 in pediatric age, according to current reports. A problem is that the authorization for mAbs use in children was given without studies previously evaluating the efficacy, safety and tolerability of mAbs in pediatric patients. Moreover, although the total number of children with chronic severe underlying disease is not marginal, the risk of severe COVID-19 in pediatric age is significantly reduced than in adults and the role of chronic underlying disease as a risk factor of severe COVID-19 development in pediatric patients is far from being precisely defined. In addition, criteria presently suggested for use of mAbs in children and adolescents are very broad and may cause individual clinicians or institutions to recommend these agents on a case-by-case basis, with an abuse in mAbs prescriptions and an exacerbation of health inequalities while resources are scarce. Several questions need to be addressed before their routine use in clinical practice, including what is their associated benefit-to-risk ratio in children and adolescents, who are the patients that could really have benefit from their use, and if there is any interference of mAb therapy on recommended vaccines. While we wait for answers to these questions from well-conducted research, an effective and safe COVID-19 vaccine for vulnerable pediatric patients remains the best strategy to prevent COVID-19 and represents the priority for public health policies. Full article
(This article belongs to the Section Medicinal Chemistry)
Article
Site-Specific Antibody Conjugation to Engineered Double Cysteine Residues
Pharmaceuticals 2021, 14(7), 672; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14070672 - 14 Jul 2021
Viewed by 506
Abstract
Site-specific antibody conjugations generate homogeneous antibody-drug conjugates with high therapeutic index. However, there are limited examples for producing the site-specific conjugates with a drug-to-antibody ratio (DAR) greater than two, especially using engineered cysteines. Based on available Fc structures, we designed and introduced free [...] Read more.
Site-specific antibody conjugations generate homogeneous antibody-drug conjugates with high therapeutic index. However, there are limited examples for producing the site-specific conjugates with a drug-to-antibody ratio (DAR) greater than two, especially using engineered cysteines. Based on available Fc structures, we designed and introduced free cysteine residues into various antibody CH2 and CH3 regions to explore and expand this technology. The mutants were generated using site-directed mutagenesis with good yield and properties. Conjugation efficiency and selectivity were screened using PEGylation. The top single cysteine mutants were then selected and combined as double cysteine mutants for expression and further investigation. Thirty-six out of thirty-eight double cysteine mutants display comparable expression with low aggregation similar to the wild-type antibody. PEGylation screening identified seventeen double cysteine mutants with good conjugatability and high selectivity. PEGylation was demonstrated to be a valuable and efficient approach for quickly screening mutants for high selectivity as well as conjugation efficiency. Our work demonstrated the feasibility of generating antibody conjugates with a DAR greater than 3.4 and high site-selectivity using THIOMABTM method. The top single or double cysteine mutants identified can potentially be applied to site-specific antibody conjugation of cytotoxin or other therapeutic agents as a next generation conjugation strategy. Full article
(This article belongs to the Special Issue Evaluation of the Antitumor Mechanism of Armed Antibodies)
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