Pharmaceuticals

25 pages, 7419 KiB

Open AccessEditor’s ChoiceReview

Recent Advances in the Development of Tetrazine Ligation Tools for Pretargeted Nuclear Imaging

by Rocío García-Vázquez, Umberto Maria Battisti and Matthias M. Herth

Pharmaceuticals 2022, 15(6), 685; https://doi.org/10.3390/ph15060685 - 30 May 2022

Cited by 10 | Viewed by 5250

Tetrazine ligation has gained interest as a bio-orthogonal chemistry tool within the last decade. In nuclear medicine, tetrazine ligation is currently being explored for pretargeted approaches, which have the potential to revolutionize state-of-the-art theranostic strategies. Pretargeting has been shown to increase target-to-background ratios [...] Read more.

Tetrazine ligation has gained interest as a bio-orthogonal chemistry tool within the last decade. In nuclear medicine, tetrazine ligation is currently being explored for pretargeted approaches, which have the potential to revolutionize state-of-the-art theranostic strategies. Pretargeting has been shown to increase target-to-background ratios for radiopharmaceuticals based on nanomedicines, especially within early timeframes. This allows the use of radionuclides with short half-lives which are more suited for clinical applications. Pretargeting bears the potential to increase the therapeutic dose delivered to the target as well as reduce the respective dose to healthy tissue. Combined with the possibility to be applied for diagnostic imaging, pretargeting could be optimal for theranostic approaches. In this review, we highlight efforts that have been made to radiolabel tetrazines with an emphasis on imaging. Full article

(This article belongs to the Special Issue Click Reactions in Medicinal Chemistry)

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53 pages, 2656 KiB

Open AccessEditor’s ChoiceReview

Targeting Nuclear Receptors in Lung Cancer—Novel Therapeutic Prospects

by Shailendra Kumar Gangwar, Aviral Kumar, Kenneth Chun-Hong Yap, Sandra Jose, Dey Parama, Gautam Sethi, Alan Prem Kumar and Ajaikumar B. Kunnumakkara

Pharmaceuticals 2022, 15(5), 624; https://doi.org/10.3390/ph15050624 - 18 May 2022

Cited by 10 | Viewed by 4589

Abstract

Lung cancer, the second most commonly diagnosed cancer, is the major cause of fatalities worldwide for both men and women, with an estimated 2.2 million new incidences and 1.8 million deaths, according to GLOBOCAN 2020. Although various risk factors for lung cancer pathogenesis [...] Read more.

Lung cancer, the second most commonly diagnosed cancer, is the major cause of fatalities worldwide for both men and women, with an estimated 2.2 million new incidences and 1.8 million deaths, according to GLOBOCAN 2020. Although various risk factors for lung cancer pathogenesis have been reported, controlling smoking alone has a significant value as a preventive measure. In spite of decades of extensive research, mechanistic cues and targets need to be profoundly explored to develop potential diagnostics, treatments, and reliable therapies for this disease. Nuclear receptors (NRs) function as transcription factors that control diverse biological processes such as cell growth, differentiation, development, and metabolism. The aberrant expression of NRs has been involved in a variety of disorders, including cancer. Deregulation of distinct NRs in lung cancer has been associated with numerous events, including mutations, epigenetic modifications, and different signaling cascades. Substantial efforts have been made to develop several small molecules as agonists or antagonists directed to target specific NRs for inhibiting tumor cell growth, migration, and invasion and inducing apoptosis in lung cancer, which makes NRs promising candidates for reliable lung cancer therapeutics. The current work focuses on the importance of various NRs in the development and progression of lung cancer and highlights the different small molecules (e.g., agonist or antagonist) that influence NR expression, with the goal of establishing them as viable therapeutics to combat lung cancer. Full article

(This article belongs to the Special Issue Advances in Non-small Cell Lung Cancer Treatment - Current and Future)

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31 pages, 8247 KiB

Open AccessEditor’s ChoiceReview

Polysaccharide-Based Transdermal Drug Delivery

by Jingyuan Li, Hong Xiang, Qian Zhang and Xiaoqing Miao

Pharmaceuticals 2022, 15(5), 602; https://doi.org/10.3390/ph15050602 - 14 May 2022

Cited by 25 | Viewed by 5122

Abstract

Materials derived from natural plants and animals have great potential for transdermal drug delivery. Polysaccharides are widely derived from marine, herbal, and microbial sources. Compared with synthetic polymers, polysaccharides have the advantages of non-toxicity and biodegradability, ease of modification, biocompatibility, targeting, and antibacterial [...] Read more.

Materials derived from natural plants and animals have great potential for transdermal drug delivery. Polysaccharides are widely derived from marine, herbal, and microbial sources. Compared with synthetic polymers, polysaccharides have the advantages of non-toxicity and biodegradability, ease of modification, biocompatibility, targeting, and antibacterial properties. Currently, polysaccharide-based transdermal drug delivery vehicles, such as hydrogel, film, microneedle (MN), and tissue scaffolds are being developed. The addition of polysaccharides allows these vehicles to exhibit better-swelling properties, mechanical strength, tensile strength, etc. Due to the stratum corneum’s resistance, the transdermal drug delivery system cannot deliver drugs as efficiently as desired. The charge and hydration of polysaccharides allow them to react with the skin and promote drug penetration. In addition, polysaccharide-based nanotechnology enhances drug utilization efficiency. Various diseases are currently treated by polysaccharide-based transdermal drug delivery devices and exhibit promising futures. The most current knowledge on these excellent materials will be thoroughly discussed by reviewing polysaccharide-based transdermal drug delivery strategies. Full article

(This article belongs to the Special Issue Polysaccharide-Based Nanoparticles for Theranostic Nanomedicine)

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18 pages, 5064 KiB

Open AccessEditor’s ChoiceReview

Structural Modifications and Biological Activities of Natural α- and β-Cembrenediol: A Comprehensive Review

by Kuo Xu, Xinying Du, Xia Ren, XiuXue Li, Hui Li, Xianjun Fu and Xiaoyi Wei

Pharmaceuticals 2022, 15(5), 601; https://doi.org/10.3390/ph15050601 - 13 May 2022

Cited by 3 | Viewed by 3031

Abstract

As one of the most characteristic ingredients of glandular trichome secretions from Nicotiana tabacum L. (tobacco), natural cembrenediols, namely, (1S,2E,4S,6R,7E,11E)-2,7,11-cembratriene-4,6-diol (α-cembrenediol/α-CBD) and its C-4 epimer (β-cembrenediol/β-CBD), have attracted considerable attention for [...] Read more.

As one of the most characteristic ingredients of glandular trichome secretions from Nicotiana tabacum L. (tobacco), natural cembrenediols, namely, (1S,2E,4S,6R,7E,11E)-2,7,11-cembratriene-4,6-diol (α-cembrenediol/α-CBD) and its C-4 epimer (β-cembrenediol/β-CBD), have attracted considerable attention for their potent antitumor, neuroprotective, antimicrobial, and other activities. Many researchers are committed to exploring the possibility of utilizing these two cembrenediols and their derivatives both in human medicine and in agricultural fungicides. To the best of our knowledge, this review is the first to provide a comprehensive summary of the chemical modifications and bioactivities of α- and β-CBD from their discovery to the present day; the review highlights their potential medicinal value for humans. The extensive references from 1962 to 2022 provided herein were systematically gathered from the SciFinder, Web of Science, and Google Scholar databases. We expect this review to assist in providing practical ideas for future drug development based on α- and β-CBD and in further facilitating the utilization of the tobacco cembrenediols. Full article

(This article belongs to the Special Issue Secondary Metabolites of Plants and its Synthetic Derivatives in Cellular and Molecular Pharmacology)

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21 pages, 2475 KiB

Open AccessEditor’s ChoiceReview

Biotechnological Evolution of siRNA Molecules: From Bench Tool to the Refined Drug

by Danielle de Brito e Cunha, Ana Beatriz Teixeira Frederico, Tamiris Azamor, Juliana Gil Melgaço, Patricia Cristina da Costa Neves, Ana Paula Dinis Ano Bom, Tatiana Martins Tilli and Sotiris Missailidis

Pharmaceuticals 2022, 15(5), 575; https://doi.org/10.3390/ph15050575 - 05 May 2022

Cited by 14 | Viewed by 6294

Abstract

The depth and versatility of siRNA technologies enable their use in disease targets that are undruggable by small molecules or that seek to achieve a refined turn-off of the genes for any therapeutic area. Major extracellular barriers are enzymatic degradation of siRNAs by [...] Read more.

The depth and versatility of siRNA technologies enable their use in disease targets that are undruggable by small molecules or that seek to achieve a refined turn-off of the genes for any therapeutic area. Major extracellular barriers are enzymatic degradation of siRNAs by serum endonucleases and RNAases, renal clearance of the siRNA delivery system, the impermeability of biological membranes for siRNA, activation of the immune system, plasma protein sequestration, and capillary endothelium crossing. To overcome the intrinsic difficulties of the use of siRNA molecules, therapeutic applications require nanometric delivery carriers aiming to protect double-strands and deliver molecules to target cells. This review discusses the history of siRNAs, siRNA design, and delivery strategies, with a focus on progress made regarding siRNA molecules in clinical trials and how siRNA has become a valuable asset for biopharmaceutical companies. Full article

(This article belongs to the Special Issue siRNA Therapeutics: From Bench Lab to Clinics)

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19 pages, 4334 KiB

Open AccessEditor’s ChoiceArticle

New Quinoline–Urea–Benzothiazole Hybrids as Promising Antitubercular Agents: Synthesis, In Vitro Antitubercular Activity, Cytotoxicity Studies, and In Silico ADME Profiling

by Rashmika Moodley, Chakes Mashaba, Goitsemodimo H. Rakodi, Nomagugu B. Ncube, Mabuatsela V. Maphoru, Mohammed O. Balogun, Audrey Jordan, Digby F. Warner, Rene Khan and Matshawandile Tukulula

Pharmaceuticals 2022, 15(5), 576; https://doi.org/10.3390/ph15050576 - 05 May 2022

Cited by 14 | Viewed by 2739

Abstract

A series of 25 new benzothiazole–urea–quinoline hybrid compounds were synthesized successfully via a three-step synthetic sequence involving an amidation coupling reaction as a critical step. The structures of the synthesized compounds were confirmed by routine spectroscopic tools (¹H and ¹³C [...] Read more.

A series of 25 new benzothiazole–urea–quinoline hybrid compounds were synthesized successfully via a three-step synthetic sequence involving an amidation coupling reaction as a critical step. The structures of the synthesized compounds were confirmed by routine spectroscopic tools (¹H and ¹³C NMR and IR) and by mass spectrometry (HRMS). In vitro evaluation of these hybrid compounds for their antitubercular inhibitory activity against the Mycobacterium tuberculosis H₃₇Rv pMSp12::GPF bioreporter strain was undertaken. Of the 25 tested compounds, 17 exhibited promising anti-TB activities of less than 62.5 µM (MIC₉₀). Specifically, 13 compounds (6b, 6g, 6i–j, 6l, 6o–p, 6r–t, and 6x–y) showed promising activity with MIC₉₀ values in the range of 1–10 µM, while compound 6u, being the most active, exhibited sub-micromolar activity (0.968 µM) in the CAS assay. In addition, minimal cytotoxicity against the HepG2 cell line (cell viability above 75%) in 11 of the 17 compounds, at their respective MIC₉₀ concentrations, was observed, with 6u exhibiting 100% cell viability. The hybridization of the quinoline, urea, and benzothiazole scaffolds demonstrated a synergistic relationship because the activities of resultant hybrids were vastly improved compared to the individual entities. In silico ADME predictions showed that the majority of these compounds have drug-like properties and are less likely to potentially cause cardiotoxicity (QPlogHERG > −5). The results obtained in this study indicate that the majority of the synthesized compounds could serve as valuable starting points for future optimizations as new antimycobacterial agents. Full article

(This article belongs to the Special Issue Heterocyclic Compounds and Their Application in Therapy)

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36 pages, 9565 KiB

Open AccessEditor’s ChoiceReview

Radiotracers for the Central Serotoninergic System

by Reynald Mangeant, Emmanuelle Dubost, Thomas Cailly and Valérie Collot

Pharmaceuticals 2022, 15(5), 571; https://doi.org/10.3390/ph15050571 - 03 May 2022

Cited by 1 | Viewed by 2829

Abstract

This review lists the most important radiotracers described so far for imaging the central serotoninergic system. Single-photon emission computed tomography and positron emission tomography radiotracers are reviewed and critically discussed for each receptor. Full article

(This article belongs to the Special Issue Alliance of PET/SPECT Imaging and Drug Design/Discovery for the Development of Novel Diagnostic or Therapeutic Tools)

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22 pages, 2342 KiB

Open AccessEditor’s ChoiceArticle

A Quantitative LC–MS/MS Method for the Detection of 16 Synthetic Cathinones and 10 Metabolites and Its Application to Suspicious Clinical and Forensic Urine Samples

by Abdulaziz A. Aldubayyan, Erika Castrignanò, Simon Elliott and Vincenzo Abbate

Pharmaceuticals 2022, 15(5), 510; https://doi.org/10.3390/ph15050510 - 22 Apr 2022

Cited by 6 | Viewed by 3787

Abstract

Background: Synthetic cathinones currently represent one of the most predominant (sub)-classes of new psychoactive substance (NPS) in illicit drug markets. Despite the increased concerns caused by the constant introduction of new analogues, these drugs are not commonly assayed in routine drug testing procedures [...] Read more.

Background: Synthetic cathinones currently represent one of the most predominant (sub)-classes of new psychoactive substance (NPS) in illicit drug markets. Despite the increased concerns caused by the constant introduction of new analogues, these drugs are not commonly assayed in routine drug testing procedures and may not be detected in standard screening procedures. This study presents a validated liquid chromatography–tandem mass spectrometry (LC–MS/MS) method for the detection and quantification of 16 synthetic cathinones and 10 metabolites in human urine. Methods: The method was validated for all analytes using published guidelines. The evaluated parameters achieved acceptable values according to the set criteria. Potential abuse of synthetic cathinones was investigated in suspicious urine samples from Saudi Arabia originating from workplace drug testing, pre-employment and Accident & Emergency (A&E). Such samples generated a presumptive positive immunoassay for amphetamine; however, they yielded a negative LC–MS/MS confirmation for this analyte, following the recommended cutoff values of Substance of Abuse and Mental Health Services Administration (SAMHSA) guidelines. Results: 5.8% of the analyzed samples were found to contain at least one target analyte, namely mephedrone and N-ethylpentylone, as well as their dihydro-metabolites. The results also revealed polydrug use with the synthetic cathinones being present together with other classical stimulant drugs. Conclusions: This is the first report of NPS use in Saudi Arabia with respect to designer stimulant drugs. Confirmatory urine analyses for suspicious stimulant use should extend beyond classical stimulants to cover a broad range of NPSs and their metabolites in order to report any otherwise potentially undetected/new analyte. Full article

(This article belongs to the Special Issue Clinical and Forensic Toxicology: The Latest Updates)

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33 pages, 1609 KiB

Open AccessEditor’s ChoiceReview

Physiological Effects and Human Health Benefits of Hibiscus sabdariffa: A Review of Clinical Trials

by Efigenia Montalvo-González, Zuamí Villagrán, Sughey González-Torres, Laura Elena Iñiguez-Muñoz, Mario Alberto Isiordia-Espinoza, José Martín Ruvalcaba-Gómez, Ramón Ignacio Arteaga-Garibay, José Luis Acosta, Napoleón González-Silva and Luis Miguel Anaya-Esparza

Pharmaceuticals 2022, 15(4), 464; https://doi.org/10.3390/ph15040464 - 12 Apr 2022

Cited by 15 | Viewed by 8882

Abstract

Hibiscus sabdariffa Linn. Malvaceae (HS) is characterized by its edible calyxes. The HS calyxes are widely used for cosmetic, food, and medicinal applications. According to ethnobotanical evidence, decoction, infusion, or maceration extracts from HS calyxes have been used in folk medicine to treat [...] Read more.

Hibiscus sabdariffa Linn. Malvaceae (HS) is characterized by its edible calyxes. The HS calyxes are widely used for cosmetic, food, and medicinal applications. According to ethnobotanical evidence, decoction, infusion, or maceration extracts from HS calyxes have been used in folk medicine to treat many ailments. Moreover, several in vitro and in vivo studies have demonstrated the pharmacological properties and potential human health benefits of HS consumption. On the other hand, the evaluation of the physiological effects and health benefits of HS in clinical studies is most challenging. Therefore, this narrative review summarizes and discusses the physiological effects and health benefits of HS calyxes reported in clinical trials. Preparations obtained from HS calyxes (extracts, infusions, decoction, teas, beverages, capsules, and pills) are used as non-pharmacological therapies to prevent/control diverse chronic non-communicable diseases. The most-reported HS health benefits are its antihypertensive, antidyslipidemic, hypoglycemic, body fat mass reduction, nephroprotective, antianemic, antioxidant, anti-inflammatory, and anti-xerostomic activities; these effects are associated with the phytochemicals found in HS. Moreover, no adverse effects were reported during the clinical trials. However, clinical studies exhibited some limitations; thus, further studies are required to validate the clinical efficacy of HS in large-scale studies with higher doses and a good experimental design Full article

(This article belongs to the Special Issue Bioactive Compounds from Plants and Foods with Pharmaceutical Interest 2022)

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18 pages, 6678 KiB

Open AccessEditor’s ChoiceArticle

Cilia Stimulatory and Antibacterial Activities of T2R Bitter Taste Receptor Agonist Diphenhydramine: Insights into Repurposing Bitter Drugs for Nasal Infections

by Li Eon Kuek, Derek B. McMahon, Ray Z. Ma, Zoey A. Miller, Jennifer F. Jolivert, Nithin D. Adappa, James N. Palmer and Robert J. Lee

Pharmaceuticals 2022, 15(4), 452; https://doi.org/10.3390/ph15040452 - 06 Apr 2022

Cited by 7 | Viewed by 2549

Abstract

T2R bitter taste receptors in airway motile cilia increase ciliary beat frequency (CBF) and nitric oxide (NO) production. Polymorphisms in some T2Rs are linked to disease outcomes in chronic rhinosinusitis (CRS) and cystic fibrosis (CF). We examined the expression of cilia T2Rs during [...] Read more.

T2R bitter taste receptors in airway motile cilia increase ciliary beat frequency (CBF) and nitric oxide (NO) production. Polymorphisms in some T2Rs are linked to disease outcomes in chronic rhinosinusitis (CRS) and cystic fibrosis (CF). We examined the expression of cilia T2Rs during the differentiation of human nasal epithelial cells grown at air–liquid interface (ALI). The T2R expression increased with differentiation but did not vary between CF and non-CF cultures. Treatment with Pseudomonas aeruginosa flagellin decreased the expression of diphenhydramine-responsive T2R14 and 40, among others. Diphenhydramine increased both NO production, measured by fluorescent dye DAF-FM, and CBF, measured via high-speed imaging. Increases in CBF were disrupted after flagellin treatment. Diphenhydramine impaired the growth of lab and clinical strains of P. aeruginosa, a major pathogen in CF and CF-related CRS. Diphenhydramine impaired biofilm formation of P. aeruginosa, measured via crystal violet staining, as well as the surface attachment of P. aeruginosa to CF airway epithelial cells, measured using colony-forming unit counting. Because the T2R agonist diphenhydramine increases NO production and CBF while also decreasing bacterial growth and biofilm production, diphenhydramine-derived compounds may have potential clinical usefulness in CF-related CRS as a topical therapy. However, utilizing T2R agonists as therapeutics within the context of P. aeruginosa infection may require co-treatment with anti-inflammatories to enhance T2R expression. Full article

(This article belongs to the Section Pharmacology)

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35 pages, 6667 KiB

Open AccessEditor’s ChoiceReview

The Development of Positron Emission Tomography Tracers for In Vivo Targeting the Kinase Domain of the Epidermal Growth Factor Receptor

by Antonia Högnäsbacka, Alex J. Poot, Danielle J. Vugts, Guus A. M. S. van Dongen and Albert D. Windhorst

Pharmaceuticals 2022, 15(4), 450; https://doi.org/10.3390/ph15040450 - 05 Apr 2022

Cited by 7 | Viewed by 2472

Abstract

Multiple small molecule PET tracers have been developed for the imaging of the epidermal growth factor receptor (EGFR). These tracers target the tyrosine kinase (TK) domain of the receptor and have been used for both quantifying EGFR expression and to differentiate between EGFR [...] Read more.

Multiple small molecule PET tracers have been developed for the imaging of the epidermal growth factor receptor (EGFR). These tracers target the tyrosine kinase (TK) domain of the receptor and have been used for both quantifying EGFR expression and to differentiate between EGFR mutational statuses. However, the approaches for in vivo evaluation of these tracers are diverse and have resulted in data that are hard to compare. In this review, we analyze the historical development of the in vivo evaluation approaches, starting from the first EGFR TK PET tracer [¹¹C]PD153035 to tracers developed based on TK inhibitors used for the clinical treatment of mutated EGFR expressing non-small cell lung cancer like [¹¹C]erlotinib and [¹⁸F]afatinib. The evaluation of each tracer has been compiled to allow for a comparison between studies and ultimately between tracers. The main challenges for each group of tracers are thereafter discussed. Finally, this review addresses the challenges that need to be overcome to be able to efficiently drive EGFR PET imaging forward. Full article

(This article belongs to the Special Issue Targets, Tracers and Translation, Part 2 - New Horizons in Radiopharmaceutical Development)

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31 pages, 5217 KiB

Open AccessEditor’s ChoiceReview

Theranostic Nanomedicines for the Treatment of Cardiovascular and Related Diseases: Current Strategies and Future Perspectives

by Natasha Manners, Vishnu Priya, Abhishesh Kumar Mehata, Manoj Rawat, Syam Mohan, Hafiz A. Makeen, Mohammed Albratty, Ali Albarrati, Abdulkarim M. Meraya and Madaswamy S. Muthu

Pharmaceuticals 2022, 15(4), 441; https://doi.org/10.3390/ph15040441 - 01 Apr 2022

Cited by 13 | Viewed by 3825

Abstract

Cardiovascular and related diseases (CVRDs) are among the most prevalent chronic diseases in the 21st century, with a high mortality rate. This review summarizes the various nanomedicines for diagnostic and therapeutic applications in CVRDs, including nanomedicine for angina pectoris, myocarditis, myocardial infarction, pericardial [...] Read more.

Cardiovascular and related diseases (CVRDs) are among the most prevalent chronic diseases in the 21st century, with a high mortality rate. This review summarizes the various nanomedicines for diagnostic and therapeutic applications in CVRDs, including nanomedicine for angina pectoris, myocarditis, myocardial infarction, pericardial disorder, thrombosis, atherosclerosis, hyperlipidemia, hypertension, pulmonary arterial hypertension and stroke. Theranostic nanomedicines can prolong systemic circulation, escape from the host defense system, and deliver theranostic agents to the targeted site for imaging and therapy at a cellular and molecular level. Presently, discrete non-invasive and non-surgical theranostic methodologies are such an advancement modality capable of targeted diagnosis and therapy and have better efficacy with fewer side effects than conventional medicine. Additionally, we have presented the recent updates on nanomedicine in clinical trials, targeted nanomedicine and its translational challenges for CVRDs. Theranostic nanomedicine acts as a bridge towards CVRDs amelioration and its management. Full article

(This article belongs to the Special Issue Nanoparticle-Mediated Drug Delivery, Imaging, and Control of Cellular Functions)

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27 pages, 5779 KiB

Open AccessEditor’s ChoiceReview

Dual-Labelling Strategies for Nuclear and Fluorescence Molecular Imaging: Current Status and Future Perspectives

by Manja Kubeil, Irma Ivette Santana Martínez, Michael Bachmann, Klaus Kopka, Kellie L. Tuck and Holger Stephan

Pharmaceuticals 2022, 15(4), 432; https://doi.org/10.3390/ph15040432 - 31 Mar 2022

Cited by 8 | Viewed by 3330

Abstract

Molecular imaging offers the possibility to investigate biological and biochemical processes non-invasively and to obtain information on both anatomy and dysfunctions. Based on the data obtained, a fundamental understanding of various disease processes can be derived and treatment strategies can be planned. In [...] Read more.

Molecular imaging offers the possibility to investigate biological and biochemical processes non-invasively and to obtain information on both anatomy and dysfunctions. Based on the data obtained, a fundamental understanding of various disease processes can be derived and treatment strategies can be planned. In this context, methods that combine several modalities in one probe are increasingly being used. Due to the comparably high sensitivity and provided complementary information, the combination of nuclear and optical probes has taken on a special significance. In this review article, dual-labelled systems for bimodal nuclear and optical imaging based on both modular ligands and nanomaterials are discussed. Particular attention is paid to radiometal-labelled molecules for single-photon emission computed tomography (SPECT) and positron emission tomography (PET) and metal complexes combined with fluorescent dyes for optical imaging. The clinical potential of such probes, especially for fluorescence-guided surgery, is assessed. Full article

(This article belongs to the Special Issue Hybrid Agents for Multimodal Imaging)

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21 pages, 3673 KiB

Open AccessEditor’s ChoiceArticle

5-Aryl-1,3,4-oxadiazol-2-amines Decorated with Long Alkyl and Their Analogues: Synthesis, Acetyl- and Butyrylcholinesterase Inhibition and Docking Study

by Václav Pflégr, Šárka Štěpánková, Katarína Svrčková, Markéta Švarcová, Jarmila Vinšová and Martin Krátký

Pharmaceuticals 2022, 15(4), 400; https://doi.org/10.3390/ph15040400 - 25 Mar 2022

Cited by 4 | Viewed by 2357

Abstract

2,5-Disubstituted 1,3,4-oxadiazoles are privileged versatile scaffolds in medicinal chemistry that have exhibited diverse biological activities. Acetyl- (AChE) and butyrylcholinesterase (BChE) inhibitors are used, e.g., to treat dementias and myasthenia gravis. 5-Aryl-1,3,4-oxadiazoles decorated with dodecyl linked via nitrogen, sulfur or directly to this heterocycle [...] Read more.

2,5-Disubstituted 1,3,4-oxadiazoles are privileged versatile scaffolds in medicinal chemistry that have exhibited diverse biological activities. Acetyl- (AChE) and butyrylcholinesterase (BChE) inhibitors are used, e.g., to treat dementias and myasthenia gravis. 5-Aryl-1,3,4-oxadiazoles decorated with dodecyl linked via nitrogen, sulfur or directly to this heterocycle have been designed as potential inhibitors of AChE and BChE. They were prepared from commercially available or in-house prepared hydrazides by reaction with dodecyl isocyanate to form hydrazine-1-carboxamides 2 (yields 67–98%) followed by cyclization using p-toluenesulfonyl chloride and triethylamine in 41–100% yields. Thiadiazole isostere was also synthesized. The derivatives were screened for inhibition of AChE and BChE using Ellman’s spectrophotometric method. The compounds showed a moderate dual inhibition with IC₅₀ values of 12.8–99.2 for AChE and from 53.1 µM for BChE. All the heterocycles were more efficient inhibitors of AChE. The most potent inhibitor, N-dodecyl-5-(pyridin-4-yl)-1,3,4-thiadiazol-2-amine 3t, was subjected to advanced reversibility and type of inhibition evaluation. Structure–activity relationships were identified. Many oxadiazoles showed lower IC₅₀ values against AChE than established drug rivastigmine. According to molecular docking, the compounds interact non-covalently with AChE and BChE and block entry into enzyme gorge and catalytic site, respectively. Full article

(This article belongs to the Section Medicinal Chemistry)

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22 pages, 8202 KiB

Open AccessEditor’s ChoiceReview

Targeted Drug Delivery to the Central Nervous System Using Extracellular Vesicles

by Lina Zhou, Sunitha Kodidela, Sandip Godse, Stacey Thomas-Gooch, Asit Kumar, Babatunde Raji, Kaining Zhi, Harry Kochat and Santosh Kumar

Pharmaceuticals 2022, 15(3), 358; https://doi.org/10.3390/ph15030358 - 15 Mar 2022

Cited by 17 | Viewed by 4320

Abstract

The blood brain barrier (BBB) maintains the homeostasis of the central nervous system (CNS) and protects the brain from toxic substances present in the circulating blood. However, the impermeability of the BBB to drugs is a hurdle for CNS drug development, which hinders [...] Read more.

The blood brain barrier (BBB) maintains the homeostasis of the central nervous system (CNS) and protects the brain from toxic substances present in the circulating blood. However, the impermeability of the BBB to drugs is a hurdle for CNS drug development, which hinders the distribution of the most therapeutic molecules into the brain. Therefore, scientists have been striving to develop safe and effective technologies to advance drug penetration into the CNS with higher targeting properties and lower off-targeting side effects. This review will discuss the limitation of artificial nanomedicine in CNS drug delivery and the use of natural extracellular vesicles (EVs), as therapeutic vehicles to achieve targeted delivery to the CNS. Information on clinical trials regarding CNS targeted drug delivery using EVs is very limited. Thus, this review will also briefly highlight the recent clinical studies on targeted drug delivery in the peripheral nervous system to shed light on potential strategies for CNS drug delivery. Different technologies engaged in pre- and post-isolation have been implemented to further utilize and optimize the natural property of EVs. EVs from various sources have also been applied in the engineering of EVs for CNS targeted drug delivery in vitro and in vivo. Here, the future feasibility of those studies in clinic will be discussed. Full article

(This article belongs to the Special Issue Targeted and Stimulus-Responsive Nanomedicines for the Treatment of Central Nervous System (CNS) Disorders)

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11 pages, 825 KiB

Open AccessEditor’s ChoiceArticle

Optimization of Precursor Preparation in PSMA-11 Radiolabeling to Obtain a Highly Reproducible Radiochemical Yield

by Antonella Iudicello, Stefano Boschi, Pietro Ghedini, Frank Lohr and Stefano Panareo

Pharmaceuticals 2022, 15(3), 343; https://doi.org/10.3390/ph15030343 - 11 Mar 2022

Cited by 2 | Viewed by 3106

Abstract

[⁶⁸Ga]Ga-PSMA-11 PET/CT plays a pivotal role in the diagnosis and staging of prostate cancer because of its higher sensitivity and detection rate compared with traditional choline PET/CT. A highly reproducible radiochemical yield of the radiopharmaceutical to be used in the clinical [...] Read more.

[⁶⁸Ga]Ga-PSMA-11 PET/CT plays a pivotal role in the diagnosis and staging of prostate cancer because of its higher sensitivity and detection rate compared with traditional choline PET/CT. A highly reproducible radiochemical yield of the radiopharmaceutical to be used in the clinical routine is an important parameter for planning and optimization of clinical activity. During radiometallation of PSMA-11, the presence of metal ion contaminants in the peptide precursor may cause a decrease in the [⁶⁸Ga]Ga-PSMA-11 radiochemical yield because of metal ion contaminants competition with gallium-68. To optimize the radiochemical yield of [⁶⁸Ga]Ga-PSMA-11 radiosynthesis, data obtained by preparing the solution of the PSMA-11 precursor with three different methods (A, B, and C) were compared. Methods A and B consisted of the reconstitution of different quantities of precursor (1000 µg and 30 µg, respectively) to obtain a 1 µg/mL solution. In Method A, the precursor solution was aliquoted and stored frozen, while the precursor solution obtained with Method B was entirely used. Method C consisted of the reconstitution of 1000 µg of precursor taking into account net peptide content as described in European Pharmacopoeia. Radiosynthesis data demonstrated that reconstitution methods B and C gave a consistently higher and reproducible radiochemical yield, highlighting the role of metals and precursor storage conditions on the synthesis performance. Full article

(This article belongs to the Section Radiopharmaceutical Sciences)

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8 pages, 567 KiB

Open AccessEditor’s ChoiceReview

Small Molecule Induced FLT3 Degradation

by Sun-Young Han

Pharmaceuticals 2022, 15(3), 320; https://doi.org/10.3390/ph15030320 - 08 Mar 2022

Cited by 3 | Viewed by 3130

Abstract

Target protein degrader is a new paradigm in the small molecule drug discovery field and relates to the term ‘event-driven pharmacology’. Fms-like tyrosine kinase 3 (FLT3) is a significant target for treating acute myeloid leukemia (AML). A few FLT3 kinase inhibitors are currently [...] Read more.

Target protein degrader is a new paradigm in the small molecule drug discovery field and relates to the term ‘event-driven pharmacology’. Fms-like tyrosine kinase 3 (FLT3) is a significant target for treating acute myeloid leukemia (AML). A few FLT3 kinase inhibitors are currently used in the clinic for AML patients. However, resistance to current FLT3 inhibitors has emerged, and strategies to overcome this resistance are required. Small molecules downregulating FLT3 protein level are reported, exhibiting antileukemic effects against AML cell lines. Small molecules with various mechanisms such as Hsp90 inhibition, proteasome inhibition, RET inhibition, and USP10 inhibition are explained. In addition, reports of FLT3 as a client of Hsp90, current knowledge of the ubiquitin proteasome system for FLT3 degradation, the relationship with FLT3 phosphorylation status and susceptibility of FLT3 degradation are discussed. Full article

(This article belongs to the Special Issue Protein Kinases and Cancer)

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19 pages, 8738 KiB

Open AccessEditor’s ChoiceArticle

In Silico and In Vitro Identification of Pan-Coronaviral Main Protease Inhibitors from a Large Natural Product Library

by Nasim Shahhamzehei, Sara Abdelfatah and Thomas Efferth

Pharmaceuticals 2022, 15(3), 308; https://doi.org/10.3390/ph15030308 - 03 Mar 2022

Cited by 24 | Viewed by 6301

Abstract

The main protease (M^pro or 3CL^pro) in coronaviruses represents a promising specific drug target as it is essential for the cleavage of the virus polypeptide and has a unique cleavage site that does not exist in human host proteases. In [...] Read more.

The main protease (M^pro or 3CL^pro) in coronaviruses represents a promising specific drug target as it is essential for the cleavage of the virus polypeptide and has a unique cleavage site that does not exist in human host proteases. In this study, we explored potential natural pan-coronavirus drugs using in vitro and in silico approaches and three coronavirus main proteases as treatment targets. The PyRx program was used to screen 39,442 natural-product-like compounds from the ZINC database and 121 preselected phytochemicals from medicinal plants with known antiviral activity. After assessment with Lipinski’s rule of five, molecular docking was performed for the top 33 compounds of both libraries. Enzymatic assays were applied for the top candidates from both in silico approaches to test their ability to inhibit SARS-CoV-2 M^pro. The four compounds (hypericin, rosmarinic acid, isorhamnetin, and luteolin) that most efficiently inhibited SARS-CoV-2 M^pro in vitro were further tested for their efficacy in inhibiting M^pro of SARS-CoV-1 and MERS-CoV. Microscale thermophoresis was performed to determine dissociation constant (Kd) values to validate the binding of these active compounds to recombinant M^pro proteins of SARS-CoV-2, SARS-CoV-1, and MERS-CoV. The cytotoxicity of hypericin, rosmarinic acid, isorhamnetin, and luteolin was assessed in human diploid MRC-5 lung fibroblasts using the resazurin cell viability assay to determine their therapeutic indices. Sequence alignment of M^pro of SARS-CoV-2 demonstrated 96.08%, 50.83%, 49.17%, 48.51%, 44.04%, and 41.06% similarity to M^pro of other human-pathogenic coronaviruses (SARS-CoV-1, MERS-CoV, HCoV-NL63, HCoV-OC43, HCoV-HKU1, and HCoV-229E, respectively). Molecular docking showed that 12 out of 121 compounds were bound to SARS-CoV-2 M^pro at the same binding site as the control inhibitor, GC376. Enzyme inhibition assays revealed that hypericin, rosmarinic acid, isorhamnetin, and luteolin inhibited M^pro of SARS-CoV-2, while hypericin and isorhamnetin inhibited M^pro of SARS-CoV-1; hypericin showed inhibitory effects toward M^pro of MERS-CoV. Microscale thermophoresis confirmed the binding of these compounds to M^pro with high affinity. Resazurin assays showed that rosmarinic acid and luteolin were not cytotoxic toward MRC-5 cells, whereas hypericin and isorhamnetin were slightly cytotoxic. We demonstrated that hypericin represents a potential novel pan-anti-coronaviral agent by binding to and inhibiting M^pro of several human-pathogenic coronaviruses. Moreover, isorhamnetin showed inhibitory effects toward SARS-CoV-2 and SARS-CoV-1 M^pro, indicating that this compound may have some pan-coronaviral potential. Luteolin had inhibitory effects against SARS-CoV-2 M^pro. Full article

(This article belongs to the Special Issue Antiviral Compounds in Medicinal Plants)

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30 pages, 6782 KiB

Open AccessEditor’s ChoiceArticle

Characterization of Novel Lytic Myoviridae Phage Infecting Multidrug-Resistant Acinetobacter baumannii and Synergistic Antimicrobial Efficacy between Phage and Sacha Inchi Oil

by Phitchayapak Wintachai and Supayang Piyawan Voravuthikunchai

Pharmaceuticals 2022, 15(3), 291; https://doi.org/10.3390/ph15030291 - 26 Feb 2022

Cited by 10 | Viewed by 3542

Abstract

Multidrug-resistant (MDR) strains of Acinetobacter baumannii have become a major cause of hospital-acquired infections, resulting in an increase in morbidity and mortality worldwide. Many alternative treatments, including phage therapy, are attractive approaches for overcoming problems posed by antibiotic resistance. A newly isolated phage, [...] Read more.

Multidrug-resistant (MDR) strains of Acinetobacter baumannii have become a major cause of hospital-acquired infections, resulting in an increase in morbidity and mortality worldwide. Many alternative treatments, including phage therapy, are attractive approaches for overcoming problems posed by antibiotic resistance. A newly isolated phage, vWUPSU-specific MDR A. baumannii, showed a narrow host range against MDR A. baumannii. This research was conducted to isolate, characterize, and apply the phage with sacha inchi oil as an alternative antimicrobial agent. Genome analysis suggested that phage vWUPSU is a novel phage belonging to the family Myoviridae, order Caudoviridae. This phage prevented biofilm formation and eradicated preformed biofilms in a dose-dependent manner. In addition, a synergistic antimicrobial effect of the interaction between phage vWUPSU and sacha inchi oil on planktonic cells was observed. The combination of phage and sacha inchi oil significantly inhibited and removed biofilms, compared with the effects of either single treatment. The results of this work indicate that phage vWUPSU could potentially be applied to control MDR A. baumannii. The antibacterial and antibiofilm activities of the combination of phage vWUPSU and sacha inchi oil have attracted significant interests in the development of antibacterial phage products as beneficial treatment options. Full article

(This article belongs to the Special Issue Phage Therapy and Phage-Mediated Biological Control 2021)

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26 pages, 6934 KiB

Open AccessEditor’s ChoiceReview

UV Filters: Challenges and Prospects

by Ana Jesus, Emília Sousa, Maria T. Cruz, Honorina Cidade, José M. Sousa Lobo and Isabel F. Almeida

Pharmaceuticals 2022, 15(3), 263; https://doi.org/10.3390/ph15030263 - 22 Feb 2022

Cited by 43 | Viewed by 7532

Abstract

The use of sunscreens is an established and recommended practice to protect skin from solar-induced damage. Around 30 UV filters can be used in sunscreen products in the European Union, which ought to follow the requirements of the regulation 1223/2009 to ensure their [...] Read more.

The use of sunscreens is an established and recommended practice to protect skin from solar-induced damage. Around 30 UV filters can be used in sunscreen products in the European Union, which ought to follow the requirements of the regulation 1223/2009 to ensure their efficacy and safety for humans. Nevertheless, low photostability and putative toxicity for humans and environment have been reported for some UV filters. Particularly, the negative impact in marine organisms has recently raised concern on the scientific community. Therefore, it is important to develop new UV filters with improved safety profile and photostability. Over the last two decades, nearly 200 new compounds have revealed promising photoprotection properties. The explored compounds were obtained through different approaches, including exploration of natural sources, synthetic pathways, and nanotechnology. Almost 50 natural products and around 140 synthetic derivatives, such as benzimidazoles, benzotriazoles, hydroxycinnamic acids, xanthones, triazines, among others, have been studied aiming the discovery of novel, effective, and safer future photoprotective agents. Herein, we provide the reader with an overview about UV filters’ challenges and prospects, offering a forward-looking to the next-generation of UV filters. Full article

(This article belongs to the Section Medicinal Chemistry)

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11 pages, 664 KiB

Open AccessEditor’s ChoiceArticle

UHPLC-MS/MS Analysis of Antibiotics Transfer and Concentrations in Porcine Oral Fluid after Intramuscular Application

by Anna Gajda, Ewelina Nowacka-Kozak, Małgorzata Gbylik-Sikorska and Piotr Cybulski

Pharmaceuticals 2022, 15(2), 225; https://doi.org/10.3390/ph15020225 - 14 Feb 2022

Cited by 3 | Viewed by 1800

Abstract

The monitoring of antibiotic use in animals is a crucial element to ensure food safety. The main goal of this study was to analyse the distribution of selected antibiotics to porcine oral fluid, as well as to demonstrate that an oral fluid is [...] Read more.

The monitoring of antibiotic use in animals is a crucial element to ensure food safety. The main goal of this study was to analyse the distribution of selected antibiotics to porcine oral fluid, as well as to demonstrate that an oral fluid is an alternative to other biological matrices used in the control of antibacterials. Therefore, an animal study with pigs treated using seven different antibiotics was performed. Sulfadoxine (SDX) with trimethoprim (TRMP), lincomycin (LIN), tiamulin (TIAM), tylosin (TYL), amoxicillin (AMX) and penicillin G (PEN G) were injected intramuscularly to pigs, and concentrations of these analytes in the oral fluid were assessed. Ultra-high-performance liquid chromatography coupled with mass spectrometry (UHPLC-MS/MS) was used to quantify the analytes. On the first day of medication, the highest concentrations for SDX and TRMP at the level of 22,300 µg/kg and 14,100 µg/kg were found, respectively. The concentrations of LIN (10,500 µg/kg) and TIAM (7600 µg/kg) were also relatively high. The peak of TYL was recorded on the second day of drug administration. Most of the analytes were present in oral fluid for 30 days, apart from TYL, which was detected for 27 days. It was found that AMX and PEN G were quantified only for 5 and 8 days, respectively, at very low concentrations. It was found that oral fluid can be used for the verification of antibiotics on pig farms. Full article

(This article belongs to the Special Issue Liquid Chromatography in Analysis of Bioactive Compounds for Pharmaceuticals, Cosmetics, and Functional Food Interest)

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17 pages, 2355 KiB

Open AccessEditor’s ChoiceArticle

A Convenient Route to New (Radio)Fluorinated and (Radio)Iodinated Cyclic Tyrosine Analogs

by Maria Noelia Chao, Jean-Michel Chezal, Eric Debiton, Damien Canitrot, Tiffany Witkowski, Sophie Levesque, Françoise Degoul, Sébastien Tarrit, Barbara Wenzel, Elisabeth Miot-Noirault, Audrey Serre and Aurélie Maisonial-Besset

Pharmaceuticals 2022, 15(2), 162; https://doi.org/10.3390/ph15020162 - 28 Jan 2022

Cited by 2 | Viewed by 2631

Abstract

The use of radiolabeled non-natural amino acids can provide high contrast SPECT/PET metabolic imaging of solid tumors. Among them, radiohalogenated tyrosine analogs (i.e., [¹²³I]IMT, [¹⁸F]FET, [¹⁸F]FDOPA, [¹²³I]8-iodo-L-TIC(OH), etc.) are of particular interest. While radioiodinated derivatives, [...] Read more.

The use of radiolabeled non-natural amino acids can provide high contrast SPECT/PET metabolic imaging of solid tumors. Among them, radiohalogenated tyrosine analogs (i.e., [¹²³I]IMT, [¹⁸F]FET, [¹⁸F]FDOPA, [¹²³I]8-iodo-L-TIC(OH), etc.) are of particular interest. While radioiodinated derivatives, such as [¹²³I]IMT, are easily available via electrophilic aromatic substitutions, the production of radiofluorinated aryl tyrosine analogs was a long-standing challenge for radiochemists before the development of innovative radiofluorination processes using arylboronate, arylstannane or iodoniums salts as precursors. Surprisingly, despite these methodological advances, no radiofluorinated analogs have been reported for [¹²³I]8-iodo-L-TIC(OH), a very promising radiotracer for SPECT imaging of prostatic tumors. This work describes a convenient synthetic pathway to obtain new radioiodinated and radiofluorinated derivatives of TIC(OH), as well as their non-radiolabeled counterparts. Using organotin compounds as key intermediates, [¹²⁵I]5-iodo-L-TIC(OH), [¹²⁵I]6-iodo-L-TIC(OH) and [¹²⁵I]8-iodo-L-TIC(OH) were efficiently prepared with good radiochemical yield (RCY, 51–78%), high radiochemical purity (RCP, >98%), molar activity (Am, >1.5–2.9 GBq/µmol) and enantiomeric excess (e.e. >99%). The corresponding [¹⁸F]fluoro-L-TIC(OH) derivatives were also successfully obtained by radiofluorination of the organotin precursors in the presence of tetrakis(pyridine)copper(II) triflate and nucleophilic [¹⁸F]F⁻ with 19–28% RCY d.c., high RCP (>98.9%), Am (20–107 GBq/µmol) and e.e. (>99%). Full article

(This article belongs to the Special Issue Alliance of PET/SPECT Imaging and Drug Design/Discovery for the Development of Novel Diagnostic or Therapeutic Tools)

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12 pages, 3721 KiB

Open AccessEditor’s ChoiceArticle

Sensitization of Antibiotic-Resistant Gram-Negative Bacteria to Photodynamic Therapy via Perfluorocarbon Nanoemulsion

by Peiyuan Niu, Jialing Dai, Zeyu Wang, Yueying Wang, Duxiang Feng, Yuanyuan Li and Wenjun Miao

Pharmaceuticals 2022, 15(2), 156; https://doi.org/10.3390/ph15020156 - 27 Jan 2022

Cited by 9 | Viewed by 3867

Abstract

With the merits of excellent efficacy, safety, and facile implementation, antibacterial photodynamic therapy (APDT) represents a promising means for treating bacterial infections. However, APDT shows an unsatisfactory efficacy in combating antibiotic-resistant Gram-negative bacteria due to their specific cell wall structure. In this work, [...] Read more.

With the merits of excellent efficacy, safety, and facile implementation, antibacterial photodynamic therapy (APDT) represents a promising means for treating bacterial infections. However, APDT shows an unsatisfactory efficacy in combating antibiotic-resistant Gram-negative bacteria due to their specific cell wall structure. In this work, we report a perfluorocarbon nanoemulsion (Ce6@FDC) used as a multifunctional nanocargo of photosensitizer and oxygen for sensitizing antibiotic-resistant Gram-negative bacteria to APDT. Ce6@FDC was fabricated via ultrasonic emulsification with good colloidal stability, efficient Ce6 and oxygen delivery, and excellent photodynamic activity. Meanwhile, Ce6@FDC could strongly bind with Gram-negative Acinetobacter baumannii (A. baumannii) and Escherichia coli (E. coli) via electrostatic interaction, thus leading to notable photodynamic bactericidal potency upon irradiation. In addition, oxygenated Ce6@FDC also exhibited a remarkable efficacy in eradicating Gram-negative bacteria biofilm, averaging five log units lower than the Ce6 group under identical conditions. Taken together, we demonstrate that photodynamic perfluorocarbon nanoemulsion with oxygen-delivery ability could effectively kill planktonic bacteria and remove biofilm, representing a novel strategy in fighting against antibiotic-resistant Gram-negative bacteria. Full article

(This article belongs to the Special Issue Recent Advances in Antimicrobial Nanodrugs)

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14 pages, 323 KiB

Open AccessEditor’s ChoiceReview

Cytokines in the Brain and Neuroinflammation: We Didn’t Starve the Fire!

by Jan Pieter Konsman

Pharmaceuticals 2022, 15(2), 140; https://doi.org/10.3390/ph15020140 - 25 Jan 2022

Cited by 19 | Viewed by 5309

Abstract

In spite of the brain-protecting tissues of the skull, meninges, and blood-brain barrier, some forms of injury to or infection of the CNS can give rise to cerebral cytokine production and action and result in drastic changes in brain function and behavior. Interestingly, [...] Read more.

In spite of the brain-protecting tissues of the skull, meninges, and blood-brain barrier, some forms of injury to or infection of the CNS can give rise to cerebral cytokine production and action and result in drastic changes in brain function and behavior. Interestingly, peripheral infection-induced systemic inflammation can also be accompanied by increased cerebral cytokine production. Furthermore, it has been recently proposed that some forms of psychological stress may have similar CNS effects. Different conditions of cerebral cytokine production and action will be reviewed here against the background of neuroinflammation. Within this context, it is important to both deepen our understanding along already taken paths as well as to explore new ways in which neural functioning can be modified by cytokines. This, in turn, should enable us to put forward different modes of cerebral cytokine production and action in relation to distinct forms of neuroinflammation. Full article

(This article belongs to the Special Issue Cerebral Production and Action of Pro-inflammatory Cytokines)

12 pages, 330 KiB

Open AccessEditor’s ChoiceReview

Laboratory Selection of Trypanosomatid Pathogens for Drug Resistance

by Sabina Beilstein, Radhia El Phil, Suzanne Sherihan Sahraoui, Leonardo Scapozza, Marcel Kaiser and Pascal Mäser

Pharmaceuticals 2022, 15(2), 135; https://doi.org/10.3390/ph15020135 - 24 Jan 2022

Cited by 1 | Viewed by 2876

Abstract

The selection of parasites for drug resistance in the laboratory is an approach frequently used to investigate the mode of drug action, estimate the risk of emergence of drug resistance, or develop molecular markers for drug resistance. Here, we focused on the How [...] Read more.

The selection of parasites for drug resistance in the laboratory is an approach frequently used to investigate the mode of drug action, estimate the risk of emergence of drug resistance, or develop molecular markers for drug resistance. Here, we focused on the How rather than the Why of laboratory selection, discussing different experimental set-ups based on research examples with Trypanosoma brucei, Trypanosoma cruzi, and Leishmania spp. The trypanosomatids are particularly well-suited to illustrate different strategies of selecting for drug resistance, since it was with African trypanosomes that Paul Ehrlich performed such an experiment for the first time, more than a century ago. While breakthroughs in reverse genetics and genome editing have greatly facilitated the identification and validation of candidate resistance mutations in the trypanosomatids, the forward selection of drug-resistant mutants still relies on standard in vivo models and in vitro culture systems. Critical questions are: is selection for drug resistance performed in vivo or in vitro? With the mammalian or with the insect stages of the parasites? Under steady pressure or by sudden shock? Is a mutagen used? While there is no bona fide best approach, we think that a methodical consideration of these questions provides a helpful framework for selection of parasites for drug resistance in the laboratory. Full article

(This article belongs to the Collection Drug Discovery and Development for Tropical Diseases (TDs))

13 pages, 1647 KiB

Open AccessEditor’s ChoiceReview

The Effects of Statins on Prostate Cancer Patients Receiving Androgen Deprivation Therapy or Definitive Therapy: A Systematic Review and Meta-Analysis

by Yu-Chen Hou and Yu-Hsuan Shao

Pharmaceuticals 2022, 15(2), 131; https://doi.org/10.3390/ph15020131 - 22 Jan 2022

Cited by 6 | Viewed by 2807

Abstract

Mortality associated with statin use has been reported in prostate cancer (PCa) patients treated with androgen deprivation therapy (ADT) or definitive therapy in several observational studies, although the results have varied. This study aimed to analyze the association of statin use with all-cause [...] Read more.

Mortality associated with statin use has been reported in prostate cancer (PCa) patients treated with androgen deprivation therapy (ADT) or definitive therapy in several observational studies, although the results have varied. This study aimed to analyze the association of statin use with all-cause mortality and cancer-specific mortality among PCa patients receiving ADT or definitive therapy as their primary treatment and to examine the effect of statin initiation (pre-ADT) timing on outcomes. A systematic literature search of PubMed, the Cochrane library, and Embase was conducted from database inception to 4 October 2021. In total, 12 eligible studies from 976 references were included in the final analysis. The results showed that statin use was associated with a significant reduction in the risks of all-cause mortality (hazard ratio (HR) = 0.73, 95% confidence interval (CI) = 0.64–0.84, p < 0.0001) and cancer-specific mortality (HR = 0.61, 95% CI = 0.49–0.77, p < 0.0001) in PCa patients receiving ADT. However, statin use before ADT initiation did not significantly lower the risk of all-cause mortality (HR = 0.87, 95% CI = 0.66–1.16, p = 0.35) or cancer-specific mortality (HR = 0.84, 95% CI = 0.62–1.13, p = 0.25) in advanced PCa patients receiving ADT. In contrast, statin use was not associated with a significantly reduced risk of all-cause mortality (HR = 0.69, 95% CI = 0.39–1.21, p = 0.20), but it was associated with a reduced risk of cancer-specific mortality (HR = 0.82, 95% CI = 0.68–0.98, p = 0.03) in PCa patients receiving definitive therapy. This review indicated that statin use in combination with ADT was correlated with better all-cause and cancer-specific mortality in PCa patients. However, the beneficial effect might not come from statin use before ADT initiation. In addition, statin use in combination with definitive therapy was correlated with a reduced risk of cancer-specific mortality in PCa patients. In the future, randomized controlled trials are needed to validate the efficacy of statin use in combination with primary treatment for PCa among PCa patients. Full article

(This article belongs to the Special Issue Statins Use and Cancer)

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20 pages, 1767 KiB

Open AccessEditor’s ChoiceArticle

Mirogabalin Decreases Pain-like Behaviours and Improves Opioid and Ketamine Antinociception in a Mouse Model of Neuropathic Pain

by Renata Zajączkowska, Ewelina Rojewska, Agata Ciechanowska, Katarzyna Pawlik, Katarzyna Ciapała, Magdalena Kocot-Kępska, Wioletta Makuch, Jerzy Wordliczek and Joanna Mika

Pharmaceuticals 2022, 15(1), 88; https://doi.org/10.3390/ph15010088 - 13 Jan 2022

Cited by 3 | Viewed by 2639

Abstract

Neuropathic pain remains a difficult clinical challenge due to its diverse aetiology and complex pathomechanisms, which are yet to be fully understood. Despite the variety of available therapies, many patients suffer from ineffective pain relief; hence, the search for more efficacious treatments continues. [...] Read more.

Neuropathic pain remains a difficult clinical challenge due to its diverse aetiology and complex pathomechanisms, which are yet to be fully understood. Despite the variety of available therapies, many patients suffer from ineffective pain relief; hence, the search for more efficacious treatments continues. The new gabapentinoid, mirogabalin has recently been approved for clinical use. Although its main mechanism of action occurs at the α2σ-1 and α2σ-2 subunits of calcium channels and is well documented, how the drug affects the disturbed neuropathic interactions at the spinal cord level has not been clarified, which is crucial information from a clinical perspective. The findings of our study suggest that several indirect mechanisms may be responsible for the beneficial analgesic effect of mirogabalin. This is the first study to report that mirogabalin enhances the mRNA expression of spinal antinociceptive factors, such as IL-10 and IL-18BP, and reduces the concentration of the pronociceptive substance P. Importantly, mirogabalin improves the morphine-, buprenorphine-, oxycodone-, and ketamine-induced antinociceptive effects in a neuropathic pain model. Our findings support the hypothesis that enhancing opioid and ketamine analgesia by combining these drugs with mirogabalin may represent a new strategy for the effective pharmacotherapy of neuropathic pain. Full article

(This article belongs to the Section Pharmacology)

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12 pages, 1769 KiB

Open AccessEditor’s ChoiceArticle

Extraction and Fractionation of Bioactives from Dipsacus fullonum L. Leaves and Evaluation of Their Anti-Borrelia Activity

by Piret Saar-Reismaa, Olga Bragina, Maria Kuhtinskaja, Indrek Reile, Pille-Riin Laanet, Maria Kulp and Merike Vaher

Pharmaceuticals 2022, 15(1), 87; https://doi.org/10.3390/ph15010087 - 12 Jan 2022

Cited by 4 | Viewed by 4884

Abstract

Lyme disease (LD) is a tick-borne bacterial disease that is caused by Borrelia burgdorferi. Although acute LD is treated with antibiotics, it can develop into relapsing chronic form caused by latent forms of B. burgdorferi. This leads to the search for [...] Read more.

Lyme disease (LD) is a tick-borne bacterial disease that is caused by Borrelia burgdorferi. Although acute LD is treated with antibiotics, it can develop into relapsing chronic form caused by latent forms of B. burgdorferi. This leads to the search for phytochemicals against resistant LD. Therefore, this study aimed to evaluate the activity of Dipsacus fullonum L. leaves extract (DE) and its fractions against stationary phase B. burgdorferi in vitro. DE showed high activity against stationary phase B. burgdorferi (residual viability 19.8 ± 4.7%); however, it exhibited a noticeable cytotoxicity on NIH cells (viability 20.2 ± 5.2%). The iridoid-glycoside fraction showed a remarkable anti-Borrelia effect and reduced cytotoxicity. The iridoid-glycoside fraction was, therefore, further purified and showed to contain two main bioactives—sylvestrosides III and IV, that showed a considerable anti-Borrelia activity being the least toxic to murine fibroblast NIH/3T3 cells. Moreover, the concentration of sylvestrosides was about 15% of DE, endorsing the feasibility of purification of the compounds from D. fullonum L. leaves. Full article

(This article belongs to the Special Issue Identification of Phytochemicals and Derivatives against Infectious Diseases)

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32 pages, 886 KiB

Open AccessEditor’s ChoiceReview

Jakinibs of All Trades: Inhibiting Cytokine Signaling in Immune-Mediated Pathologies

by Madison Alexander, Yiming Luo, Giorgio Raimondi, John J. O’Shea and Massimo Gadina

Pharmaceuticals 2022, 15(1), 48; https://doi.org/10.3390/ph15010048 - 30 Dec 2021

Cited by 16 | Viewed by 6736

Abstract

Over the last 25 years, inhibition of Janus kinases (JAKs) has been pursued as a modality for treating various immune and inflammatory disorders. While the clinical development of JAK inhibitors (jakinibs) began with the investigation of their use in allogeneic transplantation, their widest [...] Read more.

Over the last 25 years, inhibition of Janus kinases (JAKs) has been pursued as a modality for treating various immune and inflammatory disorders. While the clinical development of JAK inhibitors (jakinibs) began with the investigation of their use in allogeneic transplantation, their widest successful application came in autoimmune and allergic diseases. Multiple molecules have now been approved for diseases ranging from rheumatoid and juvenile arthritis to ulcerative colitis, atopic dermatitis, graft-versus-host-disease (GVHD) and other inflammatory pathologies in 80 countries around the world. Moreover, two jakinibs have also shown surprising efficacy in the treatment of hospitalized coronavirus disease-19 (COVID-19) patients, indicating additional roles for jakinibs in infectious diseases, cytokine storms and other hyperinflammatory syndromes. Jakinibs, as a class of pharmaceutics, continue to expand in clinical applications and with the development of more selective JAK-targeting and organ-selective delivery. Importantly, jakinib safety and pharmacokinetics have been investigated alongside clinical development, further cementing the potential benefits and limits of jakinib use. This review covers jakinibs that are approved or are under late phase investigation, focusing on clinical applications, pharmacokinetic and safety profiles, and future opportunities and challenges. Full article

(This article belongs to the Special Issue The Regulation of JAKs in Health and in Disease)

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11 pages, 1671 KiB

Open AccessEditor’s ChoiceReview

Baloxavir Marboxil: An Original New Drug against Influenza

by François Dufrasne

Pharmaceuticals 2022, 15(1), 28; https://doi.org/10.3390/ph15010028 - 24 Dec 2021

Cited by 19 | Viewed by 4433

Abstract

Baloxavir marboxil is a new drug developed in Japan by Shionogi to treat seasonal flu infection. This cap-dependent endonuclease inhibitor is a prodrug that releases the biologically active baloxavir acid. This new medicine has been marketed in Japan, the USA and Europe. It [...] Read more.

Baloxavir marboxil is a new drug developed in Japan by Shionogi to treat seasonal flu infection. This cap-dependent endonuclease inhibitor is a prodrug that releases the biologically active baloxavir acid. This new medicine has been marketed in Japan, the USA and Europe. It is well tolerated (more than 1% of the patients experienced diarrhea, bronchitis, nausea, nasopharyngitis, and headache), and both influenza A and B viruses are sensitive, although the B strain is more resistant due to variations in the amino acid residues in the binding site. The drug is now in post-marketing pharmacovigilance phase, and its interest will be especially re-evaluated in the future during the annual flu outbreaks. It has been also introduced in a recent clinical trial against COVID-19 with favipiravir. Full article

(This article belongs to the Special Issue The Story of Successful Drugs and Recent FDA-Approved Molecules)

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22 pages, 4517 KiB

Open AccessEditor’s ChoiceReview

PCR-Based Analytical Methods for Quantification and Quality Control of Recombinant Adeno-Associated Viral Vector Preparations

by Anna A. Shmidt and Tatiana V. Egorova

Pharmaceuticals 2022, 15(1), 23; https://doi.org/10.3390/ph15010023 - 24 Dec 2021

Cited by 7 | Viewed by 5942

Abstract

Recombinant adeno-associated viral vectors (rAAV) represent a gene therapy tool of ever-increasing importance. Their utilization as a delivery vehicle for gene replacement, silencing and editing, among other purposes, demonstrate considerable versatility. Emerging vector utilization in various experimental, preclinical and clinical applications establishes the [...] Read more.

Recombinant adeno-associated viral vectors (rAAV) represent a gene therapy tool of ever-increasing importance. Their utilization as a delivery vehicle for gene replacement, silencing and editing, among other purposes, demonstrate considerable versatility. Emerging vector utilization in various experimental, preclinical and clinical applications establishes the necessity of producing and characterizing a wide variety of rAAV preparations. Critically important characteristics concerning quality control are rAAV titer quantification and the detection of impurities. Differences in rAAV constructs necessitate the development of highly standardized quantification assays to make direct comparisons of different preparations in terms of assembly or purification efficiency, as well as experimental or therapeutic dosages. The development of universal methods for impurities quantification is rather complicated, since variable production platforms are utilized for rAAV assembly. However, general agreements also should be achieved to address this issue. The majority of methods for rAAV quantification and quality control are based on PCR techniques. Despite the progress made, increasing evidence concerning high variability in titration assays indicates poor standardization of the methods undertaken to date. This review summarizes successes in the field of rAAV quality control and emphasizes ongoing challenges in PCR applications for rAAV characterization. General considerations regarding possible solutions are also provided. Full article

(This article belongs to the Section Biopharmaceuticals)

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20 pages, 1276 KiB

Open AccessEditor’s ChoiceReview

Expanding Theranostic Radiopharmaceuticals for Tumor Diagnosis and Therapy

by Cristina Barca, Christoph M. Griessinger, Andreas Faust, Dominic Depke, Markus Essler, Albert D. Windhorst, Nick Devoogdt, Kevin M. Brindle, Michael Schäfers, Bastian Zinnhardt and Andreas H. Jacobs

Pharmaceuticals 2022, 15(1), 13; https://doi.org/10.3390/ph15010013 - 22 Dec 2021

Cited by 19 | Viewed by 6397

Abstract

Radioligand theranostics (RT) in oncology use cancer-type specific biomarkers and molecular imaging (MI), including positron emission tomography (PET), single-photon emission computed tomography (SPECT) and planar scintigraphy, for patient diagnosis, therapy, and personalized management. While the definition of theranostics was initially restricted to a [...] Read more.

Radioligand theranostics (RT) in oncology use cancer-type specific biomarkers and molecular imaging (MI), including positron emission tomography (PET), single-photon emission computed tomography (SPECT) and planar scintigraphy, for patient diagnosis, therapy, and personalized management. While the definition of theranostics was initially restricted to a single compound allowing visualization and therapy simultaneously, the concept has been widened with the development of theranostic pairs and the combination of nuclear medicine with different types of cancer therapies. Here, we review the clinical applications of different theranostic radiopharmaceuticals in managing different tumor types (differentiated thyroid, neuroendocrine prostate, and breast cancer) that support the combination of innovative oncological therapies such as gene and cell-based therapies with RT. Full article

(This article belongs to the Special Issue Forward Thinking towards Theranostic (Radio)ligands Targeting the Tumor Microenvironment (TME))

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19 pages, 2981 KiB

Open AccessEditor’s ChoiceArticle

Limitations and Challenges in the Stability of Cysteamine Eye Drop Compounded Formulations

by Cristina Martín-Sabroso, Mario Alonso-González, Ana Fernández-Carballido, Juan Aparicio-Blanco, Damián Córdoba-Díaz, Federico Navarro-García, Manuel Córdoba-Díaz and Ana I. Torres-Suárez

Pharmaceuticals 2022, 15(1), 2; https://doi.org/10.3390/ph15010002 - 21 Dec 2021

Cited by 4 | Viewed by 4259

Abstract

Accumulation of cystine crystals in the cornea of patients suffering from cystinosis is considered pathognomonic and can lead to severe ocular complications. Cysteamine eye drop compounded formulations, commonly prepared by hospital pharmacy services, are meant to diminish the build-up of corneal cystine crystals. [...] Read more.

Accumulation of cystine crystals in the cornea of patients suffering from cystinosis is considered pathognomonic and can lead to severe ocular complications. Cysteamine eye drop compounded formulations, commonly prepared by hospital pharmacy services, are meant to diminish the build-up of corneal cystine crystals. The objective of this work was to analyze whether the shelf life proposed for six formulations prepared following different protocols used in hospital pharmacies is adequate to guarantee the quality and efficacy of cysteamine eye drops. The long-term and in-use stabilities of these preparations were studied using different parameters: content of cysteamine and its main degradation product cystamine; appearance, color and odor; pH and viscosity; and microbiological analysis. The results obtained show that degradation of cysteamine was between 20% and 50% after one month of storage in the long-term stability study and between 35% and 60% in the in-use study. These data confirm that cysteamine is a very unstable molecule in aqueous solution, the presence of oxygen being the main degradation factor. Saturation with nitrogen gas of the solutions offers a means of reducing cysteamine degradation. Overall, all the formulae studied presented high instability at the end of their shelf life, suggesting that their clinical efficacy might be dramatically compromised. Full article

(This article belongs to the Section Pharmaceutical Technology)

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19 pages, 62446 KiB

Open AccessEditor’s ChoiceArticle

Co-Delivery of Letrozole and Cyclophosphamide via Folic Acid-Decorated Nanoniosomes for Breast Cancer Therapy: Synergic Effect, Augmentation of Cytotoxicity, and Apoptosis Gene Expression

by Hamidreza Sahrayi, Elham Hosseini, Sara Karimifard, Nazanin Khayam, Seyed Mohammadmahdi Meybodi, Sahar Amiri, Mahsa Bourbour, Bahareh Farasati Far, Iman Akbarzadeh, Mohammed Bhia, Clare Hoskins and Chaiyavat Chaiyasut

Pharmaceuticals 2022, 15(1), 6; https://doi.org/10.3390/ph15010006 - 21 Dec 2021

Cited by 28 | Viewed by 4842

Abstract

Breast cancer is one of the most prevalent causes of cancer mortality in women. In order to increase patient prognosis and survival rates, new technologies are urgently required to deliver therapeutics in a more effective and efficient manner. Niosome nanoparticles have been recently [...] Read more.

Breast cancer is one of the most prevalent causes of cancer mortality in women. In order to increase patient prognosis and survival rates, new technologies are urgently required to deliver therapeutics in a more effective and efficient manner. Niosome nanoparticles have been recently employed as therapeutic platforms capable of loading and carrying drugs within their core for both mono and combination therapy. Here, niosome-based nanoscale carriers were investigated as a targeted delivery system for breast cancer therapy. The platform developed consists of niosomes loaded with letrozole and cyclophosphamide (NLC) and surface-functionalized with a folic-acid-targeting moiety (NLCPFA). Drug release from the formulated particles exhibited pH-sensitive properties in which the niosome showed low and high release in physiological and cancerous conditions, respectively. The results revealed a synergic effect in cytotoxicity by co-loading letrozole and cyclophosphamide with an efficacy increment in NLCPFA use in comparison with NLC. The NLCPFA resulted in the greatest drug internalization compared to the non-targeted formulation and the free drug. Additionally, downregulation of cyclin-D, cyclin-E, MMP-2, and MMP-9 and upregulating the expression of caspase-3 and caspase-9 genes were observed more prominently in the nanoformulation (particularly for NLCPFA) compared to the free drug. This exciting data indicated that niosome-based nanocarriers containing letrozole and cyclophosphamide with controlled release could be a promising platform for drug delivery with potential in breast cancer therapy. Full article

(This article belongs to the Section Pharmaceutical Technology)

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16 pages, 3733 KiB

Open AccessEditor’s ChoiceArticle

A Humanized Monoclonal Antibody Targeting Extracellular Nicotinamide Phosphoribosyltransferase Prevents Aggressive Prostate Cancer Progression

by Belinda L. Sun, Lin Tang, Xiaoguang Sun, Alexander N. Garcia, Sara M. Camp, Edwin Posadas, Anne E. Cress and Joe G. N. Garcia

Pharmaceuticals 2021, 14(12), 1322; https://doi.org/10.3390/ph14121322 - 17 Dec 2021

Cited by 12 | Viewed by 2901

Abstract

Prostate cancer (PCa) is the major cause of cancer-related death in males; however, effective treatments to prevent aggressive progression remain an unmet need. We have previously demonstrated that secreted extracellular nicotinamide phosphoribosyltransferase (eNAMPT) is a multifunctional innate immunity regulator that promotes PCa invasion. [...] Read more.

Prostate cancer (PCa) is the major cause of cancer-related death in males; however, effective treatments to prevent aggressive progression remain an unmet need. We have previously demonstrated that secreted extracellular nicotinamide phosphoribosyltransferase (eNAMPT) is a multifunctional innate immunity regulator that promotes PCa invasion. In the current study, we further investigate the therapeutic effects of an eNAMPT-neutralizing humanized monoclonal antibody (ALT-100 mAb) in preclinical PCa orthotopic xenograft models. We utilized human aggressive PCa cells (DU145 or PC3) for prostate implantation in SCID mice receiving weekly intraperitoneal injections of either ALT-100 mAb or IgG/PBS (control) for 12 weeks. Prostatic tumors and solid organs were examined for tumor growth, invasion, and metastasis and for biochemical and immunohistochemistry evidence of NFκB activation. ALT-100 mAb treatment significantly improved overall survival of SCID mice implanted with human PCa orthotopic prostate xenografts while inducing tumor necrosis, decreasing PCa proliferation and reducing local invasion and distal metastases. The ALT-100 mAb inhibits NFκB phosphorylation and signaling in PCa cells both in vitro and in vivo. This study demonstrates that eNAMPT neutralization effectively prevents human PCa aggressive progression in preclinical models, indicating its high potential to directly address the unmet need for an effective targeted therapy for patients with aggressive PCa. Full article

(This article belongs to the Special Issue Novel Therapeutic Targets in Cancer)

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21 pages, 3739 KiB

Open AccessEditor’s ChoiceReview

Advances in Antifungal Drug Development: An Up-To-Date Mini Review

by Ghada Bouz and Martin Doležal

Pharmaceuticals 2021, 14(12), 1312; https://doi.org/10.3390/ph14121312 - 16 Dec 2021

Cited by 48 | Viewed by 6821

Abstract

The utility of clinically available antifungals is limited by their narrow spectrum of activity, high toxicity, and emerging resistance. Antifungal drug discovery has always been a challenging area, since fungi and their human host are eukaryotes, making it difficult to identify unique targets [...] Read more.

The utility of clinically available antifungals is limited by their narrow spectrum of activity, high toxicity, and emerging resistance. Antifungal drug discovery has always been a challenging area, since fungi and their human host are eukaryotes, making it difficult to identify unique targets for antifungals. Novel antifungals in clinical development include first-in-class agents, new structures for an established target, and formulation modifications to marketed antifungals, in addition to repurposed agents. Membrane interacting peptides and aromatherapy are gaining increased attention in the field. Immunotherapy is another promising treatment option, with antifungal antibodies advancing into clinical trials. Novel targets for antifungal therapy are also being discovered, allowing the design of new promising agents that may overcome the resistance issue. In this mini review, we will summarize the current status of antifungal drug pipelines in clinical stages, and the most recent advancements in preclinical antifungal drug development, with special focus on their chemistry. Full article

(This article belongs to the Special Issue Advances in Antifungal Development: Discovery of New Drugs and Drug Repurposing)

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17 pages, 662 KiB

Open AccessEditor’s ChoiceReview

Monoclonal Antibodies against SARS-CoV-2: Current Scenario and Future Perspectives

by Eugenia Quiros-Roldan, Silvia Amadasi, Isabella Zanella, Melania Degli Antoni, Samuele Storti, Giorgio Tiecco and Francesco Castelli

Pharmaceuticals 2021, 14(12), 1272; https://doi.org/10.3390/ph14121272 - 06 Dec 2021

Cited by 23 | Viewed by 5238

Abstract

Monoclonal antibodies (mAbs) have been known since the 1970s. However, their therapeutic potential in the medical field has recently emerged, with the advancement of manufacturing techniques. Initially exploited mainly in the oncology field, mAbs have become increasingly relevant in Infectious Diseases. Numerous mAbs [...] Read more.

Monoclonal antibodies (mAbs) have been known since the 1970s. However, their therapeutic potential in the medical field has recently emerged, with the advancement of manufacturing techniques. Initially exploited mainly in the oncology field, mAbs have become increasingly relevant in Infectious Diseases. Numerous mAbs have been developed against SARS-CoV 2 and have proven their effectiveness, especially in the management of the mild-to-moderate disease. In this review, we describe the monoclonal antibodies currently authorized for the treatment of the coronavirus disease 19 (COVID-19) and offer an insight into the clinical trials that led to their approval. We discuss the mechanisms of action and methods of administration as well as the prophylactic and therapeutic labelled indications (both in outpatient and hospital settings). Furthermore, we address the critical issues regarding mAbs, focusing on their effectiveness against the variants of concern (VoC) and their role now that a large part of the population has been vaccinated. The purpose is to offer the clinician an up-to-date overview of a therapeutic tool that could prove decisive in treating patients at high risk of progression to severe disease. Full article

(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)

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12 pages, 14655 KiB

Open AccessEditor’s ChoiceReview

Exosome microRNAs in Metabolic Syndrome as Tools for the Early Monitoring of Diabetes and Possible Therapeutic Options

by Erika Cione, Roberto Cannataro, Luca Gallelli, Giovambattista De Sarro and Maria Cristina Caroleo

Pharmaceuticals 2021, 14(12), 1257; https://doi.org/10.3390/ph14121257 - 02 Dec 2021

Cited by 15 | Viewed by 3788

Abstract

Exosomes are nano-sized extracellular vesicles produced and released by almost all cell types. They play an essential role in cell–cell communications by delivering cellular bioactive compounds such as functional proteins, metabolites, and nucleic acids, including microRNA, to recipient cells. Thus, they are involved [...] Read more.

Exosomes are nano-sized extracellular vesicles produced and released by almost all cell types. They play an essential role in cell–cell communications by delivering cellular bioactive compounds such as functional proteins, metabolites, and nucleic acids, including microRNA, to recipient cells. Thus, they are involved in various physio-pathological conditions. Exosome-miRNAs are associated with numerous diseases, including type 2 diabetes, a complex multifactorial metabolic disorder linked to obesity. In addition, exosome-miRNAs are emerging as essential regulators in the progression of diabetes, principally for pancreatic β-cell injury and insulin resistance. Here, we have clustered the recent findings concerning exosome-miRNAs associated with β-cell dysfunction to provide a novel approach for the early diagnosis and therapy of diabetes. Full article

(This article belongs to the Special Issue Exosomes as a Tool for Disease Progression Monitoring in Humans and Animals)

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15 pages, 2623 KiB

Open AccessEditor’s ChoiceArticle

Discovery of SARS-CoV-2 Nsp14 and Nsp16 Methyltransferase Inhibitors by High-Throughput Virtual Screening

by Raitis Bobrovs, Iveta Kanepe, Nauris Narvaiss, Liene Patetko, Gints Kalnins, Mihails Sisovs, Anna L. Bula, Solveiga Grinberga, Martins Boroduskis, Anna Ramata-Stunda, Nils Rostoks, Aigars Jirgensons, Kaspars Tars and Kristaps Jaudzems

Pharmaceuticals 2021, 14(12), 1243; https://doi.org/10.3390/ph14121243 - 30 Nov 2021

Cited by 20 | Viewed by 3266

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses mRNA capping to evade the human immune system. The cap formation is performed by the SARS-CoV-2 mRNA cap methyltransferases (MTases) nsp14 and nsp16, which are emerging targets for the development of broad-spectrum antiviral agents. [...] Read more.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses mRNA capping to evade the human immune system. The cap formation is performed by the SARS-CoV-2 mRNA cap methyltransferases (MTases) nsp14 and nsp16, which are emerging targets for the development of broad-spectrum antiviral agents. Here, we report results from high-throughput virtual screening against these two enzymes. The docking of seven million commercially available drug-like compounds and S-adenosylmethionine (SAM) co-substrate analogues against both MTases resulted in 80 virtual screening hits (39 against nsp14 and 41 against nsp16), which were purchased and tested using an enzymatic homogeneous time-resolved fluorescent energy transfer (HTRF) assay. Nine compounds showed micromolar inhibition activity (IC₅₀ < 200 μM). The selectivity of the identified inhibitors was evaluated by cross-checking their activity against human glycine N-methyltransferase. The majority of the compounds showed poor selectivity for a specific MTase, no cytotoxic effects, and rather poor cell permeability. Nevertheless, the identified compounds represent good starting points that have the potential to be developed into efficient viral MTase inhibitors. Full article

(This article belongs to the Special Issue Design of Enzyme Inhibitors as Potential Drugs 2022)

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18 pages, 527 KiB

Open AccessEditor’s ChoiceReview

Psilocybin, a Naturally Occurring Indoleamine Compound, Could Be Useful to Prevent Suicidal Behaviors

by Robertas Strumila, Bénédicte Nobile, Laura Korsakova, Aiste Lengvenyte, Emilie Olie, Jorge Lopez-Castroman, Sébastien Guillaume and Philippe Courtet

Pharmaceuticals 2021, 14(12), 1213; https://doi.org/10.3390/ph14121213 - 24 Nov 2021

Cited by 15 | Viewed by 10913

Abstract

The available interventions for people who are at risk of suicide have limited efficacy. Recently, research on new mental health treatments has started to consider psychedelic compounds, particularly psilocybin, a molecule with a few thousand years of history of use in human societies. [...] Read more.

The available interventions for people who are at risk of suicide have limited efficacy. Recently, research on new mental health treatments has started to consider psychedelic compounds, particularly psilocybin, a molecule with a few thousand years of history of use in human societies. The possible effects of psilocybin on suicidal ideation and behaviors have not been specifically studied yet; however, the current knowledge on the suicidal process and the available data on es/ketamine suggest that psylocibin could be used to modulate the thoughts and behavioral patterns in individuals who are at risk of suicidal behaviors. Here, we summarize the available evidence on the possible mechanisms underlying psilocybin positive effects on suicide risk. Major pathways related to suicidal behaviors that might be modulated by psylocibin include serotonin receptors. Specifically, psylocibin directly stimulates the serotonin 2A receptor (5HT_2A), targeting the inflammatory and oxidative stress pathways and leading to a rapid increase in brain plasticity and inflammation suppression and increases in cognitive flexibility, spirituality, and empathy. We also present preliminary epidemiological data and provide a rationale for studying psilocybin in individuals with suicidal ideation or who are at risk of suicidal behaviors. This review presents a framework to understand the basis for psilocybin use in individuals who are at risk of suicidal behaviors and calls for clinical studies. Full article

(This article belongs to the Special Issue Natural Pharmacons: Biologically Active Plant Based Pharmaceuticals)

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42 pages, 2679 KiB

Open AccessEditor’s ChoiceReview

Cellulosic Polymers for Enhancing Drug Bioavailability in Ocular Drug Delivery Systems

by Bharti Gupta, Varsha Mishra, Sankalp Gharat, Munira Momin and Abdelwahab Omri

Pharmaceuticals 2021, 14(11), 1201; https://doi.org/10.3390/ph14111201 - 22 Nov 2021

Cited by 37 | Viewed by 6264

Abstract

One of the major impediments to drug development is low aqueous solubility and thus poor bioavailability, which leads to insufficient clinical utility. Around 70–80% of drugs in the discovery pipeline are suffering from poor aqueous solubility and poor bioavailability, which is a major [...] Read more.

One of the major impediments to drug development is low aqueous solubility and thus poor bioavailability, which leads to insufficient clinical utility. Around 70–80% of drugs in the discovery pipeline are suffering from poor aqueous solubility and poor bioavailability, which is a major challenge when one has to develop an ocular drug delivery system. The outer lipid layer, pre-corneal, dynamic, and static ocular barriers limit drug availability to the targeted ocular tissues. Biopharmaceutical Classification System (BCS) class II drugs with adequate permeability and limited or no aqueous solubility have been extensively studied for various polymer-based solubility enhancement approaches. The hydrophilic nature of cellulosic polymers and their tunable properties make them the polymers of choice in various solubility-enhancement techniques. This review focuses on various cellulose derivatives, specifically, their role, current status and novel modified cellulosic polymers for enhancing the bioavailability of BCS class II drugs in ocular drug delivery systems. Full article

(This article belongs to the Section Pharmaceutical Technology)

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25 pages, 4121 KiB

Open AccessEditor’s ChoiceReview

Positron Emission Tomography in Animal Models of Alzheimer’s Disease Amyloidosis: Translational Implications

by Ruiqing Ni

Pharmaceuticals 2021, 14(11), 1179; https://doi.org/10.3390/ph14111179 - 18 Nov 2021

Cited by 10 | Viewed by 4244

Abstract

Animal models of Alzheimer’s disease amyloidosis that recapitulate cerebral amyloid-beta pathology have been widely used in preclinical research and have greatly enabled the mechanistic understanding of Alzheimer’s disease and the development of therapeutics. Comprehensive deep phenotyping of the pathophysiological and biochemical features in [...] Read more.

Animal models of Alzheimer’s disease amyloidosis that recapitulate cerebral amyloid-beta pathology have been widely used in preclinical research and have greatly enabled the mechanistic understanding of Alzheimer’s disease and the development of therapeutics. Comprehensive deep phenotyping of the pathophysiological and biochemical features in these animal models is essential. Recent advances in positron emission tomography have allowed the non-invasive visualization of the alterations in the brain of animal models and in patients with Alzheimer’s disease. These tools have facilitated our understanding of disease mechanisms and provided longitudinal monitoring of treatment effects in animal models of Alzheimer’s disease amyloidosis. In this review, we focus on recent positron emission tomography studies of cerebral amyloid-beta accumulation, hypoglucose metabolism, synaptic and neurotransmitter receptor deficits (cholinergic and glutamatergic system), blood–brain barrier impairment, and neuroinflammation (microgliosis and astrocytosis) in animal models of Alzheimer’s disease amyloidosis. We further propose the emerging targets and tracers for reflecting the pathophysiological changes and discuss outstanding challenges in disease animal models and future outlook in the on-chip characterization of imaging biomarkers towards clinical translation. Full article

(This article belongs to the Special Issue In Vivo Nuclear Molecular Imaging in Drug Development and Pharmacological Research)

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18 pages, 2475 KiB

Open AccessEditor’s ChoiceArticle

Cannabidiol Induces Cell Death in Human Lung Cancer Cells and Cancer Stem Cells

by Hussein Hamad and Birgitte Brinkmann Olsen

Pharmaceuticals 2021, 14(11), 1169; https://doi.org/10.3390/ph14111169 - 17 Nov 2021

Cited by 23 | Viewed by 8878

Abstract

Currently, there is no effective therapy against lung cancer due to the development of resistance. Resistance contributes to disease progression, recurrence, and mortality. The presence of so-called cancer stem cells could explain the ineffectiveness of conventional treatment, and the development of successful cancer [...] Read more.

Currently, there is no effective therapy against lung cancer due to the development of resistance. Resistance contributes to disease progression, recurrence, and mortality. The presence of so-called cancer stem cells could explain the ineffectiveness of conventional treatment, and the development of successful cancer treatment depends on the targeting also of cancer stem cells. Cannabidiol (CBD) is a cannabinoid with anti-tumor properties. However, the effects on cancer stem cells are not well understood. The effects of CBD were evaluated in spheres enriched in lung cancer stem cells and adherent lung cancer cells. We found that CBD decreased viability and induced cell death in both cell populations. Furthermore, we found that CBD activated the effector caspases 3/7, increased the expression of pro-apoptotic proteins, increased the levels of reactive oxygen species, as well as a leading to a loss of mitochondrial membrane potential in both populations. We also found that CBD decreased self-renewal, a hallmark of cancer stem cells. Overall, our results suggest that CBD is effective against the otherwise treatment-resistant cancer stem cells and joins a growing list of compounds effective against cancer stem cells. The effects and mechanisms of CBD in cancer stem cells should be further explored to find their Achilles heel. Full article

(This article belongs to the Topic Advances in Cannabinoid Research)

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22 pages, 4487 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Sweetening Pharmaceutical Radiochemistry by ¹⁸F-Fluoroglycosylation: Recent Progress and Future Prospects

by Sandip S. Shinde, Simone Maschauer and Olaf Prante

Pharmaceuticals 2021, 14(11), 1175; https://doi.org/10.3390/ph14111175 - 17 Nov 2021

Cited by 13 | Viewed by 2315

Abstract

In the field of ¹⁸F-chemistry for the development of radiopharmaceuticals for positron emission tomography (PET), various labeling strategies by the use of prosthetic groups have been implemented, including chemoselective ¹⁸F-labeling of biomolecules. Among those, chemoselective ¹⁸F-fluoroglycosylation methods focus on the [...] Read more.

In the field of ¹⁸F-chemistry for the development of radiopharmaceuticals for positron emission tomography (PET), various labeling strategies by the use of prosthetic groups have been implemented, including chemoselective ¹⁸F-labeling of biomolecules. Among those, chemoselective ¹⁸F-fluoroglycosylation methods focus on the sweetening of pharmaceutical radiochemistry by offering a highly valuable tool for the synthesis of ¹⁸F-glycoconjugates with suitable in vivo properties for PET imaging studies. A previous review covered the various ¹⁸F-fluoroglycosylation methods that were developed and applied as of 2014 (Maschauer and Prante, BioMed. Res. Int. 2014, 214748). This paper is an updated review, providing the recent progress in ¹⁸F-fluoroglycosylation reactions and the preclinical application of ¹⁸F-glycoconjugates, including small molecules, peptides, and high-molecular-weight proteins. Full article

(This article belongs to the Special Issue Targets, Tracers and Translation, Part 2 - New Horizons in Radiopharmaceutical Development)

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39 pages, 2966 KiB

Open AccessEditor’s ChoiceReview

An Update on the Anticancer Activity of Xanthone Derivatives: A Review

by Yehezkiel Steven Kurniawan, Krisfian Tata Aneka Priyangga, Jumina, Harno Dwi Pranowo, Eti Nurwening Sholikhah, Abdul Karim Zulkarnain, Hana Anisa Fatimi and Jeffry Julianus

Pharmaceuticals 2021, 14(11), 1144; https://doi.org/10.3390/ph14111144 - 11 Nov 2021

Cited by 41 | Viewed by 5160

Abstract

The annual number of cancer deaths continues increasing every day; thus, it is urgent to search for and find active, selective, and efficient anticancer drugs as soon as possible. Among the available anticancer drugs, almost all of them contain heterocyclic moiety in their [...] Read more.

The annual number of cancer deaths continues increasing every day; thus, it is urgent to search for and find active, selective, and efficient anticancer drugs as soon as possible. Among the available anticancer drugs, almost all of them contain heterocyclic moiety in their chemical structure. Xanthone is a heterocyclic compound with a dibenzo-γ-pyrone framework and well-known to have “privileged structures” for anticancer activities against several cancer cell lines. The wide anticancer activity of xanthones is produced by caspase activation, RNA binding, DNA cross-linking, as well as P-gp, kinase, aromatase, and topoisomerase inhibition. This anticancer activity depends on the type, number, and position of the attached functional groups in the xanthone skeleton. This review discusses the recent advances in the anticancer activity of xanthone derivatives, both from natural products isolation and synthesis methods, as the anticancer agent through in vitro, in vivo, and clinical assays. Full article

(This article belongs to the Special Issue Anticancer Drugs 2021)

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28 pages, 11365 KiB

Open AccessEditor’s ChoiceArticle

New Multi-Targeted Antiproliferative Agents: Design and Synthesis of IC261-Based Oxindoles as Potential Tubulin, CK1 and EGFR Inhibitors

by Momen R. Fareed, Mai E. Shoman, Mohammed I. A. Hamed, Mohamed Badr, Hanin A. Bogari, Sameh S. Elhady, Tarek S. Ibrahim, Gamal El-Din A. Abuo-Rahma and Taha F. S. Ali

Pharmaceuticals 2021, 14(11), 1114; https://doi.org/10.3390/ph14111114 - 30 Oct 2021

Cited by 10 | Viewed by 2726

Abstract

A series of 3-benzylideneindolin-2-one compounds was designed and synthesized based on combretastatin A-4 and compound IC261, a dual casein kinase (CK1)/tubulin polymerization inhibitor, taking into consideration the pharmacophore required for EGFR-tyrosine kinase inhibition. The new molecular entities provoked significant growth inhibition against [...] Read more.

A series of 3-benzylideneindolin-2-one compounds was designed and synthesized based on combretastatin A-4 and compound IC261, a dual casein kinase (CK1)/tubulin polymerization inhibitor, taking into consideration the pharmacophore required for EGFR-tyrosine kinase inhibition. The new molecular entities provoked significant growth inhibition against PC-3, MCF-7 and COLO-205 at a 10 μM dose. Compounds 6-chloro-3-(2,4,6-trimethoxybenzylidene) indolin-2-one, 4b, and 5-methoxy-3-(2,4,6-trimethoxybenzylidene)indolin-2-one, 4e, showed potent activity against the colon cancer COLO-205 cell line with an IC₅₀ value of 0.2 and 0.3 μM. A mechanistic study demonstrated 4b’s efficacy in inhibiting microtubule assembly (IC₅₀ = 1.66 ± 0.08 μM) with potential binding to the colchicine binding site (docking study). With an IC₅₀ of 1.92 ± 0.09 μg/mL, 4b inhibited CK1 almost as well as IC261. Additionally, 4b and 4e were effective inhibitors of EGFR-TK with IC₅₀s of 0.19 μg/mL and 0.40 μg/mL compared to Gifitinib (IC₅₀ = 0.05 μg/mL). Apoptosis was induced in COLO-205 cells treated with 4b, with apoptotic markers dysregulated. Caspase 3 levels were elevated to more than three-fold, while Cytochrome C levels were doubled. The cell cycle was arrested in the pre-G1 phase with extensive cellular accumulation in the pre-G1 phase, confirming apoptosis induction. Levels of cell cycle regulating proteins BAX and Bcl-2 were also defective. The binding interaction patterns of these compounds at the colchicine binding site of tubulin and the Gifitinib binding site of EGFR were verified by molecular docking, which adequately matched the reported experimental result. Hence, 4b and 4e are considered promising potent multitarget agents against colon cancer that require optimization. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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20 pages, 5024 KiB

Open AccessEditor’s ChoiceReview

Antiviral Activities of Andrographolide and Its Derivatives: Mechanism of Action and Delivery System

by Sya’ban Putra Adiguna, Jonathan Ardhianto Panggabean, Akhirta Atikana, Febriana Untari, Fauzia Izzati, Asep Bayu, A’liyatur Rosyidah, Siti Irma Rahmawati and Masteria Yunovilsa Putra

Pharmaceuticals 2021, 14(11), 1102; https://doi.org/10.3390/ph14111102 - 28 Oct 2021

Cited by 19 | Viewed by 8424

Abstract

Andrographispaniculata (Burm.f.) Nees has been used as a traditional medicine in Asian countries, especially China, India, Vietnam, Malaysia, and Indonesia. This herbaceous plant extract contains active compounds with multiple biological activities against various diseases, including the flu, colds, fever, diabetes, hypertension, and [...] Read more.

Andrographispaniculata (Burm.f.) Nees has been used as a traditional medicine in Asian countries, especially China, India, Vietnam, Malaysia, and Indonesia. This herbaceous plant extract contains active compounds with multiple biological activities against various diseases, including the flu, colds, fever, diabetes, hypertension, and cancer. Several isolated compounds from A. paniculata, such as andrographolide and its analogs, have attracted much interest for their potential treatment against several virus infections, including SARS-CoV-2. The mechanisms of action in inhibiting viral infections can be categorized into several types, including regulating the viral entry stage, gene replication, and the formation of mature functional proteins. The efficacy of andrographolide as an antiviral candidate was further investigated since the phytoconstituents of A. paniculata exhibit various physicochemical characteristics, including low solubility and low bioavailability. A discussion on the delivery systems of these active compounds could accelerate their development for commercial applications as antiviral drugs. This study critically reviewed the current antiviral development based on andrographolide and its derivative compounds, especially on their mechanism of action as antiviral drugs and drug delivery systems. Full article

(This article belongs to the Special Issue Antiviral Compounds in Medicinal Plants)

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14 pages, 804 KiB

Open AccessEditor’s ChoiceReview

Rutin (Bioflavonoid) as Cell Signaling Pathway Modulator: Prospects in Treatment and Chemoprevention

by Pratibha Pandey, Fahad Khan, Huda A. Qari and Mohammad Oves

Pharmaceuticals 2021, 14(11), 1069; https://doi.org/10.3390/ph14111069 - 22 Oct 2021

Cited by 37 | Viewed by 5367

Abstract

Cancer is a complex ailment orchestrated by numerous intrinsic and extrinsic pathways. Recent research has displayed a deep interest in developing plant-based cancer therapeutics for better management of the disease and limited side effects. A wide range of plant-derived compounds have been reported [...] Read more.

Cancer is a complex ailment orchestrated by numerous intrinsic and extrinsic pathways. Recent research has displayed a deep interest in developing plant-based cancer therapeutics for better management of the disease and limited side effects. A wide range of plant-derived compounds have been reported for their anticancer potential in the quest of finding an effective therapeutic approach. Rutin (vitamin P) is a low-molecular weight flavonoid glycoside (polyphenolic compound), abundantly present in various vegetables, fruits (especially berries and citrus fruits), and medicinal herbs. Numerous studies have delineated several pharmacological properties of rutin such as its antiprotozoal, antibacterial, anti-inflammatory, antitumor, antiviral, antiallergic, vasoactive, cytoprotective, antispasmodic, hypolipidemic, antihypertensive, and antiplatelet properties. Specifically, rutin-mediated anticancerous activities have been reported in several cancerous cell lines, but the most common scientific evidence, encompassing several molecular processes and interactions, including apoptosis pathway regulation, aberrant cell signaling pathways, and oncogenic genes, has not been thoroughly studied. In this direction, we attempted to project rutin-mediated oncogenic pathway regulation in various carcinomas. Additionally, we also incorporated advanced research that has uncovered the notable potential of rutin in the modulation of several key cellular functions via interaction with mRNAs, with major emphasis on elucidating direct miRNA targets of rutin as well as the process needed to transform these approaches for developing novel therapeutic interventions for the treatment of several cancers. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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16 pages, 854 KiB

Open AccessEditor’s ChoiceArticle

Side Effects of mRNA-Based COVID-19 Vaccines among Young Adults (18–30 Years Old): An Independent Post-Marketing Study

by Abanoub Riad, Andrea Pokorná, Jitka Klugarová, Natália Antalová, Lucia Kantorová, Michal Koščík and Miloslav Klugar

Pharmaceuticals 2021, 14(10), 1049; https://doi.org/10.3390/ph14101049 - 15 Oct 2021

Cited by 30 | Viewed by 5998

Abstract

Young adults had been widely perceived as a low-risk group for COVID-19 severity; therefore, they were deprioritised within the mass vaccination strategies as their prognosis of COVID-19 infection is relatively more favourable than older age groups. On the other hand, vaccination of this [...] Read more.

Young adults had been widely perceived as a low-risk group for COVID-19 severity; therefore, they were deprioritised within the mass vaccination strategies as their prognosis of COVID-19 infection is relatively more favourable than older age groups. On the other hand, vaccination of this demographic group is indispensable to achieve herd immunity. A cross-sectional survey-based study was used to evaluate the side effects of mRNA-based COVID-19 vaccines among university students in the Czech Republic. The validated questionnaire was delivered in a digital form, and it consisted of demographic data; COVID-19 vaccine-related anamnesis; and local, systemic, orofacial, and skin-related side effects’ prevalence, onset, and duration. Out of the 539 included participants, 70.1% were females and 45.8% were <23 years old. The vast majority (95.2%) reported at least one side effect. The most common side effect was injection site pain (91.8%), followed by fatigue (62.5%), headache (36.4%), and muscle pain (34.9%). The majority of local side effects occurred after both doses (74.4%), while most systemic side effects occurred after the second dose only (56.2%). Most local (94.2%) and systemic (93.3%) side effects resolved within three days after vaccination. Females participants’ adjusted odds ratio (AOR) showed they were 2.566 (CI 95%: 1.103–5.970) times more likely to experience post-vaccination side effects, and the participants who received two doses reported an increased AOR of 1.896 (0.708–5.077) for experiencing side effects. The results of this study imply that mRNA-based COVID-19 vaccines are highly probably safe for young adults, and further studies are required to investigate the role of medical anamnesis, prior COVID-19 infection, and gender in side effects incidence. Full article

(This article belongs to the Section Biopharmaceuticals)

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12 pages, 2993 KiB

Open AccessEditor’s ChoiceArticle

Corylin Ameliorates LPS-Induced Acute Lung Injury via Suppressing the MAPKs and IL-6/STAT3 Signaling Pathways

by I-Chen Chen, Shu-Chi Wang, Yi-Ting Chen, Hsin-Han Tseng, Po-Len Liu, Tzu-Chieh Lin, Hsin-En Wu, Yuan-Ru Chen, Yu-Hsin Tseng, Jong-Hau Hsu, Zen-Kong Dai, Jau-Ling Suen and Chia-Yang Li

Pharmaceuticals 2021, 14(10), 1046; https://doi.org/10.3390/ph14101046 - 14 Oct 2021

Cited by 16 | Viewed by 3249

Abstract

Acute lung injury (ALI) is a high mortality disease with acute inflammation. Corylin is a compound isolated from the whole plant of Psoralea corylifolia L. and has been reported to have anti-inflammatory activities. Herein, we investigated the therapeutic potential of corylin on lipopolysaccharides [...] Read more.

Acute lung injury (ALI) is a high mortality disease with acute inflammation. Corylin is a compound isolated from the whole plant of Psoralea corylifolia L. and has been reported to have anti-inflammatory activities. Herein, we investigated the therapeutic potential of corylin on lipopolysaccharides (LPS)-induced ALI, both in vitro and in vivo. The levels of proinflammatory cytokine secretions were analyzed by ELISA; the expressions of inflammation-associated proteins were detected using Western blot; and the number of immune cell infiltrations in the bronchial alveolar lavage fluid (BALF) were detected by multicolor flow cytometry and lung tissues by hematoxylin and eosin (HE) staining, respectively. Experimental results indicated that corylin attenuated LPS-induced IL-6 production in human bronchial epithelial cells (HBEC3-KT cells). In intratracheal LPS-induced ALI mice, corylin attenuated tissue damage, suppressed inflammatory cell infiltration, and decreased IL-6 and TNF-α secretions in the BALF and serum. Moreover, it further inhibited the phosphorylation of mitogen-activated protein kinases (MAPKs), including p-JNK, p-ERK, p-p38, and repressed the activation of signal transducer and activator of transcription 3 (STAT3) in lungs. Collectively, our results are the first to demonstrate the anti-inflammatory effects of corylin on LPS-induced ALI and suggest corylin has significant potential as a novel therapeutic agent for ALI. Full article

(This article belongs to the Special Issue Lung Injury and Repair)

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