Pharmaceuticals

11 pages, 529 KiB

Open AccessReview

The Potential Application of Natural Photosensitizers Used in Antimicrobial Photodynamic Therapy against Oral Infections

by Shima Afrasiabi, Alireza Partoazar, Nasim Chiniforush and Ramin Goudarzi

Pharmaceuticals 2022, 15(6), 767; https://doi.org/10.3390/ph15060767 - 20 Jun 2022

Cited by 20 | Viewed by 4041

Abstract

Oral health problems and the emergence of antimicrobial resistance among pathogenic bacterial strains have become major global challenges and are essential elements that negatively affect general well-being. Antimicrobial photodynamic therapy (APDT) is based on a light source and oxygen that activates a nontoxic [...] Read more.

Oral health problems and the emergence of antimicrobial resistance among pathogenic bacterial strains have become major global challenges and are essential elements that negatively affect general well-being. Antimicrobial photodynamic therapy (APDT) is based on a light source and oxygen that activates a nontoxic photosensitizer, resulting in microbial destruction. Synthetic and natural products can be used to help the APDT against oral microorganisms. The undesirable consequences of conventional photosensitizers, including toxicity, and cost encourage researchers to explore new promising photosensitizers based on natural compounds such as curcumin, chlorella, chlorophyllin, phycocyanin, 5-aminolevulinic acid, and riboflavin. In this review, we summarize in vitro studies describing the potential use of APDT therapy conjugated with some natural products against selected microorganisms that are considered to be responsible for oral infections. Full article

(This article belongs to the Special Issue Photodynamic Therapy 2022)

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24 pages, 3376 KiB

Open AccessArticle

Inhibitors of O-Acetylserine Sulfhydrylase with a Cyclopropane-Carboxylic Acid Scaffold Are Effective Colistin Adjuvants in Gram Negative Bacteria

by Giannamaria Annunziato, Costanza Spadini, Marialaura Marchetti, Nina Franko, Marialaura Pavone, Mattia Iannarelli, Agostino Bruno, Marco Pieroni, Stefano Bettati, Clotilde Silvia Cabassi, Barbara Campanini and Gabriele Costantino

Pharmaceuticals 2022, 15(6), 766; https://doi.org/10.3390/ph15060766 - 20 Jun 2022

Cited by 6 | Viewed by 2595

Abstract

Antibacterial adjuvants are of great significance, since they allow one to downscale the therapeutic dose of conventional antibiotics and reduce the insurgence of antibacterial resistance. Herein, we report that O-acetylserine sulfhydrylase (OASS) inhibitors could be used as colistin adjuvants to treat infections [...] Read more.

Antibacterial adjuvants are of great significance, since they allow one to downscale the therapeutic dose of conventional antibiotics and reduce the insurgence of antibacterial resistance. Herein, we report that O-acetylserine sulfhydrylase (OASS) inhibitors could be used as colistin adjuvants to treat infections caused by critical pathogens spreading worldwide, Escherichia coli, Salmonella enterica serovar Typhimurium, and Klebsiella pneumoniae. Starting from a hit compound endowed with a nanomolar dissociation constant, we have rationally designed and synthesized a series of derivatives to be tested against S. Typhimurium OASS isoenzymes, StOASS-A and StOASS-B. All acidic derivatives have shown good activities in the nanomolar range against both OASS isoforms in vitro. Minimal Inhibitory Concentrations (MICs) were then evaluated, as well as compounds’ toxicity. The compounds endowed with good activity in vitro and low cytotoxicity have been challenged as a potential colistin adjuvant against pathogenic bacteria in vitro and the fractional inhibitory concentration (FIC) index has been calculated to define additive or synergistic effects. Finally, the target engagement inside the S. Typhimurium cells was confirmed by using a mutant strain in which the OASS enzymes were inactivated. Our results provide a robust proof of principle supporting OASS as a potential nonessential antibacterial target to develop a new class of adjuvants. Full article

(This article belongs to the Section Medicinal Chemistry)

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11 pages, 1052 KiB

Open AccessBrief Report

Cardio- and Neurotoxicity of Selected Anti-COVID-19 Drugs

by Martin W. Nicholson, Ching-Ying Huang, Jyun-Yuan Wang, Chien-Yu Ting, Yu-Che Cheng, Darien Z. H. Chan, Yi-Chan Lee, Ching-Chuan Hsu, Yu-Hung Hsu, Cindy M. C. Chang, Marvin L. Hsieh, Yuan-Yuan Cheng, Yi-Ling Lin, Chien-Hsiun Chen, Ying-Ta Wu, Timothy A. Hacker, Joseph C. Wu, Timothy J. Kamp and Patrick C. H. Hsieh

Pharmaceuticals 2022, 15(6), 765; https://doi.org/10.3390/ph15060765 - 20 Jun 2022

Cited by 3 | Viewed by 2738

Abstract

Since December 2019, the novel coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected ~435 million people and caused ~6 million related deaths as of March 2022. To combat COVID-19, there have been many attempts to repurpose [...] Read more.

Since December 2019, the novel coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected ~435 million people and caused ~6 million related deaths as of March 2022. To combat COVID-19, there have been many attempts to repurpose FDA-approved drugs or revive old drugs. However, many of the current treatment options have been known to cause adverse drug reactions. We employed a population-based drug screening platform using 13 human leukocyte antigen (HLA) homozygous human induced pluripotent cell (iPSC) lines to assess the cardiotoxicity and neurotoxicity of the first line of anti-COVID-19 drugs. We also infected iPSC-derived cells to understand the viral infection of cardiomyocytes and neurons. We found that iPSC-derived cardiomyocytes express the ACE2 receptor which correlated with a higher infection of the SARS-CoV-2 virus (r = 0.86). However, we were unable to detect ACE2 expression in neurons which correlated with a low infection rate. We then assessed the toxicity of anti-COVID-19 drugs and identified two cardiotoxic compounds (remdesivir and arbidol) and four neurotoxic compounds (arbidol, remdesivir, hydroxychloroquine, and chloroquine). These data show that this platform can quickly and easily be employed to further our understanding of cell-specific infection and identify drug toxicity of potential treatment options helping clinicians better decide on treatment options. Full article

(This article belongs to the Section Pharmacology)

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38 pages, 15698 KiB

Open AccessSystematic Review

Discovery of Therapeutics Targeting Oxidative Stress in Autosomal Recessive Cerebellar Ataxia: A Systematic Review

by Sze Yuen Lew, Michael Weng Lok Phang, Pit Shan Chong, Jaydeep Roy, Chi Him Poon, Wing Shan Yu, Lee Wei Lim and Kah Hui Wong

Pharmaceuticals 2022, 15(6), 764; https://doi.org/10.3390/ph15060764 - 19 Jun 2022

Cited by 11 | Viewed by 6332

Abstract

Autosomal recessive cerebellar ataxias (ARCAs) are a heterogeneous group of rare neurodegenerative inherited disorders. The resulting motor incoordination and progressive functional disabilities lead to reduced lifespan. There is currently no cure for ARCAs, likely attributed to the lack of understanding of the multifaceted [...] Read more.

Autosomal recessive cerebellar ataxias (ARCAs) are a heterogeneous group of rare neurodegenerative inherited disorders. The resulting motor incoordination and progressive functional disabilities lead to reduced lifespan. There is currently no cure for ARCAs, likely attributed to the lack of understanding of the multifaceted roles of antioxidant defense and the underlying mechanisms. This systematic review aims to evaluate the extant literature on the current developments of therapeutic strategies that target oxidative stress for the management of ARCAs. We searched PubMed, Web of Science, and Science Direct Scopus for relevant peer-reviewed articles published from 1 January 2016 onwards. A total of 28 preclinical studies fulfilled the eligibility criteria for inclusion in this systematic review. We first evaluated the altered cellular processes, abnormal signaling cascades, and disrupted protein quality control underlying the pathogenesis of ARCA. We then examined the current potential therapeutic strategies for ARCAs, including aromatic, organic and pharmacological compounds, gene therapy, natural products, and nanotechnology, as well as their associated antioxidant pathways and modes of action. We then discussed their potential as antioxidant therapeutics for ARCAs, with the long-term view toward their possible translation to clinical practice. In conclusion, our current understanding is that these antioxidant therapies show promise in improving or halting the progression of ARCAs. Tailoring the therapies to specific disease stages could greatly facilitate the management of ARCAs. Full article

(This article belongs to the Special Issue Neuromuscular Disorders: Current Gene and Cell Therapeutic Approaches)

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12 pages, 2731 KiB

Open AccessArticle

Advanced Analytical Approach Based on Combination of FT-IR and Chemometrics for Quality Control of Pharmaceutical Preparations

by Martina Foschi, Mariagrazia Marziale and Alessandra Biancolillo

Pharmaceuticals 2022, 15(6), 763; https://doi.org/10.3390/ph15060763 - 18 Jun 2022

Cited by 6 | Viewed by 2432

Abstract

Background: The present work represents a feasibility study for the realization of an analytical method finalized to the detection of expired antibiotic tablets. The work focuses on a specific antibiotic drug and represents the preliminary study upstream of a larger-scale work. Methods: attenuated [...] Read more.

Background: The present work represents a feasibility study for the realization of an analytical method finalized to the detection of expired antibiotic tablets. The work focuses on a specific antibiotic drug and represents the preliminary study upstream of a larger-scale work. Methods: attenuated Total reflection-Fourier transform infrared spectroscopy (ATR-FTIR) spectra coupled with sequential preprocessing through an orthogonalization (SPORT) chemometric approach were used to discriminate between expired and compliant tablets. Conclusions: The highest predictive accuracy (93.3% of correct classification rate in external validation, corresponding to 1 misclassified test sample over 15) was achieved by analyzing intact tablets. This represents an excellent result because it gives indications regarding the possibility of determining, in a completely non-destructive way, the presence of expired drugs. Full article

(This article belongs to the Section Pharmaceutical Technology)

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20 pages, 1717 KiB

Open AccessReview

A Review on the Role of Pilocarpine on the Management of Xerostomia and the Importance of the Topical Administration Systems Development

by Afroditi Kapourani, Konstantinos N. Kontogiannopoulos and Panagiotis Barmpalexis

Pharmaceuticals 2022, 15(6), 762; https://doi.org/10.3390/ph15060762 - 18 Jun 2022

Cited by 22 | Viewed by 7559

Abstract

Xerostomia is linked to an increased risk of dental caries, oral fungal infections, and speaking/swallowing difficulties, factors that may significantly degrade patients’ life, socially- or emotionally-wise. Consequently, there is an increasing interest in developing management approaches for confronting this oral condition, at which [...] Read more.

Xerostomia is linked to an increased risk of dental caries, oral fungal infections, and speaking/swallowing difficulties, factors that may significantly degrade patients’ life, socially- or emotionally-wise. Consequently, there is an increasing interest in developing management approaches for confronting this oral condition, at which pilocarpine, a parasympathomimetic agent, plays a vital role. Although the therapeutic effects of orally administrated pilocarpine on the salivary gland flow and the symptoms of xerostomia have been proved by numerous studies, the systemic administration of this drug is affiliated with various adverse effects. Some of the typical adverse effects include sweating, nausea, vomiting, diarrhea, rhinitis, dizziness and increased urinary frequency. In this vein, new strategies to develop novel and effective dosage forms for topical (i.e., in the oral cavity) pilocarpine administration, in order for the salivary flow to be enhanced with minimal systemic manifestations, have emerged. Therefore, the purpose of the current review is to survey the literature concerning the performance of topical pilocarpine delivery systems. According to the findings, the topical delivery of pilocarpine can be regarded as the equivalent to systemic delivery of the drug, efficacy-wise, but with improved patient tolerance and less adverse effects. Full article

(This article belongs to the Section Pharmaceutical Technology)

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15 pages, 3252 KiB

Open AccessArticle

Multi-Dose Intravenous Administration of Neutral and Cationic Liposomes in Mice: An Extensive Toxicity Study

by Stéphanie Andrade, Joana A. Loureiro, Santiago Ramirez, Celso S. G. Catumbela, Claudio Soto, Rodrigo Morales and Maria Carmo Pereira

Pharmaceuticals 2022, 15(6), 761; https://doi.org/10.3390/ph15060761 - 18 Jun 2022

Cited by 11 | Viewed by 2770

Abstract

Liposomes are widely used as delivery systems for therapeutic purposes. However, the toxicity associated with the multi-dose administration of these nanoparticles is not fully elucidated. Here, we evaluated the toxicity of the prolonged administration of liposomes composed of neutral or cationic phospholipids often [...] Read more.

Liposomes are widely used as delivery systems for therapeutic purposes. However, the toxicity associated with the multi-dose administration of these nanoparticles is not fully elucidated. Here, we evaluated the toxicity of the prolonged administration of liposomes composed of neutral or cationic phospholipids often used in drug and gene delivery. For that purpose, adult wild-type mice (C57Bl6) were randomly distributed into three groups receiving either vehicle (PBS), neutral, or cationic liposomes and subjected to repeated intravenous injections for a total of 10 doses administered over 3 weeks. Several parameters, including mortality, body weight, and glucose levels, were monitored throughout the trial. While these variables did not change in the group treated with neutral liposomes, the group treated with the positively charged liposomes displayed a mortality rate of 45% after 10 doses of administration. Additional urinalysis, blood tests, and behavioral assays to evaluate impairments of motor functions or lesions in major organs were also performed. The cationic group showed less forelimb peak force than the control group, alterations at the hematological level, and inflammatory components, unlike the neutral group. Overall, the results demonstrate that cationic liposomes are toxic for multi-dose administration, while the neutral liposomes did not induce changes associated with toxicity. Therefore, our results support the use of the well-known neutral liposomes as safe drug shuttles, even when repetitive administrations are needed. Full article

(This article belongs to the Special Issue Current Insights on Lipid-Based Nanosystems)

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19 pages, 3206 KiB

Open AccessArticle

Development of a Citric-Acid-Modified Cellulose Adsorbent Derived from Moringa peregrina Leaf for Adsorptive Removal of Citalopram HBr in Aqueous Solutions

by Syed Najmul Hejaz Azmi, Wafa Mustafa Al Lawati, Umaima Hamed Abdullah Al Hoqani, Ekhlas Al Aufi, Khalsa Al Hatmi, Jumana Salim Al Zadjali, Nafisur Rahman, Mohd Nasir, Habibur Rahman and Shah A. Khan

Pharmaceuticals 2022, 15(6), 760; https://doi.org/10.3390/ph15060760 - 17 Jun 2022

Cited by 16 | Viewed by 2786

Abstract

A citric-acid-modified Moringa peregrina leaf substrate was prepared and studied as an effective adsorbent for the adsorptive removal of citalopram HBr (CTM). FTIR spectra were utilized to characterize the prepared solid. The effects of experimental variables on the percentage removal of citalopram HBr [...] Read more.

A citric-acid-modified Moringa peregrina leaf substrate was prepared and studied as an effective adsorbent for the adsorptive removal of citalopram HBr (CTM). FTIR spectra were utilized to characterize the prepared solid. The effects of experimental variables on the percentage removal of citalopram HBr were investigated using response surface methodology. The optimum conditions selected for removal of CTM were 7 and 4 min, 0.17 g per 50 mL and 35 mg·L⁻¹ for pH, contact time, adsorbent dose and initial concentration of CTM, respectively. Under the optimized experimental conditions, 82.59% CTM (35 mg·L⁻¹) was removed. The Langmuir isotherm, Freundlich isotherm, pseudo second-order kinetic model and diffusion-chemisorption model explained the adsorption data successfully. The maximum adsorption capacity at 298 K was 8.58 mg·g⁻¹. A thermodynamic study illustrated that CTM adsorption was spontaneous and endothermic in nature. Full article

(This article belongs to the Topic Emerging Material-Based Approaches to Chronic and Infectious Diseases)

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19 pages, 4493 KiB

Open AccessArticle

Use of an Electronic Medication Management Support System in Patients with Polypharmacy in General Practice: A Quantitative Process Evaluation of the AdAM Trial

by Robin Brünn, Dorothea Lemke, Jale Basten, Petra Kellermann-Mühlhoff, Juliane Köberlein-Neu, Christiane Muth, Marjan van den Akker and on behalf of the AdAM Study Group

Pharmaceuticals 2022, 15(6), 759; https://doi.org/10.3390/ph15060759 - 17 Jun 2022

Cited by 3 | Viewed by 2717

Abstract

Polypharmacy is associated with a risk of negative health outcomes. Potentially inappropriate medications, interactions resulting from contradicting medical guidelines, and inappropriate monitoring, all increase the risk. This process evaluation (PE) of the AdAM study investigates implementation and use of a computerized decision-support system [...] Read more.

Polypharmacy is associated with a risk of negative health outcomes. Potentially inappropriate medications, interactions resulting from contradicting medical guidelines, and inappropriate monitoring, all increase the risk. This process evaluation (PE) of the AdAM study investigates implementation and use of a computerized decision-support system (CDSS). The CDSS analyzes medication appropriateness by including claims data, and hence provides general practitioners (GPs) with full access to patients’ medical treatments. We based our PE on pseudonymized logbook entries into the CDSS and used the four dimensions of the Medical Research Council PE framework. Reach, which examines the extent to which the intended study population was included, and Dose, Fidelity, and Tailoring, which examine how the software was actually used by GPs. The PE was explorative and descriptive. Study participants were representative of the target population, except for patients receiving a high level of nursing care, as they were treated less frequently. GPs identified and corrected inappropriate prescriptions flagged by the CDSS. The frequency and intensity of interventions documented in the form of logbook entries lagged behind expectations, raising questions about implementation barriers to the intervention and the limitations of the PE. Impossibility to connect the CDSS to GPs’ electronic medical records (EMR) of GPs due to technical conditions in the German healthcare system may have hindered the implementation of the intervention. Data logged in the CDSS may underestimate medication changes in patients, as documentation was voluntary and already included in EMR. Full article

(This article belongs to the Special Issue Clinical Utility of Applying PGx and Deprescribing-Based Decision Support in Polypharmacy: Future Perspectives)

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20 pages, 7498 KiB

Open AccessArticle

Ginsenoside Rh3 Inhibits Lung Cancer Metastasis by Targeting Extracellular Signal-Regulated Kinase: A Network Pharmacology Study

by Xiaodan Xue, Yannan Liu, Linlin Qu, Cuiying Fan, Xiaoxuan Ma, Pingkai Ouyang and Daidi Fan

Pharmaceuticals 2022, 15(6), 758; https://doi.org/10.3390/ph15060758 - 17 Jun 2022

Cited by 9 | Viewed by 3052

Abstract

Lung cancer has a high mortality rate and is very common. One of the main reasons for the poor prognosis of patients with lung cancer is the high incidence of metastasis. Ginsenoside Rh3, a rare ginsenoside extracted from Panax notoginseng, exhibits excellent anti-inflammatory [...] Read more.

Lung cancer has a high mortality rate and is very common. One of the main reasons for the poor prognosis of patients with lung cancer is the high incidence of metastasis. Ginsenoside Rh3, a rare ginsenoside extracted from Panax notoginseng, exhibits excellent anti-inflammatory and anti-tumor effects. Nonetheless, the inhibitory potential of Rh3 against lung cancer remains unknown. The target genes of Rh3 were screened by the PharmMapper database; the proliferation of lung cancer cells was detected by MTT assay; the migration and invasion of cells were detected by the Transwell method; and the expression of extracellular signal-regulated kinase (ERK) and EMT-related proteins in vivo and in vitro were detected by Western blotting. In addition, we established a lung metastasis model in nude mice using A549 cells to assess the effect of Rh3 on NSCLC tumor metastasis in vivo. Our findings suggest that Rh3 significantly inhibited lung cancer metastasis both in vivo and in vitro. It was determined by flow cytometry analysis that Rh3 notably inhibited cell proliferation by blocking the G1 phase. In addition, Rh3 inhibited metastasis in lung cancer cells and regulated the expression of metastasis-related proteins under hypoxia. Mechanistic studies suggested that Rh3 targeted ERK to inhibit lung cancer metastasis. The ERK inhibitor U0126 or siRNA-mediated knockdown of ERK had an enhanced effect on Rh3’s ability to inhibit lung cancer metastasis. The studies revealed that the inhibitory effect of Rh3 on the metastatic ability of lung cancer cells may be supported by ERK-related signaling pathways. Full article

(This article belongs to the Section Pharmacology)

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12 pages, 904 KiB

Open AccessArticle

Effect of Norelgestromin and Ethinylestradiol in Transdermal Patches on the Clinical Outcomes and Biochemical Parameters of COVID-19 Patients: A Clinical Trial Pilot Study

by Cortés-Algara Alfredo, Cárdenas-Rodríguez Noemí, Reyes-Long Samuel, Ortega-Cuellar Daniel, Ruz-Barros Rodrigo, Mondragón-Terán Paul, Escamilla-Tilch Mónica, Correa-Basurto José, Lara-Padilla Eleazar, Alfaro-Rodríguez Alfonso, Cortes-Altamirano José Luis and Bandala Cindy

Pharmaceuticals 2022, 15(6), 757; https://doi.org/10.3390/ph15060757 - 17 Jun 2022

Cited by 5 | Viewed by 2478

Abstract

The disease caused by SARS-CoV-2 is still considered a global pandemic. Transdermal patches (TP) with immunoregulators such as estrogen and progesterone compounds could be a feasible option to treat COVID-19 because of their accessibility and relative safety. The objective of the current study [...] Read more.

The disease caused by SARS-CoV-2 is still considered a global pandemic. Transdermal patches (TP) with immunoregulators such as estrogen and progesterone compounds could be a feasible option to treat COVID-19 because of their accessibility and relative safety. The objective of the current study was to evaluate the additional treatment with norelgestromin and ethinylestradiol in TP on the clinical and biochemical evolution of COVID-19 patients. The present is a clinical-trial pilot study that included subjects diagnosed with COVID-19, randomized into two groups; the experimental Evra^® TP (norelgestromin 6 mg and ethinylestradiol 0.60 mg) was administered such that it was applied on arrival and replaced at day 8 and day 15. The control continued with the conventional COVID-19 treatment protocol. A blood sample was taken each week in order to evaluate relevant biochemical parameters, clinical signs, and evolution. In total, 44 subjects participated in this study, 30 in the experimental group and 14 in the control group. Both groups were homogeneous in terms of age and comorbidities. The experimental group had a significantly lower hospital stay (p = 0.01), high flow supplemental oxygen (p = 0.001), mechanical ventilation (p = 0.003), and intubation (p = 0.01), and the oxygen saturation significantly increased (p = 0.01) in comparison with control group when patients were exposed to room air. A decrease in ferritin (p < 0.05) was observed, with no significant increase in ESR (p > 0.05), D dimer (p > 0.05) and platelets (p > 0.05) in an auto-controlled analysis in the experimental group. Norelgestromin and ethinylestradiol TP could be a safe and effective treatment for moderate and severe COVID-19 patients. Full article

(This article belongs to the Section Pharmacology)

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28 pages, 1642 KiB

Open AccessEditor’s ChoiceReview

Tetanus Toxin Fragment C: Structure, Drug Discovery Research and Production

by Caroline Bayart, Angélique Mularoni, Nada Hemmani, Soumeya Kerachni, Joachim Jose, Patrice Gouet, Joseph Paladino and Marc Le Borgne

Pharmaceuticals 2022, 15(6), 756; https://doi.org/10.3390/ph15060756 - 17 Jun 2022

Cited by 9 | Viewed by 6751

Abstract

Tetanus toxoid (TTd) plays an important role in the pharmaceutical world, especially in vaccines. The toxoid is obtained after formaldehyde treatment of the tetanus toxin. In parallel, current emphasis in the drug discovery field is put on producing well-defined and safer drugs, explaining [...] Read more.

Tetanus toxoid (TTd) plays an important role in the pharmaceutical world, especially in vaccines. The toxoid is obtained after formaldehyde treatment of the tetanus toxin. In parallel, current emphasis in the drug discovery field is put on producing well-defined and safer drugs, explaining the interest in finding new alternative proteins. The tetanus toxin fragment C (TTFC) has been extensively studied both as a neuroprotective agent for central nervous system disorders owing to its neuronal properties and as a carrier protein in vaccines. Indeed, it is derived from a part of the tetanus toxin and, as such, retains its immunogenic properties without being toxic. Moreover, this fragment has been well characterized, and its entire structure is known. Here, we propose a systematic review of TTFC by providing information about its structural features, its properties and its methods of production. We also describe the large uses of TTFC in the field of drug discovery. TTFC can therefore be considered as an attractive alternative to TTd and remarkably offers a wide range of uses, including as a carrier, delivery vector, conjugate, booster, inducer, and neuroprotector. Full article

(This article belongs to the Section Biopharmaceuticals)

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15 pages, 3820 KiB

Open AccessArticle

Development and Validation of an HPLC-UV Method for the Dissolution Studies of 3D-Printed Paracetamol Formulations in Milk-Containing Simulated Gastrointestinal Media

by Natalia Manousi, Christina Karavasili, Dimitrios G. Fatouros, Paraskevas D. Tzanavaras and Constantinos K. Zacharis

Pharmaceuticals 2022, 15(6), 755; https://doi.org/10.3390/ph15060755 - 16 Jun 2022

Cited by 2 | Viewed by 2897

Abstract

Herein, a simple and rapid HPLC method for the determination of paracetamol milk-containing biorelevant media is proposed. The separation of the analyte from the milk-containing biorelevant media was accomplished isocratically using a mobile phase containing 25 mM phosphate buffer (pH = 3.0) and [...] Read more.

Herein, a simple and rapid HPLC method for the determination of paracetamol milk-containing biorelevant media is proposed. The separation of the analyte from the milk-containing biorelevant media was accomplished isocratically using a mobile phase containing 25 mM phosphate buffer (pH = 3.0) and methanol, 80:20, v/v at a flow rate of 1 mL min⁻¹. Following a protein precipitation-based sample clean-up, a thorough investigation of the effect of the precipitation reagent (methanol, acetonitrile, 10% v/v trifluoroacetic acid solution) on the analyte recovery was performed. The matrix effect was assessed in each biorelevant medium by comparing the slopes of the calibration curves of aqueous and matrix-matched calibration curves. The method was comprehensively validated using the accuracy profiles. The β-expectation tolerance intervals did not exceed the acceptance criteria of ±15%, meaning that 95% of future results will be included in the defined bias limits. The relative bias ranged between −4.5 and +3.9% for all analytes, while the RSD values for repeatability and intermediate precision were less than 2.7% and 3.0%, respectively. The achieved limit of detection (LOD) was 0.02 μg mL⁻¹ and the lower limits of quantitation (LLOQ) were established as 10 μg mL⁻¹, which corresponded to 2% of the highest expected concentration of paracetamol. The proposed scheme was utilized for the determination of paracetamol in dissolution studies of its 3D-printed formulation in milk-containing biorelevant media. Full article

(This article belongs to the Special Issue Applications of Liquid Chromatography in Analysis of Pharmaceuticals and Natural Products)

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16 pages, 3809 KiB

Open AccessArticle

Quercetin-Rich Extracts from Onions (Allium cepa) Play Potent Cytotoxicity on Adrenocortical Carcinoma Cell Lines, and Quercetin Induces Important Anticancer Properties

by Alan A. Veiga, Ana Carolina Irioda, Bassam F. Mogharbel, Sandro J. R. Bonatto and Lauro M. Souza

Pharmaceuticals 2022, 15(6), 754; https://doi.org/10.3390/ph15060754 - 16 Jun 2022

Cited by 7 | Viewed by 2926

Abstract

Adrenocortical carcinoma (ACC) is a rare subtype of cancer, with a poor prognosis in children and adults. Mitotane is the only approved adrenolytic drug for the treatment of ACC, which has controversies regarding its efficacy and side effects on patients. Onion (Allium [...] Read more.

Adrenocortical carcinoma (ACC) is a rare subtype of cancer, with a poor prognosis in children and adults. Mitotane is the only approved adrenolytic drug for the treatment of ACC, which has controversies regarding its efficacy and side effects on patients. Onion (Allium cepa), a worldwide consumed food, is associated with many health benefits. Along with its glycosides, the flavonoid quercetin is abundant in onions. After evaluating the cytotoxicity of A. cepa extracts on adrenocortical carcinoma cell line (H295R), the rich quercetin fractions had better results. Then, we aimed to compare the quercetin vs. mitotane effectiveness, using adrenocortical carcinoma cell lines H295R and SW-13. Quercetin showed a higher cytotoxicity response on both cancerous cell lines after 10 µM concentration, while mitotane only after 30 µM. Cell cycle dynamics were altered upon quercetin treatments, with G2 phase increase with 30 µM of quercetin on H295R cell line and G1 arrest on SW-13 cell line with 15 µM. Early and late apoptosis, alongside intracellular calcium, were increased on SW-13 treated with 30 µM of quercetin, and ROS rates were reduced by quercetin on H295R. Therefore, quercetin-rich onions have the potential to be a natural source of anticancer agents for adrenocortical carcinoma. Full article

(This article belongs to the Special Issue Molecular and Cellular Studies of Natural Antioxidants as Potential Therapeutics for Cancer)

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17 pages, 724 KiB

Open AccessReview

Pharmacological Induction of Fetal Hemoglobin in β-Thalassemia and Sickle Cell Disease: An Updated Perspective

by Rayan Bou-Fakhredin, Lucia De Franceschi, Irene Motta, Maria Domenica Cappellini and Ali T. Taher

Pharmaceuticals 2022, 15(6), 753; https://doi.org/10.3390/ph15060753 - 16 Jun 2022

Cited by 21 | Viewed by 5320

Abstract

A significant amount of attention has recently been devoted to the mechanisms involved in hemoglobin (Hb) switching, as it has previously been established that the induction of fetal hemoglobin (HbF) production in significant amounts can reduce the severity of the clinical course in [...] Read more.

A significant amount of attention has recently been devoted to the mechanisms involved in hemoglobin (Hb) switching, as it has previously been established that the induction of fetal hemoglobin (HbF) production in significant amounts can reduce the severity of the clinical course in diseases such as β-thalassemia and sickle cell disease (SCD). While the induction of HbF using lentiviral and genome-editing strategies has been made possible, they present limitations. Meanwhile, progress in the use of pharmacologic agents for HbF induction and the identification of novel HbF-inducing strategies has been made possible as a result of a better understanding of γ-globin regulation. In this review, we will provide an update on all current pharmacological inducer agents of HbF in β-thalassemia and SCD in addition to the ongoing research into other novel, and potentially therapeutic, HbF-inducing agents. Full article

(This article belongs to the Special Issue Drug Design and Development for Rare Hematologic Diseases)

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15 pages, 2837 KiB

Open AccessArticle

Application of In Silico Filtering and Isothermal Titration Calorimetry for the Discovery of Small Molecule Inhibitors of MDM2

by Hen Alali, Itai Bloch, Irena Rapaport, Luisa Rodrigues, Inbal Sher, Tamar Ansbacher and Maayan Gal

Pharmaceuticals 2022, 15(6), 752; https://doi.org/10.3390/ph15060752 - 16 Jun 2022

Viewed by 2975

Abstract

The initial discovery phase of protein modulators, which consists of filtering molecular libraries and in vitro direct binding validation, is central in drug discovery. Thus, virtual screening of large molecular libraries, together with the evaluation of binding affinity by isothermal calorimetry, generates an [...] Read more.

The initial discovery phase of protein modulators, which consists of filtering molecular libraries and in vitro direct binding validation, is central in drug discovery. Thus, virtual screening of large molecular libraries, together with the evaluation of binding affinity by isothermal calorimetry, generates an efficient experimental setup. Herein, we applied virtual screening for discovering small molecule inhibitors of MDM2, a major negative regulator of the tumor suppressor p53, and thus a promising therapeutic target. A library of 20 million small molecules was screened against an averaged model derived from multiple structural conformations of MDM2 based on published structures. Selected molecules originating from the computational filtering were tested in vitro for their direct binding to MDM2 via isothermal titration calorimetry. Three new molecules, representing distinct chemical scaffolds, showed binding to MDM2. These were further evaluated by exploring structure-similar chemical analogues. Two scaffolds were further evaluated by de novo synthesis of molecules derived from the initial molecules that bound MDM2, one with a central oxoazetidine acetamide and one with benzene sulfonamide. Several molecules derived from these scaffolds increased wild-type p53 activity in MCF7 cancer cells. These set a basis for further chemical optimization and the development of new chemical entities as anticancer drugs. Full article

(This article belongs to the Special Issue Targeting p53 by Small Molecules: Application in Oncology)

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15 pages, 2430 KiB

Open AccessArticle

The Synthesis, Characterization, Molecular Docking and In Vitro Antitumor Activity of Benzothiazole Aniline (BTA) Conjugated Metal-Salen Complexes as Non-Platinum Chemotherapeutic Agents

by Md. Kamrul Islam, Seongmin Ha, Ah-Rum Baek, Byeong-Woo Yang, Yeoun-Hee Kim, Hyun-Jin Park, Minsup Kim, Sung-Wook Nam, Gang-Ho Lee and Yongmin Chang

Pharmaceuticals 2022, 15(6), 751; https://doi.org/10.3390/ph15060751 - 15 Jun 2022

Cited by 6 | Viewed by 3316

Abstract

Here, we describe the synthesis, characterization, and in vitro biological evaluation of a series of transition metal complexes containing benzothiazole aniline (BTA). We employed BTA, which is known for its selective anticancer activity, and a salen-type Schiff-based ligand to coordinate several transition metals [...] Read more.

Here, we describe the synthesis, characterization, and in vitro biological evaluation of a series of transition metal complexes containing benzothiazole aniline (BTA). We employed BTA, which is known for its selective anticancer activity, and a salen-type Schiff-based ligand to coordinate several transition metals to achieve selective and synergistic cytotoxicity. The compounds obtained were characterized by NMR spectroscopy, mass spectrometry, Fourier transform infrared spectroscopy, and elemental analysis. The compounds L, MnL, FeL, CoL, and ZnL showed promising in vitro cytotoxicity against cancer cells, and they had a lower IC₅₀ than that of the clinically used cisplatin. In particular, MnL had synergistic cytotoxicity against liver, breast, and colon cancer cells. Moreover, MnL, CoL, and CuL promoted the production of reactive oxygen species in HepG2 tumor cell lines. The lead compound of this series, MnL, remained stable in physiological settings, and docking results showed that it interacted rationally with the minor groove of DNA. Therefore, MnL may serve as a viable alternative to platinum-based chemotherapy. Full article

(This article belongs to the Special Issue Metal-Based Agents in Drug Discovery)

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16 pages, 2677 KiB

Open AccessArticle

Multifunctional Gel Films of Marine Polysaccharides Cross-Linked with Poly-Metal Ions for Wound Healing

by Di Zhao, Chao Shi, Tingting Guo, Kun Zhang, Shenghao Cui, Liqi Chen, Faming Yang and Jingdi Chen

Pharmaceuticals 2022, 15(6), 750; https://doi.org/10.3390/ph15060750 - 15 Jun 2022

Cited by 5 | Viewed by 2681

Abstract

The development of an efficient and convenient material to improve skin tissue regeneration is a major challenge in healthcare. Inspired by the theory of moist wound healing, portable chitooligosaccharide (COS)/sodium alginate (SA) dual-net gel films containing multiple metal ions were prepared by a [...] Read more.

The development of an efficient and convenient material to improve skin tissue regeneration is a major challenge in healthcare. Inspired by the theory of moist wound healing, portable chitooligosaccharide (COS)/sodium alginate (SA) dual-net gel films containing multiple metal ions were prepared by a casting and in-situ spray method, which can be used to significantly promote wound healing without the use of therapeutic drugs. A variety of divalent cations was introduced in this experiment to improve the advantages of each metal ion by forming metal ion chelates with COS. Moreover, the physicochemical properties and antioxidant properties of nIon²⁺-COS/SA gel films were systematically characterized and evaluated by in vitro experiments. The gel films showed good antibacterial activity against Gram-negative and Gram-positive bacteria. In addition, the gel films showed good cytocompatibility in cellular experiments, and the gel films with Zn²⁺ and Sr²⁺ addition significantly accelerated wound healing in whole skin defect model experiments. Therefore, this nIon²⁺-COS/SA gel film is an ideal candidate material for wound dressing. Full article

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

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27 pages, 1276 KiB

Open AccessSystematic Review

Adverse Drug Reactions of Olanzapine, Clozapine and Loxapine in Children and Youth: A Systematic Pharmacogenetic Review

by Diane Merino, Arnaud Fernandez, Alexandre O. Gérard, Nouha Ben Othman, Fanny Rocher, Florence Askenazy, Céline Verstuyft, Milou-Daniel Drici and Susanne Thümmler

Pharmaceuticals 2022, 15(6), 749; https://doi.org/10.3390/ph15060749 - 14 Jun 2022

Cited by 4 | Viewed by 4319

Abstract

Children and youth treated with antipsychotic drugs (APs) are particularly vulnerable to adverse drug reactions (ADRs) and prone to poor treatment response. In particular, interindividual variations in drug exposure can result from differential metabolism of APs by cytochromes, subject to genetic polymorphism. CYP1A2 [...] Read more.

Children and youth treated with antipsychotic drugs (APs) are particularly vulnerable to adverse drug reactions (ADRs) and prone to poor treatment response. In particular, interindividual variations in drug exposure can result from differential metabolism of APs by cytochromes, subject to genetic polymorphism. CYP1A2 is pivotal in the metabolism of the APs olanzapine, clozapine, and loxapine, whose safety profile warrants caution. We aimed to shed some light on the pharmacogenetic profiles possibly associated with these drugs’ ADRs and loss of efficacy in children and youth. We conducted a systematic review relying on four databases, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 recommendations and checklist, with a quality assessment. Our research yielded 32 publications. The most frequent ADRs were weight gain and metabolic syndrome (18; 56.3%), followed by lack of therapeutic effect (8; 25%) and neurological ADRs (7; 21.8%). The overall mean quality score was 11.3/24 (±2.7). In 11 studies (34.3%), genotyping focused on the study of cytochromes. Findings regarding possible associations were sometimes conflicting. Nonetheless, cases of major clinical improvement were fostered by genotyping. Yet, CYP1A2 remains poorly investigated. Further studies are required to improve the assessment of the risk–benefit balance of prescription for children and youth treated with olanzapine, clozapine, and/or loxapine. Full article

(This article belongs to the Special Issue Clinical Utility of Applying PGx and Deprescribing-Based Decision Support in Polypharmacy: Future Perspectives)

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11 pages, 1034 KiB

Open AccessArticle

Pharmacophore-Based Discovery of Viral RNA Conformational Modulators

by María Martín-Villamil, Isaías Sanmartín, Ángela Moreno and José Gallego

Pharmaceuticals 2022, 15(6), 748; https://doi.org/10.3390/ph15060748 - 14 Jun 2022

Cited by 2 | Viewed by 2250

Abstract

New RNA-binding small-molecule scaffolds are needed to unleash the pharmacological potential of RNA targets. Here we have applied a pharmacophore-based virtual screening approach, seldom used in the RNA recognition field, to identify novel conformational inhibitors of the hepatitis C virus internal ribosome entry [...] Read more.

New RNA-binding small-molecule scaffolds are needed to unleash the pharmacological potential of RNA targets. Here we have applied a pharmacophore-based virtual screening approach, seldom used in the RNA recognition field, to identify novel conformational inhibitors of the hepatitis C virus internal ribosome entry site. The conformational effect of the screening hits was assessed with a fluorescence resonance energy transfer assay, and the affinity, specificity, and binding site of the ligands were determined using a combination of fluorescence intensity and NMR spectroscopy experiments. The results indicate that this strategy can be successfully applied to discover RNA conformational inhibitors bearing substantially less positive charge than the reference ligands. This methodology can potentially be accommodated to other RNA motifs of pharmacological interest, facilitating the discovery of novel RNA-targeted molecules. Full article

(This article belongs to the Special Issue Pharmacophore Modeling and Applications in Drug Discovery: Challenges and Recent Advances)

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34 pages, 4071 KiB

Open AccessEditor’s ChoiceReview

Development of Radiotracers for Imaging of the PD-1/PD-L1 Axis

by Fabian Krutzek, Klaus Kopka and Sven Stadlbauer

Pharmaceuticals 2022, 15(6), 747; https://doi.org/10.3390/ph15060747 - 14 Jun 2022

Cited by 24 | Viewed by 5995

Abstract

Immune checkpoint inhibitor (ICI) therapy has emerged as a major treatment option for a variety of cancers. Among the immune checkpoints addressed, the programmed death receptor 1 (PD-1) and its ligand PD-L1 are the key targets for an ICI. PD-L1 has especially been [...] Read more.

Immune checkpoint inhibitor (ICI) therapy has emerged as a major treatment option for a variety of cancers. Among the immune checkpoints addressed, the programmed death receptor 1 (PD-1) and its ligand PD-L1 are the key targets for an ICI. PD-L1 has especially been proven to be a reproducible biomarker allowing for therapy decisions and monitoring therapy success. However, the expression of PD-L1 is not only heterogeneous among and within tumor lesions, but the expression is very dynamic and changes over time. Immunohistochemistry, which is the standard diagnostic tool, can only inadequately address these challenges. On the other hand, molecular imaging techniques such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT) provide the advantage of a whole-body scan and therefore fully address the issue of the heterogeneous expression of checkpoints over time. Here, we provide an overview of existing PET, SPECT, and optical imaging (OI) (radio)tracers for the imaging of the upregulation levels of PD-1 and PD-L1. We summarize the preclinical and clinical data of the different molecule classes of radiotracers and discuss their respective advantages and disadvantages. At the end, we show possible future directions for developing new radiotracers for the imaging of PD-1/PD-L1 status in cancer patients. Full article

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

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17 pages, 3458 KiB

Open AccessArticle

L-Asparaginase from Penicillium sizovae Produced by a Recombinant Komagataella phaffii Strain

by Marcela Freitas, Paula Souza, Mauricio Homem-de-Mello, Yris M. Fonseca-Bazzo, Damaris Silveira, Edivaldo X. Ferreira Filho, Adalberto Pessoa Junior, Dipak Sarker, David Timson, João Inácio and Pérola O. Magalhães

Pharmaceuticals 2022, 15(6), 746; https://doi.org/10.3390/ph15060746 - 14 Jun 2022

Cited by 5 | Viewed by 3453

Abstract

L-asparaginase is an important enzyme in the pharmaceutical field used as treatment for acute lymphoblastic leukemia due to its ability to hydrolyze L-asparagine, an essential amino acid synthesized by normal cells, but not by neoplastic cells. Adverse effects of L-asparaginase formulations are associated [...] Read more.

L-asparaginase is an important enzyme in the pharmaceutical field used as treatment for acute lymphoblastic leukemia due to its ability to hydrolyze L-asparagine, an essential amino acid synthesized by normal cells, but not by neoplastic cells. Adverse effects of L-asparaginase formulations are associated with its glutaminase activity and bacterial origin; therefore, it is important to find new sources of L-asparaginase produced by eukaryotic microorganisms with low glutaminase activity. This work aimed to identify the L-asparaginase gene sequence from Penicillium sizovae, a filamentous fungus isolated from the Brazilian Savanna (Cerrado) soil with low glutaminase activity, and to biosynthesize higher yields of this enzyme in the yeast Komagataella phaffii. The L-asparaginase gene sequence of P. sizovae was identified by homology to L-asparaginases from species of Penicillium of the section Citrina: P. citrinum and P. steckii. Partial L-asparaginase from P. sizovae, lacking the periplasmic signaling sequence, was cloned, and expressed intracellularly with highest enzymatic activity achieved by a MUT⁺ clone cultured in BMM expression medium; a value 5-fold greater than that obtained by native L-asparaginase in P. sizovae cells. To the best of our knowledge, this is the first literature report of the heterologous production of an L-asparaginase from a filamentous fungus by a yeast. Full article

(This article belongs to the Section Biopharmaceuticals)

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15 pages, 3583 KiB

Open AccessArticle

Mechanistic Analysis of Chemically Diverse Bromodomain-4 Inhibitors Using Balanced QSAR Analysis and Supported by X-ray Resolved Crystal Structures

by Magdi E. A. Zaki, Sami A. Al-Hussain, Aamal A. Al-Mutairi, Vijay H. Masand, Abdul Samad and Rahul D. Jawarkar

Pharmaceuticals 2022, 15(6), 745; https://doi.org/10.3390/ph15060745 - 14 Jun 2022

Cited by 3 | Viewed by 2392

Abstract

Bromodomain-4 (BRD-4) is a key enzyme in post-translational modifications, transcriptional activation, and many other cellular processes. Its inhibitors find their therapeutic usage in cancer, acute heart failure, and inflammation to name a few. In the present study, a dataset of 980 molecules with [...] Read more.

Bromodomain-4 (BRD-4) is a key enzyme in post-translational modifications, transcriptional activation, and many other cellular processes. Its inhibitors find their therapeutic usage in cancer, acute heart failure, and inflammation to name a few. In the present study, a dataset of 980 molecules with a significant diversity of structural scaffolds and composition was selected to develop a balanced QSAR model possessing high predictive capability and mechanistic interpretation. The model was built as per the OECD (Organisation for Economic Co-operation and Development) guidelines and fulfills the endorsed threshold values for different validation parameters (R²_tr = 0.76, Q²_LMO = 0.76, and R²_ex = 0.76). The present QSAR analysis identified that anti-BRD-4 activity is associated with structural characters such as the presence of saturated carbocyclic rings, the occurrence of carbon atoms near the center of mass of a molecule, and a specific combination of planer or aromatic nitrogen with ring carbon, donor, and acceptor atoms. The outcomes of the present analysis are also supported by X-ray-resolved crystal structures of compounds with BRD-4. Thus, the QSAR model effectively captured salient as well as unreported hidden pharmacophoric features. Therefore, the present study successfully identified valuable novel pharmacophoric features, which could be beneficial for the future optimization of lead/hit compounds for anti-BRD-4 activity. Full article

(This article belongs to the Special Issue Bromodomains: A New Target Class for Drug Development)

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15 pages, 3661 KiB

Open AccessArticle

Discovery of Triple Inhibitors of Both SARS-CoV-2 Proteases and Human Cathepsin L

by Ittipat Meewan, Jacob Kattoula, Julius Y. Kattoula, Danielle Skinner, Pavla Fajtová, Miriam A. Giardini, Brendon Woodworth, James H. McKerrow, Jair Lage de Siqueira-Neto, Anthony J. O’Donoghue and Ruben Abagyan

Pharmaceuticals 2022, 15(6), 744; https://doi.org/10.3390/ph15060744 - 13 Jun 2022

Cited by 7 | Viewed by 3448

Abstract

One inhibitor of the main SARS-CoV-2 protease has been approved recently by the FDA, yet it targets only SARS-CoV-2 main protease (Mpro). Here, we discovered inhibitors containing thiuram disulfide or dithiobis-(thioformate) tested against three key proteases involved in SARS-CoV-2 replication, including Mpro, SARS-CoV-2 [...] Read more.

One inhibitor of the main SARS-CoV-2 protease has been approved recently by the FDA, yet it targets only SARS-CoV-2 main protease (Mpro). Here, we discovered inhibitors containing thiuram disulfide or dithiobis-(thioformate) tested against three key proteases involved in SARS-CoV-2 replication, including Mpro, SARS-CoV-2 papain-like protease (PLpro), and human cathepsin L. The use of thiuram disulfide and dithiobis-(thioformate) covalent inhibitor warheads was inspired by an idea to find a better alternative than disulfiram, an approved treatment for chronic alcoholism that is currently in phase 2 clinical trials against SARS-CoV-2. Our goal was to find more potent inhibitors that target both viral proteases and one essential human protease to reduce the dosage, improve the efficacy, and minimize the adverse effects associated with these agents. We found that compounds coded as RI175, RI173, and RI172 were the most potent inhibitors in an enzymatic assay against SARS-CoV-2 Mpro, SARS-CoV-2 PLpro, and human cathepsin L, with IC₅₀s of 300, 200, and 200 nM, which is about 5-, 19-, and 11-fold more potent than disulfiram, respectively. In addition, RI173 was tested against SARS-CoV-2 in a cell-based and toxicity assay and was shown to have a greater antiviral effect than disulfiram. The identified compounds demonstrated the promising potential of thiuram disulfide or dithiobis-(thioformate) as a reactive functional group in small molecules that could be further developed for treatment of the COVID-19 virus or related variants. Full article

(This article belongs to the Special Issue Multitarget Drug Discovery and Pharmacology)

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20 pages, 3566 KiB

Open AccessArticle

In Vivo and In Vitro Antioxidant Activity of Less Polar Fractions of Dasycladus vermicularis (Scopoli) Krasser 1898 and the Chemical Composition of Fractions and Macroalga Volatilome

by Sanja Radman, Ana-Marija Cikoš, Sanja Babić, Lara Čižmek, Rozelindra Čož-Rakovac, Stela Jokić and Igor Jerković

Pharmaceuticals 2022, 15(6), 743; https://doi.org/10.3390/ph15060743 - 13 Jun 2022

Cited by 5 | Viewed by 2475

Abstract

The present research is a comprehensive investigation of Dasycladus vermicularis (Scopoli) Krasser 1898 from the Adriatic Sea (Croatia) regarding volatilome–volatile organic compounds (VOCs, mostly nonpolar compounds) and less polar nonvolatile compounds for the first time. Headspace solid-phase microextraction (HS-SPME) and hydrodistillation (HD) were [...] Read more.

The present research is a comprehensive investigation of Dasycladus vermicularis (Scopoli) Krasser 1898 from the Adriatic Sea (Croatia) regarding volatilome–volatile organic compounds (VOCs, mostly nonpolar compounds) and less polar nonvolatile compounds for the first time. Headspace solid-phase microextraction (HS-SPME) and hydrodistillation (HD) were used showing the great volatilome variability among fresh (HS-FrDV and HD-FrDV) and dried (HS-DrDV and HD-DrDV) samples after GC–MS analysis. Aromatic aldehydes were dominant in both fresh and air-dried HS samples with benzaldehyde as the most abundant in fresh samples and decreasing 2.7–3.7 times after drying together with 2-phenylbut-2-enal that was not present after drying. Aliphatic compounds (unsaturated hydrocarbons in HS-FrDV; saturated hydrocarbons in HS-DrDV) were also present. C₁₁-hydrocarbons (dictyopterpene C’ and dictyopterpene D’) were detected in HS-FrDV. (E)-Phytol was the most dominant compound in HD-FrDV and HD-DrDV. Diterpene alcohols (cembra-4,7,11,15-tetraen-3-ol and (Z)-falcarinol) and sesquiterpene alcohol, cubenol, were dominant in HD-FrDV, and their abundance decreased after drying. C₁₃-norisoprenoides (α-ionone and β-ionone) increased after drying. Aliphatic compounds were present in both HD-FrDV and HD-DrDV samples. The less polar nonvolatile compounds in the obtained fractions F3 and F4 were analysed and identified by UHPLC-ESI(+)-HRMS. Identified compounds belonged to a group of pigments (7 compounds), fatty acid derivatives (13 compounds), as well as steroids and terpenes (10 compounds). Porphyrin-based compounds (C₅₅H₇₄N₄O_5–7), xanthophylls, sphingolipid compounds, fatty acid amides, and phytosterols represented the majority of identified compounds. By implementing both in vitro and in vivo assays for antioxidant activity determination, F3 showed a higher activity than F4. Inhibitory concentrations (IC₅₀) for F3 and F4 were 498.00 ± 0.01 µg/mL and 798.00 ± 0.81 µg/mL, respectively, while a 1.5-fold reduction in the ROS level was observed after pre-treatment of zebrafish larvae with 45 µg/mL of F3. Full article

(This article belongs to the Section Natural Products)

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19 pages, 4084 KiB

Open AccessArticle

Longitudinal Consumption of Ergothioneine Reduces Oxidative Stress and Amyloid Plaques and Restores Glucose Metabolism in the 5XFAD Mouse Model of Alzheimer’s Disease

by Clayton A. Whitmore, Justin R. Haynes, William J. Behof, Adam J. Rosenberg, Mohammed N. Tantawy, Brian C. Hachey, Brian E. Wadzinski, Benjamin W. Spiller, Todd E. Peterson, Krista C. Paffenroth, Fiona E. Harrison, Robert B. Beelman, Printha Wijesinghe, Joanne A. Matsubara and Wellington Pham

Pharmaceuticals 2022, 15(6), 742; https://doi.org/10.3390/ph15060742 - 13 Jun 2022

Cited by 18 | Viewed by 5514

Abstract

Background: Ergothioneine (ERGO) is a unique antioxidant and a rare amino acid available in fungi and various bacteria but not in higher plants or animals. Substantial research data indicate that ERGO is a physiological antioxidant cytoprotectant. Different from other antioxidants that need to [...] Read more.

Background: Ergothioneine (ERGO) is a unique antioxidant and a rare amino acid available in fungi and various bacteria but not in higher plants or animals. Substantial research data indicate that ERGO is a physiological antioxidant cytoprotectant. Different from other antioxidants that need to breach the blood–brain barrier to enter the brain parenchyma, a specialized transporter called OCTN1 has been identified for transporting ERGO to the brain. Purpose: To assess whether consumption of ERGO can prevent the progress of Alzheimer’s disease (AD) on young (4-month-old) 5XFAD mice. Methods and materials: Three cohorts of mice were tested in this study, including ERGO-treated 5XFAD, non-treated 5XFAD, and WT mice. After the therapy, the animals went through various behavioral experiments to assess cognition. Then, mice were scanned with PET imaging to evaluate the biomarkers associated with AD using [¹¹C]PIB, [¹¹C]ERGO, and [¹⁸F]FDG radioligands. At the end of imaging, the animals went through cardiac perfusion, and the brains were isolated for immunohistology. Results: Young (4-month-old) 5XFAD mice did not show a cognitive deficit, and thus, we observed modest improvement in the treated counterparts. In contrast, the response to therapy was clearly detected at the molecular level. Treating 5XFAD mice with ERGO resulted in reduced amyloid plaques, oxidative stress, and rescued glucose metabolism. Conclusions: Consumption of high amounts of ERGO benefits the brain. ERGO has the potential to prevent AD. This work also demonstrates the power of imaging technology to assess response during therapy. 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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15 pages, 11793 KiB

Open AccessArticle

Computational Investigations of Traditional Chinese Medicinal Compounds against the Omicron Variant of SARS-CoV-2 to Rescue the Host Immune System

by Ziad Tareq Naman, Salim Kadhim, Zahraa J. K. Al-Isawi, Christopher J. Butch and Ziyad Tariq Muhseen

Pharmaceuticals 2022, 15(6), 741; https://doi.org/10.3390/ph15060741 - 13 Jun 2022

Cited by 3 | Viewed by 2581

Abstract

Macrodomain-I of the NSP3 (non-structural protein 3) is responsible for immune response hijacking in the SARS-CoV-2 infection known as COVID-19. In the omicron variant (B.1.1.529), this domain harbors a new mutation, V1069I, which may increase the binding of ADPr and consequently the infection [...] Read more.

Macrodomain-I of the NSP3 (non-structural protein 3) is responsible for immune response hijacking in the SARS-CoV-2 infection known as COVID-19. In the omicron variant (B.1.1.529), this domain harbors a new mutation, V1069I, which may increase the binding of ADPr and consequently the infection severity. This macrodomain-I, due to its significant role in infection, is deemed to be an important drug target. Hence, using structural bioinformatics and molecular simulation approaches, we performed a virtual screening of the traditional Chinese medicines (TCM) database for potential anti-viral drugs. The screening of 57,000 compounds yielded the 10 best compounds with docking scores better than the control ADPr. Among the top ten, the best three hits—TCM42798, with a docking score of −13.70 kcal/mol, TCM47007 of −13.25 kcal/mol, and TCM30675 of −12.49 kcal/mol—were chosen as the best hits. Structural dynamic features were explored including stability, compactness, flexibility, and hydrogen bonding, further demonstrating the anti-viral potential of these hits. Using the MM/GBSA approach, the total binding free energy for each complex was reported to be −69.78 kcal/mol, −50.11 kcal/mol, and −47.64 kcal/mol, respectively, which consequently reflect the stronger binding and inhibitory potential of these compounds. These agents might suppress NSP3 directly, allowing the host immune system to recuperate. The current study lays the groundwork for the development of new drugs to combat SARS-CoV-2 and its variants. Full article

(This article belongs to the Special Issue In Silico Approaches in Drug Design)

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17 pages, 2518 KiB

Open AccessArticle

Rational Design by Structural Biology of Industrializable, Long-Acting Antihyperglycemic GLP-1 Receptor Agonists

by Lei Sun, Zhi-Ming Zheng, Chang-Sheng Shao, Zhi-Yong Zhang, Ming-Wei Li, Li Wang, Han Wang, Gen-Hai Zhao and Peng Wang

Pharmaceuticals 2022, 15(6), 740; https://doi.org/10.3390/ph15060740 - 13 Jun 2022

Cited by 4 | Viewed by 3985

Abstract

Glucagon-like peptide-1 (GLP-1) is easily degraded by dipeptidyl peptidase-4 (DPP-4) in the human body, limiting its therapeutic effect on type II diabetes. Therefore, improving GLP-1 receptor agonist (GLP-1RA) stability is a major obstacle for drug development. We analyzed human GLP-1, DPP-4, and GLP-1 [...] Read more.

Glucagon-like peptide-1 (GLP-1) is easily degraded by dipeptidyl peptidase-4 (DPP-4) in the human body, limiting its therapeutic effect on type II diabetes. Therefore, improving GLP-1 receptor agonist (GLP-1RA) stability is a major obstacle for drug development. We analyzed human GLP-1, DPP-4, and GLP-1 receptor structures and designed three GLP-1RAs, which were introduced into fusion protein fragments and changed in the overall conformation. This modification effectively prevented GLP-1RAs from entering the DPP-4 active center without affecting GLP-1RAs’ ability to bind to GLP-1R, the new GLP-1RA hypoglycemic effect lasting for >24 h. Through molecular modeling, molecular dynamics calculation, and simulation, possible tertiary structure models of GLP-1RAs were obtained; molecular docking with DPP-4 and GLP-1R showed access to the fusion protein. The overall conformational change of GLP-1RAs prevented DPP-4 binding, without affecting GLP-1RAs’ affinity to GLP-1R. This study provides important drug design ideas for GLP-1RA development and a new example for application of structural biology-based protein design in drug development. Full article

(This article belongs to the Special Issue Small Molecules Targeting Protein-Protein Interactions (PPIs): Current Strategies for the Development of New Drugs)

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24 pages, 446 KiB

Open AccessReview

Will the Use of Pharmacogenetics Improve Treatment Efficiency in COVID-19?

by Beata Franczyk, Jacek Rysz, Jarosław Miłoński, Tomasz Konecki, Magdalena Rysz-Górzyńska and Anna Gluba-Brzózka

Pharmaceuticals 2022, 15(6), 739; https://doi.org/10.3390/ph15060739 - 13 Jun 2022

Cited by 6 | Viewed by 2715

Abstract

The COVID-19 pandemic is associated with a global health crisis and the greatest challenge for scientists and doctors. The virus causes severe acute respiratory syndrome with an outcome that is fatal in more vulnerable populations. Due to the need to find an efficient [...] Read more.

The COVID-19 pandemic is associated with a global health crisis and the greatest challenge for scientists and doctors. The virus causes severe acute respiratory syndrome with an outcome that is fatal in more vulnerable populations. Due to the need to find an efficient treatment in a short time, there were several drugs that were repurposed or repositioned for COVID-19. There are many types of available COVID-19 therapies, including antiviral agents (remdesivir, lopinavir/ritonavir, oseltamivir), antibiotics (azithromycin), antiparasitics (chloroquine, hydroxychloroquine, ivermectin), and corticosteroids (dexamethasone). A combination of antivirals with various mechanisms of action may be more efficient. However, the use of some of these medicines can be related to the occurrence of adverse effects. Some promising drug candidates have been found to be ineffective in clinical trials. The knowledge of pharmacogenetic issues, which translate into variability in drug conversion from prodrug into drug, metabolism as well as transport, could help to predict treatment efficiency and the occurrence of adverse effects in patients. However, many drugs used for the treatment of COVID-19 have not undergone pharmacogenetic studies, perhaps as a result of the lack of time. Full article

(This article belongs to the Special Issue Pharmacogenetics and Genomic Biomarkers and Their Application in Clinical Practice)

17 pages, 820 KiB

Open AccessReview

Target Therapies for Systemic Mastocytosis: An Update

by Mariarita Sciumè, Claudio De Magistris, Nicole Galli, Eleonora Ferretti, Giulia Milesi, Pasquale De Roberto, Sonia Fabris and Federica Irene Grifoni

Pharmaceuticals 2022, 15(6), 738; https://doi.org/10.3390/ph15060738 - 11 Jun 2022

Cited by 5 | Viewed by 3474

Abstract

Systemic mastocytosis (SM) results from a clonal proliferation of abnormal mast cells (MCs) in extra-cutaneous organs. It could be divided into indolent SM, smoldering SM, SM with an associated hematologic (non-MC lineage) neoplasm, aggressive SM, and mast cell leukemia. SM is generally associated [...] Read more.

Systemic mastocytosis (SM) results from a clonal proliferation of abnormal mast cells (MCs) in extra-cutaneous organs. It could be divided into indolent SM, smoldering SM, SM with an associated hematologic (non-MC lineage) neoplasm, aggressive SM, and mast cell leukemia. SM is generally associated with the presence of a gain-of-function somatic mutation in KIT at codon 816. Clinical features could be related to MC mediator release or to uncontrolled infiltration of MCs in different organs. Whereas indolent forms have a near-normal life expectancy, advanced diseases have a poor prognosis with short survival times. Indolent forms should be considered for symptom-directed therapy, while cytoreductive therapy represents the first-line treatment for advanced diseases. Since the emergence of tyrosine kinase inhibitors (TKIs), KIT inhibition has been an attractive approach. Initial reports showed that only the rare KITD816V negative cases were responsive to first-line TKI imatinib. The development of new TKIs with activity against the KITD816V mutation, such as midostaurin or avapritinib, has changed the management of this disease. This review aims to focus on the available clinical data of therapies for SM and provide insights into possible future therapeutic targets. Full article

(This article belongs to the Special Issue Drug Design and Development for Rare Hematologic Diseases)

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Pharmaceuticals, Volume 15, Issue 6 (June 2022) – 121 articles

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