Topic Editors

Freshage Research Group, Department of Physiology, Faculty of Medicine, University of Valencia, E46010 Valencia, Spain
Department of Physiology, Faculty of Pharmacy, University of Valencia, Vicente Andrés Estellés Av. s/n, 46100 Burjassot, Spain

Research in Pharmacological Therapies

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closed (31 January 2024)
Manuscript submission deadline
closed (31 March 2024)
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Topic Information

Dear Colleagues,

Drugs are bioactive compounds that are present in the chemical structures in both the plant and animal kingdoms. Both organic and inorganic compounds have been used empirically to cure diseases or to treat the symptoms that are derived from them. Much of modern pharmacology has its origins in these types of compounds. Due to the advancements in chemistry, we are able to characterize the chemical composition of any compound with a high degree of accuracy. In fact, to this day, we are continuing to discover new compounds in nature that demonstrate very promising pharmacological activities, which could lay the foundation for new, more efficient, and more effective bioactive molecules through chemical modifications. Furthermore, pharmacology is advancing, as new synthetic compounds with increasingly specific and effective pharmacological properties are being developed at a rapid pace. Therefore, in this topic, we plan to collect the latest advances in new drugs of either natural or synthetic origin in addition to describing their biological targets, their specific mechanisms of action, and their effective dosages.

Prof. Dr. Juan Gambini
Dr. Ángel Luis Ortega
Topic Editors

Keywords

  • pharmacological therapies
  • drugs
  • bioactive compounds
  • pharmacological activities
  • natural or synthetic origin
  • biological targets

Participating Journals

Journal Name Impact Factor CiteScore Launched Year First Decision (median) APC
Biomedicines
biomedicines
4.7 5.2 2013 15.4 Days CHF 2600
Drugs and Drug Candidates
ddc
- - 2022 22.4 Days CHF 1000
Molecules
molecules
4.6 7.4 1996 14.6 Days CHF 2700
Pharmaceuticals
pharmaceuticals
4.6 6.1 2004 14.6 Days CHF 2900
Pharmaceutics
pharmaceutics
5.4 7.9 2009 14.2 Days CHF 2900

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Published Papers (16 papers)

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32 pages, 3262 KiB  
Article
Anti-Vasculogenic, Antioxidant, and Anti-Inflammatory Activities of Sulfated Polysaccharide Derived from Codium tomentosum: Pharmacokinetic Assay
by Marwa Lakhrem, Malek Eleroui, Zakaria Boujhoud, Amal Feki, Amel Dghim, Sanah Essayagh, Said Hilali, Marwa Bouhamed, Choumous Kallel, Nathalie Deschamps, Bertrand de Toffol, Jean Marc Pujo, Riadh Badraoui, Hatem Kallel and Ibtissem Ben Amara
Pharmaceuticals 2024, 17(6), 672; https://0-doi-org.brum.beds.ac.uk/10.3390/ph17060672 - 23 May 2024
Viewed by 311
Abstract
The purpose of this paper was to investigate the anti-inflammatory and anti-angiogenic activities of sulfated polysaccharide from C. tomentosum (PCT) using carrageenan (CARR)-induced paw edema in a rat model and anti-vasculogenic activity on a chorioallantoic membrane assay (CAM) model. Based on in vitro [...] Read more.
The purpose of this paper was to investigate the anti-inflammatory and anti-angiogenic activities of sulfated polysaccharide from C. tomentosum (PCT) using carrageenan (CARR)-induced paw edema in a rat model and anti-vasculogenic activity on a chorioallantoic membrane assay (CAM) model. Based on in vitro tests of anti-radical, total antioxidant, and reducing power activities, PCT presents a real interest via its antioxidant activity and ability to scavenge radical species. The in vivo pharmacological tests suggest that PCT possesses anti-inflammatory action by reducing paw edema and leukocyte migration, maintaining the redox equilibrium, and stabilizing the cellular level of several pro-/antioxidant system markers. It could significantly decrease the malondialdehyde levels and increase superoxide dismutase, glutathione peroxidase, and glutathione activities in local paw edema and erythrocytes during the acute inflammatory reaction of CARR. PCT pretreatment was effective against DNA alterations in the blood lymphocytes of inflamed rats and reduced the hematological alteration by restoring blood parameters to normal levels. The anti-angiogenic activity results revealed that CAM neovascularization, defined as the formation of new vessel numbers and branching patterns, was decreased by PCT in a dose-dependent manner, which supported the in silico bioavailability and pharmacokinetic findings. These results indicated the therapeutic effects of polysaccharides from C. tomentosum and their possible use as anti-proliferative molecules based on their antioxidant, anti-inflammatory, and anti-angiogenic activities. Full article
(This article belongs to the Topic Research in Pharmacological Therapies)
14 pages, 2297 KiB  
Article
Synergistic Antinociceptive Effect of β-Caryophyllene Oxide in Combination with Paracetamol, and the Corresponding Gastroprotective Activity
by Josué Vidal Espinosa-Juárez, Jesús Arrieta, Alfredo Briones-Aranda, Leticia Cruz-Antonio, Yaraset López-Lorenzo and María Elena Sánchez-Mendoza
Biomedicines 2024, 12(5), 1037; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines12051037 - 8 May 2024
Viewed by 566
Abstract
Pain is the most frequent symptom of disease. In treating pain, a lower incidence of adverse effects is found for paracetamol versus other non-steroidal anti-inflammatory drugs. Nevertheless, paracetamol can trigger side effects when taken regularly. Combined therapy is a common way of lowering [...] Read more.
Pain is the most frequent symptom of disease. In treating pain, a lower incidence of adverse effects is found for paracetamol versus other non-steroidal anti-inflammatory drugs. Nevertheless, paracetamol can trigger side effects when taken regularly. Combined therapy is a common way of lowering the dose of a drug and thus of reducing adverse reactions. Since β-caryophyllene oxide (a natural bicyclic sesquiterpene) is known to produce an analgesic effect, this study aimed to determine the anti-nociceptive and gastroprotective activity of administering the combination of paracetamol plus β-caryophyllene oxide to CD1 mice. Anti-nociception was evaluated with the formalin model and gastroprotection with the model of ethanol-induced gastric lesions. According to the isobolographic analysis, the anti-nociceptive interaction of paracetamol and β-caryophyllene oxide was synergistic. Various pain-related pathways were explored for their possible participation in the mechanism of action of the anti-nociceptive effect of β-caryophyllene oxide, finding that NO, opioid receptors, serotonin receptors, and K+ATP channels are not involved. The combined treatment showed gastroprotective activity against ethanol-induced gastric damage. Hence, the synergistic anti-nociceptive effect of combining paracetamol with β-caryophyllene oxide could be advantageous for the management of inflammatory pain, and the gastroprotective activity should help to protect against the adverse effects of chronic use. Full article
(This article belongs to the Topic Research in Pharmacological Therapies)
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14 pages, 6394 KiB  
Article
Evaluation of the Efficacy of OSU-2S in the Treatment of Non-Small-Cell Lung Cancer and Screening of Potential Targets of Action
by Mengyuan Han, Xiangran Liu, Sendaer Hailati, Nurbiya Nurahmat, Dilihuma Dilimulati, Alhar Baishan, Alifeiye Aikebaier and Wenting Zhou
Pharmaceuticals 2024, 17(5), 582; https://0-doi-org.brum.beds.ac.uk/10.3390/ph17050582 - 1 May 2024
Viewed by 798
Abstract
(1) Background: OSU-2S is a derivative of FTY720 and exhibits significant inhibitory effects on various cancer cells. There is currently no research on the mechanism of the impact of OSU-2S on NSCLC development. We analysed and validated the hub genes and pharmacodynamic effects [...] Read more.
(1) Background: OSU-2S is a derivative of FTY720 and exhibits significant inhibitory effects on various cancer cells. There is currently no research on the mechanism of the impact of OSU-2S on NSCLC development. We analysed and validated the hub genes and pharmacodynamic effects of OSU-2S to treat NSCLC. (2) Methods: The hub genes of OSU-2S for the treatment of NSCLC were screened in PharmMapper, genecard, and KM Plotter database by survival and expression analysis. The effect of OSU-2S on hub gene expression was verified by Western blot analysis. The ex vivo and in vivo efficacy of OSU-2S on tumour growth was verified using A549 cells and a xenografted animal model. (3) Results: A total of 7 marker genes for OSU-2S treatment of NSCLC were obtained. AURKA and S1PR1 were screened as hub genes. Significant differences in the expression of AURKA and S1PR1 between normal and lung adenocarcinoma (LUAD) tissues were found in the GEPIA2 database; Western blot showed that OSU-2S could affect p-AURKA and S1PR1 protein expression. OSU-2S significantly inhibited tumour growth in A549 cells and xenografted animal models. (4) Conclusions: Our study confirms the inhibitory effect of OSU-2S on NSCLC, screens and demonstrates its potential targets AURKA(p-AURKA) and S1PR1, and provides a research basis for treating NSCLC with OSU-2S. Full article
(This article belongs to the Topic Research in Pharmacological Therapies)
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17 pages, 698 KiB  
Review
Proton-Pump Inhibitors in Eosinophilic Esophagitis: A Review Focused on the Role of Pharmacogenetics
by Leticia Rodríguez-Alcolado, Pilar Navarro, Laura Arias-González, Elena Grueso-Navarro, Alfredo J. Lucendo and Emilio J. Laserna-Mendieta
Pharmaceutics 2024, 16(4), 487; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics16040487 - 2 Apr 2024
Viewed by 1244
Abstract
Proton-pump inhibitors (PPIs) are the most administered first-line treatment for eosinophilic esophagitis (EoE). However, only around half of EoE patients respond histologically to a double dosage of PPI. In addition, 70% of responders maintain EoE in remission after tapering the PPI dose. In [...] Read more.
Proton-pump inhibitors (PPIs) are the most administered first-line treatment for eosinophilic esophagitis (EoE). However, only around half of EoE patients respond histologically to a double dosage of PPI. In addition, 70% of responders maintain EoE in remission after tapering the PPI dose. In order to avoid endoscopy with biopsies—the only accurate method of assessing PPI response—efforts have been made to identify PPI responder patients. The clinical or endoscopic features and biomarkers evaluated so far, however, have not proven to be sufficient in predicting PPI response. Although new approaches based on omics technologies have uncovered promising biomarkers, the specialized and complex procedures required are difficult to implement in clinical settings. Alternatively, PPI pharmacogenetics based on identifying variations in CYP2C19 and STAT6 genes have shown promising results in EoE, and could easily be performed in most laboratories. Other genetic variations have also been associated with PPI response and may explain those cases not related to CYP2C19 or STAT6. Here, we provide an overview of PPI treatment in EoE and evidence of how genetic variations in CYP2C19 and other genes could affect PPI effectiveness, and also discuss studies evaluating the role of pharmacogenetics in predicting PPI response in patients with EoE. Full article
(This article belongs to the Topic Research in Pharmacological Therapies)
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14 pages, 3062 KiB  
Article
Assessment of Patient-Reported Outcomes at 48 Months of Treatment with Dupilumab for Severe Atopic Dermatitis: A Single-Center Real-Life Experience with 126 Patients
by Francesca Barei, Martina Zussino, Simona Tavecchio, Luisa Angileri, Arianna Rizzo, Paolo Calzari, Angelo V. Marzano and Silvia Ferrucci
Pharmaceuticals 2024, 17(1), 117; https://0-doi-org.brum.beds.ac.uk/10.3390/ph17010117 - 16 Jan 2024
Viewed by 1129
Abstract
Background: The main objective was to analyze patient-reported outcomes (PRO) trends over a four-year period in severe atopic dermatitis (AD) patients treated with dupilumab. Methods: data from 126 severe patients receiving dupilumab for at least 48 months were collected. The clinical scores assessed [...] Read more.
Background: The main objective was to analyze patient-reported outcomes (PRO) trends over a four-year period in severe atopic dermatitis (AD) patients treated with dupilumab. Methods: data from 126 severe patients receiving dupilumab for at least 48 months were collected. The clinical scores assessed included the Eczema Area and Severity Index (EASI), Pruritus Numerical Rating Scale (NRS), Sleep NRS, Patient-Oriented Eczema Measure (POEM), Dermatology Life Quality Index (DLQI), and Atopic Dermatitis Control Tool (ADCT). Results: the study compellingly demonstrates dupilumab’s effectiveness in reducing EASI and improving PROs, with sustained enhancements observed beyond the initial twelve months of treatment. Univariate and multivariate regression analyses show that baseline factors do not significantly increase the risk of adverse outcomes related to Pruritus NRS, POEM, or ADCT at T48. The robust correlation between ADCT and other PROs suggests closely aligned changes. Conclusion: Dupilumab’s benefits endure beyond the first year, emphasizing its long-term efficacy, and consistently improves AD outcomes regardless of individual characteristics or clinical variables. ADCT appears to be a practical and versatile tool for the streamlined assessment of AD treatment outcomes. Full article
(This article belongs to the Topic Research in Pharmacological Therapies)
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14 pages, 308 KiB  
Article
At-Home Foscarnet Administration in Patients with Cytomegalovirus Infection Post-Allogeneic Stem Cell Transplantation: A Unicentric, Safe, and Feasible Program
by Sonia Ruiz-Boy, Alexandra Pedraza, Marta Prat, Maria Queralt Salas, Esther Carcelero, Gisela Riu-Viladoms, María Suárez-Lledó, Inés Monge-Escartín, Luis Gerardo Rodríguez-Lobato, Alexandra Martínez-Roca, Montserrat Rovira, Carmen Martínez, Cristina Gallego, Álvaro Urbano-Ispizua, Joan Sánchez, María Ángeles Marcos and Francesc Fernández-Avilés
Pharmaceuticals 2023, 16(12), 1741; https://0-doi-org.brum.beds.ac.uk/10.3390/ph16121741 - 18 Dec 2023
Viewed by 1099
Abstract
Cytomegalovirus (CMV) infection is a relevant cause of morbimortality in patients receiving allogeneic stem cell transplantation (allo-HCT). Foscarnet (FCN) is an effective drug against CMV administered intravenously and usually on an inpatient basis. The Home Care Unit (HCU) for hematologic patients at our [...] Read more.
Cytomegalovirus (CMV) infection is a relevant cause of morbimortality in patients receiving allogeneic stem cell transplantation (allo-HCT). Foscarnet (FCN) is an effective drug against CMV administered intravenously and usually on an inpatient basis. The Home Care Unit (HCU) for hematologic patients at our hospital designed an at-home FCN administration model to avoid the hospitalization of patients requiring FCN treatment. This study analyzes whether the at-home administration of FCN is as safe and effective as its hospital administration. We collected and compared demographic, clinical, analytical, and economic data of patients with CMV infection post-allo-HCT who received FCN in the hospital (n = 16, 17 episodes) vs. at-home (n = 67, 88 episodes). The proportions of patients with cured CMV infections were comparable between the two groups (65.9% vs. 76.5%, p = 0.395). The median duration of FCN treatment was 15 (interquartile range [IQR] 9–23) and 14 (IQR 11–19) days in the HCU and inpatient cohorts, respectively (p = 0.692). There were no significant differences in the FCN toxicities between groups except for hypocalcemia (26.1% vs. 58.8%, p = 0.007), which was more prevalent in the inpatient cohort. A significant cost-effectiveness was found in the HCU cohort, with a median savings per episode of EUR 5270. It may be concluded that home administration of FCN is a safe, effective, and cost-efficient therapeutic option for patients with CMV infection and disease. Full article
(This article belongs to the Topic Research in Pharmacological Therapies)
20 pages, 5349 KiB  
Article
Triphenylphosphine Derivatives of Allylbenzenes Express Antitumor and Adjuvant Activity When Solubilized with Cyclodextrin-Based Formulations
by Igor D. Zlotnikov, Sergey S. Krylov, Marina N. Semenova, Victor V. Semenov and Elena V. Kudryashova
Pharmaceuticals 2023, 16(12), 1651; https://0-doi-org.brum.beds.ac.uk/10.3390/ph16121651 - 26 Nov 2023
Viewed by 1080
Abstract
Allylbenzenes (apiol, dillapiol, myristicin and allyltetramethoxybenzene) are individual components of plant essential oils that demonstrate antitumor activity and can enhance the antitumor activity of cytotoxic drugs, such as paclitaxel, doxorubicin, cisplatin, etc. Triphenylphosphine (PPh3) derivatives of allylbenzenes are two to three [...] Read more.
Allylbenzenes (apiol, dillapiol, myristicin and allyltetramethoxybenzene) are individual components of plant essential oils that demonstrate antitumor activity and can enhance the antitumor activity of cytotoxic drugs, such as paclitaxel, doxorubicin, cisplatin, etc. Triphenylphosphine (PPh3) derivatives of allylbenzenes are two to three orders of magnitude more potent than original allylbenzenes in terms of IC50. The inhibition of efflux pumps has been reported for allylbenzenes, and the PPh3 moiety is deemed to be responsible for preferential mitochondrial accumulation and the depolarization of mitochondrial membranes. However, due to poor solubility, the practical use of these substances has never been an option. Here, we show that this problem can be solved by using a complex formation with cyclodextrin (CD-based molecular containers) and polyanionic heparin, stabilizing the positive charge of the PPh3 cation. Such containers can solubilize both allylbenzenes and their PPh3 derivatives up to 0.4 mM concentration. Furthermore, we have observed that solubilized PPh3 derivatives indeed work as adjuvants, increasing the antitumor activity of paclitaxel against adenocarcinomic human alveolar basal epithelial cells (A549) by an order of magnitude (in terms of IC50) in addition to being quite powerful cytostatics themselves (IC50 in the range 1–10 µM). Even more importantly, CD-solubilized PPh3 derivatives show pronounced selectivity, being highly toxic for the A549 tumor cell line and minimally toxic for HEK293T non-tumor cells, red blood cells and sea urchin embryos. Indeed, in many cancers, the mitochondrial membrane is more prone to depolarization compared to normal cells, which probably explains the observed selectivity of our compounds, since PPh3 derivatives are known to act as mitochondria-targeting agents. According to the MTT test, 100 µM solution of PPh3 derivatives of allylbenzenes causes the death of up to 85% of A549 cancer cells, while for HEK293T non-cancer cells, only 15–20% of the cells died. The hemolytic index of the studied substances did not exceed 1%, and the thrombogenicity index was < 1.5%. Thus, this study outlines the experimental foundation for developing combined cytostatic medications, where effectiveness and selectivity are achieved through decreased concentration of the primary ingredient and the inclusion of adjuvants, which are safe or practically harmless substances. Full article
(This article belongs to the Topic Research in Pharmacological Therapies)
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15 pages, 474 KiB  
Review
Effect of St. John’s Wort (Hypericum perforatum L.) on Male Sexual and Reproductive Health: A Narrative Review
by Meshari A. Alzahrani, Salman Bin Ofisan, Nasser I. Alshumaymiri, Muath Alghuwainem, Muath Altamimi, Ali Y. Alali, Muhammad Rabie, Ahmed K. AboSkena, Khalid Almaymuni, Raed Almannie and Saleh Binsaleh
Biomedicines 2023, 11(10), 2800; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines11102800 - 16 Oct 2023
Viewed by 4118
Abstract
Background: Hypericum species are widely acknowledged for their biological attributes, with notable attention being paid to Hypericum perforatum, commonly known as St. John’s wort (SJW) within the Hypericum section of the Hypericaceae family. This species is among the most thoroughly investigated herbal [...] Read more.
Background: Hypericum species are widely acknowledged for their biological attributes, with notable attention being paid to Hypericum perforatum, commonly known as St. John’s wort (SJW) within the Hypericum section of the Hypericaceae family. This species is among the most thoroughly investigated herbal medicines, particularly in terms of its application in the management of mild to moderate depression. SJW is used to treat depression, menopausal symptoms, attention-deficit hyperactivity disorder (ADHD), somatic symptom disorder, obsessive–compulsive disorder, and skin conditions, such as wounds and muscle pain. However, the usefulness and effectiveness of SJW for male sexual and reproductive health (SRH) are not well known. Objective: To assess the current evidence in the literature on the effect of SJW on male SRH. Methods: This narrative review followed a predetermined protocol and used MEDLINE and PubMed to identify articles published in English on the effects of SJW on male SRH. The search used various keywords, such as “Hypericum Perforatum”, “St. John’s Wort”, and terms related to sexual and reproductive health issues. Articles published between the inception of the database and August 2023 were included. Results: We identified 12 articles published from 1999 to 2019, the majority of which were experimental and conducted on animals. These studies demonstrate variability in terms of design, sample size, type of SJW extract used, the dosage administered, and duration of treatment. Studies have indicated potential sexual dysfunction (SD) due to SJW, which includes reduced libido, delayed ejaculation, delayed orgasm, and erectile dysfunction. Additionally, reproductive toxicity has been suggested, as evidenced by spermicidal effects through the inhibition of sperm motility, abnormal spermatozoa, chromosomal aberrations, and DNA denaturation. Furthermore, some studies have reported potential adverse events during maternal exposure, inhibition of fertilization, and disruption of reproductive parameters. Conclusions: Our review suggests that the safety and efficacy of SJW in the treatment of human SRH remain unclear. Further comprehensive, well-designed studies with larger samples, longer exposure periods, and specific dosages are needed to clarify SJW's effects of SJW. Therefore, consultation with healthcare professionals before using herbal remedies or supplements is crucial. Full article
(This article belongs to the Topic Research in Pharmacological Therapies)
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15 pages, 1590 KiB  
Article
Impact of Treatment with GLP1 Receptor Agonists, Liraglutide 3.0 mg and Semaglutide 1.0 mg, While on a Waiting List for Bariatric Surgery
by Miguel A. Rubio-Herrera, Sara Mera-Carreiro, Andrés Sánchez-Pernaute and Ana M. Ramos-Levi
Biomedicines 2023, 11(10), 2785; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines11102785 - 13 Oct 2023
Cited by 1 | Viewed by 1681
Abstract
Background: Weight loss before undergoing metabolic and bariatric surgery (MBS) has been suggested to reduce perioperative complications, although with controversial results. The objective of this study is to evaluate the impact of treatment with GLP1-R agonists (liraglutide 3.0 mg and semaglutide 1.0 mg) [...] Read more.
Background: Weight loss before undergoing metabolic and bariatric surgery (MBS) has been suggested to reduce perioperative complications, although with controversial results. The objective of this study is to evaluate the impact of treatment with GLP1-R agonists (liraglutide 3.0 mg and semaglutide 1.0 mg) on preoperative weight loss and patients’ decisions regarding MBS while on a surgical waiting list. Materials and methods: One hundred and two patients on a waiting list for MBS started treatment with GLP1-RA for at least 6 months. Changes in weight at 26 and 52 weeks, the number of patients achieving >5% weight loss, and patients’ decisions regarding MBS were evaluated. Results: After 52 weeks, patients lost 16.9 ± 7.2% of weight with semaglutide 1.0 mg and 16.1 ± 5.8% of weight with liraglutide 3.0 mg. All patients lost ≥5% of initial weight, 84.7% lost ≥10%, 54.6% lost ≥15%, and 27.5% reached ≥20%. A total of 68.6% of participants were satisfied with the achieved weight loss and withdrew from the waiting list for MBS. A threshold of >15.1% weight loss had the greatest sensitivity and specificity for the final decision regarding undergoing MBS. Conclusions: Losing >15% of initial weight after 52 weeks of treatment with liraglutide 3.0 mg or semaglutide 1.0 mg during the waiting list for MBS impacts patients’ decisions regarding the final acceptance or rejection of the procedure. Full article
(This article belongs to the Topic Research in Pharmacological Therapies)
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22 pages, 7978 KiB  
Article
Apabetalone, a Clinical-Stage, Selective BET Inhibitor, Opposes DUX4 Target Gene Expression in Primary Human FSHD Muscle Cells
by Christopher D. Sarsons, Dean Gilham, Laura M. Tsujikawa, Sylwia Wasiak, Li Fu, Brooke D. Rakai, Stephanie C. Stotz, Agostina Carestia, Michael Sweeney and Ewelina Kulikowski
Biomedicines 2023, 11(10), 2683; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines11102683 - 30 Sep 2023
Viewed by 2282
Abstract
Facioscapulohumeral dystrophy (FSHD) is a muscle disease caused by inappropriate expression of the double homeobox 4 (DUX4) gene in skeletal muscle, and its downstream activation of pro-apoptotic transcriptional programs. Inhibitors of DUX4 expression have the potential to treat FSHD. Apabetalone is a clinical-stage [...] Read more.
Facioscapulohumeral dystrophy (FSHD) is a muscle disease caused by inappropriate expression of the double homeobox 4 (DUX4) gene in skeletal muscle, and its downstream activation of pro-apoptotic transcriptional programs. Inhibitors of DUX4 expression have the potential to treat FSHD. Apabetalone is a clinical-stage bromodomain and extra-terminal (BET) inhibitor, selective for the second bromodomain on BET proteins. Using primary human skeletal muscle cells from FSHD type 1 patients, we evaluated apabetalone for its ability to counter DUX4′s deleterious effects and compared it with the pan-BET inhibitor JQ1, and the p38 MAPK inhibitor—and DUX4 transcriptional repressor—losmapimod. We applied RNA-sequencing and bioinformatic analysis to detect treatment-associated impacts on the transcriptome of these cells. Apabetalone inhibited the expression of DUX4 downstream markers, reversing hallmarks of FSHD gene expression in differentiated muscle cells. JQ1, but not apabetalone, was found to induce apoptosis. While both BET inhibitors modestly impacted differentiation marker expression, they did not affect myotube fusion. Losmapimod also reduced expression of DUX4 target genes but differed in its impact on FSHD-associated pathways. These findings demonstrate that apabetalone inhibits DUX4 target gene expression and reverses transcriptional programs that contribute to FSHD pathology, making this drug a promising candidate therapeutic for FSHD. Full article
(This article belongs to the Topic Research in Pharmacological Therapies)
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9 pages, 455 KiB  
Article
The Impact of Relapses on Pain and Quality of Life in Patients with Multiple Sclerosis Treated with Corticosteroids
by Martin Rakusa, Jeremy Chataway and Todd A. Hardy
Pharmaceuticals 2023, 16(9), 1244; https://0-doi-org.brum.beds.ac.uk/10.3390/ph16091244 - 4 Sep 2023
Viewed by 917
Abstract
Background: We assessed the prevalence and risks associated with pain during and after a multiple sclerosis (MS) relapse, and the impact of pain on quality of life (QoL), in MS patients. Methods: 117 patients suffering an acute MS relapse were evaluated with clinician- [...] Read more.
Background: We assessed the prevalence and risks associated with pain during and after a multiple sclerosis (MS) relapse, and the impact of pain on quality of life (QoL), in MS patients. Methods: 117 patients suffering an acute MS relapse were evaluated with clinician- and patient-reported outcomes, including the expanded disability status scale (EDSS), Multiple Sclerosis Impact Scale (MSIS-29), and MS Walking scale-12 (MSWS-12). Relapse-related pain was assessed via the short-form 36 (SF-36) questionnaire upon first visit (relapse onset) and at 6 weeks after treatment with intravenous methylprednisolone (follow-up visit). Results: Pain was present in 80% of patients at relapse onset. Patients with pain were more impaired physically (higher mean scores on MSIS-29phys and MSWS-12 and lower mean scores on SF-36 role physical, physical, and vitality scales) at relapse and six weeks after. In total, 74% of patients with MS relapse reported a poorer QoL due to pain. A lower psychological well-being was correlated with greater pain (MSIS29psy score). An increased number of prior relapses was a predictor of more pain at relapse onset. Conclusions: Pain was common at the time of MS relapse and improved, but was still significant, six weeks after treatment with corticosteroids. Further studies are required to better understand relapse-related pain. Full article
(This article belongs to the Topic Research in Pharmacological Therapies)
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16 pages, 4016 KiB  
Article
Mast Cell Deficiency in Mice Attenuates Insulin Phenolic Preservative-Induced Inflammation
by Shereen Kesserwan, Marianna Sadagurski, Li Mao and Ulrike Klueh
Biomedicines 2023, 11(8), 2258; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines11082258 - 12 Aug 2023
Viewed by 1000
Abstract
One major obstacle that limits the lifespan of insulin infusion pumps is surmounting the tissue site reaction at the device implantation site. All commercial insulin formulations contain insulin phenolic preservatives (IPPs) designed to ensure insulin protein stability and prolong shelf-life. However, our laboratory [...] Read more.
One major obstacle that limits the lifespan of insulin infusion pumps is surmounting the tissue site reaction at the device implantation site. All commercial insulin formulations contain insulin phenolic preservatives (IPPs) designed to ensure insulin protein stability and prolong shelf-life. However, our laboratory demonstrated that these preservatives are cytotoxic and induce inflammation. Mature mast cells (MCs) reside in cutaneous tissue and are one of the first responders to an epidermal breach. Upon activation, MCs release proinflammatory and immunomodulatory prepacked mediators that exacerbate these inflammatory reactions. Thus, we hypothesized that once the epidermis is breached, cutaneous MCs are triggered inciting the inflammatory response to IPP-induced inflammation. This hypothesis was pursued utilizing our modified in vivo mouse air pouch model, including a c-kit dependent (C57BL/6J-kitW-sh/W-sh) and a c-kit independent (Cpa3-Cre; Mcl-1fl/fl) MC-deficient mouse model. Leukocytes were quantified in the mouse air pouch lavage fluid following flow cytometry analysis for IPP infusion under three different states, insulin-containing phenolic preservatives (Humalog®), insulin preservatives alone, and normal saline as a control. The air pouch wall was assessed using histopathological evaluations. Flow cytometry analysis demonstrated a statistically significant difference in inflammatory cell recruitment for both MC-deficient mouse models when compared to the control strain including infused control saline. Significantly less inflammation was observed at the site of infusion for the MC-deficient strains compared to the control strain. Overall, concordant results were obtained in both mouse types, C57Bl6-kitW-sh/W-sh and Cpa3-Cre; Mcl-1fl/fl. These findings in multiple model systems support the conclusion that MCs have important or possible unique roles in IPP-induced inflammation. Full article
(This article belongs to the Topic Research in Pharmacological Therapies)
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14 pages, 601 KiB  
Article
Efficacy of Pregabalin and Duloxetine in Patients with Painful Diabetic Peripheral Neuropathy (PDPN): A Multi-Centre Phase IV Clinical Trial—BLOSSOM
by Martin Rakusa, Iris Marolt, Zorica Stevic, Sandra Vuckovic Rebrina, Tatjana Milenkovic and Adam Stepien
Pharmaceuticals 2023, 16(7), 1017; https://0-doi-org.brum.beds.ac.uk/10.3390/ph16071017 - 18 Jul 2023
Cited by 1 | Viewed by 4063
Abstract
Introduction: Our trial (ClinicalTrials.gov Identifier: NCT04246619) evaluates the efficacy of two generic medications, pregabalin and duloxetine, for treating pain in PDPN patients. Methods: The patients were randomised either into the pregabalin (99) or the duloxetine (102) arm. Pain was evaluated using the DN-4 [...] Read more.
Introduction: Our trial (ClinicalTrials.gov Identifier: NCT04246619) evaluates the efficacy of two generic medications, pregabalin and duloxetine, for treating pain in PDPN patients. Methods: The patients were randomised either into the pregabalin (99) or the duloxetine (102) arm. Pain was evaluated using the DN-4 questionnaire, and visual analogue scales (VASs, 0–100 mm) were used to measure the average pain intensity (API), worst pain intensity (WPI) in the last 24 h and current pain intensity (CPI). Results: The proportion of patients with a clinically significant improvement in the API at Week 12 was 88.3% [CI 81.7%, 94.8%] in the pregabalin arm and 86.9% [CI 76.7%, 97.1%] in the duloxetine arm. After 12 weeks, the CPI, API, and WPI decreased by −35.3 [−40.5, −30.0], −37.0 [−41.4, −32.6], and −41.6 [−46.6, −36.5] in the pregabalin arm, and by −35.0 [−39.2, −30.7], −36.9 [−41.5, −32.3], and −40.0 [−44.8, −35.2] in the duloxetine arm (all in mm, all p < 0.001). Conclusion: Our results demonstrate that pregabalin and duloxetine are effective medications for treating pain in PDPN in more than 86% of all randomised patients. Full article
(This article belongs to the Topic Research in Pharmacological Therapies)
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14 pages, 3494 KiB  
Article
Annexin A5 Inhibits Endothelial Inflammation Induced by Lipopolysaccharide-Activated Platelets and Microvesicles via Phosphatidylserine Binding
by Brent J. Tschirhart, Xiangru Lu, Janice Gomes, Arundhasa Chandrabalan, Gillian Bell, David A. Hess, Guangxin Xing, Hong Ling, Dylan Burger and Qingping Feng
Pharmaceuticals 2023, 16(6), 837; https://0-doi-org.brum.beds.ac.uk/10.3390/ph16060837 - 3 Jun 2023
Cited by 1 | Viewed by 1604
Abstract
Sepsis is caused by a dysregulated immune response to infection and is a leading cause of mortality globally. To date, no specific therapeutics are available to treat the underlying septic response. We and others have shown that recombinant human annexin A5 (Anx5) treatment [...] Read more.
Sepsis is caused by a dysregulated immune response to infection and is a leading cause of mortality globally. To date, no specific therapeutics are available to treat the underlying septic response. We and others have shown that recombinant human annexin A5 (Anx5) treatment inhibits pro-inflammatory cytokine production and improves survival in rodent sepsis models. During sepsis, activated platelets release microvesicles (MVs) with externalization of phosphatidylserine to which Anx5 binds with high affinity. We hypothesized that recombinant human Anx5 blocks the pro-inflammatory response induced by activated platelets and MVs in vascular endothelial cells under septic conditions via phosphatidylserine binding. Our data show that treatment with wildtype Anx5 reduced the expression of inflammatory cytokines and adhesion molecules induced by lipopolysaccharide (LPS)-activated platelets or MVs in endothelial cells (p < 0.01), which was not observed with Anx5 mutant deficient in phosphatidylserine binding. In addition, wildtype Anx5 treatment, but not Anx5 mutant, improved trans-endothelial electrical resistance (p < 0.05) and reduced monocyte (p < 0.001) and platelet (p < 0.001) adhesion to vascular endothelial cells in septic conditions. In conclusion, recombinant human Anx5 inhibits endothelial inflammation induced by activated platelets and MVs in septic conditions via phosphatidylserine binding, which may contribute to its anti-inflammatory effects in the treatment of sepsis. Full article
(This article belongs to the Topic Research in Pharmacological Therapies)
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14 pages, 2964 KiB  
Article
Effects of Taraxerol on Oxidative and Inflammatory Mediators in Isoproterenol-Induced Cardiotoxicity in an Animal Model
by Alhussain H. Aodah, Sushma Devi, Faisal K. Alkholifi, Hasan S. Yusufoglu, Ahmed I. Foudah and Aftab Alam
Molecules 2023, 28(10), 4089; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules28104089 - 15 May 2023
Cited by 2 | Viewed by 1616
Abstract
Myocardial infarction (MI) continues to be an important issue in healthcare systems worldwide, leading to high rates of morbidity and mortality. Despite ongoing efforts towards the development of preventive measures and treatments, addressing the challenges posed by MI remains difficult both in developed [...] Read more.
Myocardial infarction (MI) continues to be an important issue in healthcare systems worldwide, leading to high rates of morbidity and mortality. Despite ongoing efforts towards the development of preventive measures and treatments, addressing the challenges posed by MI remains difficult both in developed and developing countries. However, researchers recently investigated the potential cardioprotective effects of taraxerol utilizing an isoproterenol (ISO)-induced cardiotoxicity model among Sprague Dawley rats. Specifically, subcutaneous tissue injections consisting of 5.25 mg/kg or 8.5 mg/kg ISO were administered over two consecutive days as stimuli to induce cardiac injury. To investigate the possibility of preventing damage caused by ISO-induced cardiotoxicity by taraxerol treatment, five groups were formed: a normal control group (1% Tween 80), an ISO control group, an amlodipine group administered 5 mg/kg/day, and various doses of taraxerol. The study results showed that treatment significantly reduced cardiac marker enzymes. Additionally, pretreatment with taraxerol increased myocardial activity in SOD and GPx, leading to significant reductions in serum CK-MB levels along with MDA, TNF-α, and IL-6. Further histopathological analysis supported these observations, as treated animals had less cellular infiltration compared to untreated ones. These multifaceted findings suggest that oral administration of taraxerol could potentially protect hearts from ISO-caused damage by increasing endogenous antioxidant concentrations while decreasing pro-inflammatory cytokines. Full article
(This article belongs to the Topic Research in Pharmacological Therapies)
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11 pages, 1830 KiB  
Article
Chronic Effects of Apelin on Cardiovascular Regulation and Angiotensin II-Induced Hypertension
by Qi Zhang, Yue Shen, Sayeman Islam Niloy, Stephen T. O'Rourke and Chengwen Sun
Pharmaceuticals 2023, 16(4), 600; https://0-doi-org.brum.beds.ac.uk/10.3390/ph16040600 - 17 Apr 2023
Cited by 3 | Viewed by 1686
Abstract
Apelin, by stimulation of APJ receptors, induces transient blood pressure (BP) reduction and positive inotropic effects. APJ receptors share high homology with the Ang II type 1 receptor; thus, apelin was proposed to play a protective role in cardiovascular disease by antagonizing the [...] Read more.
Apelin, by stimulation of APJ receptors, induces transient blood pressure (BP) reduction and positive inotropic effects. APJ receptors share high homology with the Ang II type 1 receptor; thus, apelin was proposed to play a protective role in cardiovascular disease by antagonizing the actions of Ang II. In this regard, apelin and apelin-mimetics are currently being studied in clinical trials. However, the chronic effect of apelin in cardiovascular regulation has not been fully investigated. In the current study, blood pressure (BP) and heart rate (HR) were recorded using a telemetry implantation approach in conscious rats, before and during chronic subcutaneous infusion of apelin-13, using osmotic minipumps. At the end of the recording, the cardiac myocyte morphology was examined using H&E staining, and cardiac fibrosis was evaluated by Sirius Red in each group of rats. The results demonstrated that the chronic infusion of apelin-13 did not change either BP or HR. However, under the same condition, the chronic infusion of Ang II induced significant BP elevation, cardiac hypertrophy, and fibrosis. Co-administration of apelin-13 did not significantly alter the Ang II-induced elevation in BP, changes in cardiac morphology, and fibrosis. Taken together, our experiments showed an unexpected result indicating that the chronic administration of apelin-13 did not alter basal BP, nor did it change Ang II-induced hypertension and cardiac hypertrophy. The findings suggest that an APJ receptor biased agonist could be a better therapeutic alternative for treatment of hypertension. Full article
(This article belongs to the Topic Research in Pharmacological Therapies)
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