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Editor’s Choice Articles

Editor’s Choice articles are based on recommendations by the scientific editors of MDPI journals from around the world. Editors select a small number of articles recently published in the journal that they believe will be particularly interesting to readers, or important in the respective research area. The aim is to provide a snapshot of some of the most exciting work published in the various research areas of the journal.

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30 pages, 1334 KiB  
Review
Revolutionizing Prostate Cancer Detection: The Role of Approved PSMA-PET Imaging Agents
by Ute Hennrich, Laurène Wagner, Harun Taş, Luciana Kovacs and Martina Benešová-Schäfer
Pharmaceuticals 2025, 18(6), 906; https://doi.org/10.3390/ph18060906 - 17 Jun 2025
Viewed by 1325
Abstract
Locametz®/Illuccix®/GozellixTM (Novartis AG (Basel, Switzerland) and Telix Pharmaceuticals, Ltd. (Melbourne, Australia), all three [68Ga]Ga-PSMA-11), Pylarify®/Pylclari® (Progenics Pharmaceuticals, Inc. (New York, USA) and Curium PET France SA (Paris, France), both [18F]DCFPyL), Radelumin [...] Read more.
Locametz®/Illuccix®/GozellixTM (Novartis AG (Basel, Switzerland) and Telix Pharmaceuticals, Ltd. (Melbourne, Australia), all three [68Ga]Ga-PSMA-11), Pylarify®/Pylclari® (Progenics Pharmaceuticals, Inc. (New York, USA) and Curium PET France SA (Paris, France), both [18F]DCFPyL), Radelumin® (ABX GmbH (Radeberg, Germany), [18F]PSMA-1007), and Posluma® (Blue Earth Diagnostics, Ltd. (Oxford, UK), [18F]rhPSMA-7.3) are four approved PSMA-PET imaging agents that have significantly advanced the diagnosis and management of prostate cancer. These agents offer a new level of precision and accuracy, enabling clinicians to detect prostate cancer with enhanced sensitivity. As a result, they play a critical role in improving detection, staging, and management, ultimately enhancing clinical outcomes for patients. Their use in routine clinical practice is expected to increase diagnostic precision and provide clearer pathways for personalized therapy. This review offers a comprehensive chemical, pharmaceutical, and medicinal overview, discusses comparative studies, and highlights additional highly relevant candidates for prostate cancer detection. Full article
(This article belongs to the Special Issue Past, Present and Future Radiotracer Techniques: Radiopharmaceuticals in Cancer Theranostics)
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19 pages, 3876 KiB  
Article
Improving Ex Vivo Nasal Mucosa Experimental Design for Drug Permeability Assessments: Correcting Mucosal Thickness Interference and Reevaluating Fluorescein Sodium as an Integrity Marker for Chemically Induced Mucosal Injury
by Shengnan Zhao, Jieyu Zuo, Marlon C. Mallillin III, Ruikun Tang, Michael R. Doschak, Neal M. Davies and Raimar Löbenberg
Pharmaceuticals 2025, 18(6), 889; https://doi.org/10.3390/ph18060889 - 13 Jun 2025
Viewed by 1138
Abstract
Objectives: Ex vivo nasal mucosa models provide physiologically relevant platforms for evaluating nasal drug permeability; however, their application is often limited by high experimental variability and the absence of standardized methodologies. This study aimed to improve experimental design by addressing two major [...] Read more.
Objectives: Ex vivo nasal mucosa models provide physiologically relevant platforms for evaluating nasal drug permeability; however, their application is often limited by high experimental variability and the absence of standardized methodologies. This study aimed to improve experimental design by addressing two major limitations: the confounding effects of mucosal thickness and the questionable reliability of fluorescein sodium (Flu-Na) as an integrity marker for chemically induced mucosal injury. Methods: Permeability experiments were conducted using porcine nasal tissues mounted in Franz diffusion cells, with melatonin and Flu-Na as model compounds. Tissues of varying thickness were collected from both intra- and inter-individual sources, and a numerical simulation-based method was employed to normalize apparent permeability coefficients (Papp) to a standardized mucosal thickness of 0.80 mm. The effects of thickness normalization and chemically induced damage were systematically evaluated. Results: Thickness normalization substantially reduced variability in melatonin Papp, particularly within same-animal comparisons, thereby improving statistical power and data reliability. In contrast, Flu-Na exhibited inconsistent correlations across different pigs and failed to reflect the expected increase in permeability following isopropyl alcohol (IPA)-induced epithelial damage. These results suggest that the relationship between epithelial injury and paracellular transport may be non-linear and not universally applicable under ex vivo conditions, limiting the suitability of Flu-Na as a standalone marker of mucosal integrity. Conclusions: The findings highlight the importance of integrating mucosal thickness correction into standardized experimental protocols and call for a critical reassessment of Flu-Na in nasal drug delivery research. Full article
(This article belongs to the Section Pharmaceutical Technology)
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15 pages, 970 KiB  
Article
Potential Natural Blend Hydrosol TGLON Suppresses the Proliferation of Five Cancer Cell Lines and Also Ameliorates Idiopathic Pulmonary Fibrosis in a Mouse Model
by Wei-Hsiang Huang, Mei-Lin Chang, Ching-Che Lin, Chih-Peng Wang, Feng-Jie Tsai and Chih-Chien Lin
Pharmaceuticals 2025, 18(6), 872; https://doi.org/10.3390/ph18060872 - 11 Jun 2025
Viewed by 1400
Abstract
Background: Cancer and fibrotic diseases represent major global health challenges, underscoring the need for safe, multifunctional natural therapies. Although natural products possess notable anticancer properties, their clinical translation is often hindered by non-selective cytotoxicity toward normal cells. Moreover, their therapeutic potential against chronic [...] Read more.
Background: Cancer and fibrotic diseases represent major global health challenges, underscoring the need for safe, multifunctional natural therapies. Although natural products possess notable anticancer properties, their clinical translation is often hindered by non-selective cytotoxicity toward normal cells. Moreover, their therapeutic potential against chronic conditions such as idiopathic pulmonary fibrosis (IPF) remains insufficiently explored. This study aimed to evaluate the efficacy and safety of a natural hydrosol blend, The Greatest Love of Nature (TGLON), in inhibiting cancer cell proliferation and mitigating IPF. Methods: TGLON, composed of 12 steam-distilled plant hydrosols, was chemically characterized by gas chromatography–mass spectrometry (GC-MS). Its cytotoxicity was assessed using the MTT assay against five human cancer cell lines (A-549, HepG2, MCF-7, MKN-45, and MOLT-4) and normal human lung fibroblasts (MRC-5). In vivo safety and therapeutic efficacy were evaluated in Sprague Dawley rats and a bleomycin-induced IPF mouse model, following protocols approved by the Institutional Animal Care and Use Committee (IACUC). Results: TGLON maintained >90% viability in MRC-5 cells at an 80-fold dilution and significantly inhibited the proliferation of A-549 (41%), HepG2 (84%), MCF-7 (50%), MKN-45 (38%), and MOLT-4 (52%) cells. No signs of toxicity were observed in rats administered TGLON orally at 50% (v/v), 10 mL/kg. In mice, TGLON alleviated bleomycin-induced pulmonary inflammation and fibrosis. Conclusions: TGLON exhibited selective anticancer and anti-fibrotic activities under non-toxic conditions, supporting its potential as a bioactive agent for early-stage disease prevention and non-clinical health maintenance. Full article
(This article belongs to the Special Issue Advances in the Chemical-Biological Knowledge of Essential Oils)
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23 pages, 834 KiB  
Review
Metabolic Reprogramming in Melanoma: An Epigenetic Point of View
by Stefano Giuliani, Celeste Accetta, Simona di Martino, Claudia De Vitis, Elena Messina, Edoardo Pescarmona, Maurizio Fanciulli, Gennaro Ciliberto, Rita Mancini and Italia Falcone
Pharmaceuticals 2025, 18(6), 853; https://doi.org/10.3390/ph18060853 - 6 Jun 2025
Cited by 2 | Viewed by 1234
Abstract
Metabolic reprogramming and epigenetic alterations are fundamental hallmarks of cancer cells, contributing to adaptation, progression, and resistance. In melanoma, high metabolic-epigenetic plasticity enables the rapid modulation of cell states in response to environmental and therapeutic pressures. Recent studies have highlighted a bidirectional crosstalk [...] Read more.
Metabolic reprogramming and epigenetic alterations are fundamental hallmarks of cancer cells, contributing to adaptation, progression, and resistance. In melanoma, high metabolic-epigenetic plasticity enables the rapid modulation of cell states in response to environmental and therapeutic pressures. Recent studies have highlighted a bidirectional crosstalk between cellular metabolism and epigenetic regulation. Epigenetic modifications influence the transcriptional control of metabolic genes, thereby shaping metabolic phenotypes. Conversely, specific metabolites are essential cofactors or substrates for epigenetic enzymes, directly modulating the epigenome. Understanding the intricate mechanisms of this interaction offers opportunities for the development of innovative tumor management that combines epigenetic, metabolic, and therapy interventions. In this review, we summarize the latest evidence on the role of the metabolism–epigenetics axis in melanoma and discuss its potential clinical implications, aiming to provide a comprehensive overview of metabolic/epigenetic interconnections. Full article
(This article belongs to the Section Biopharmaceuticals)
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13 pages, 3110 KiB  
Article
Intraoperative Confocal Laser Endomicroscopy Detects Prostate Cancer at the Single-Cell Level with High Specificity and in Real Time: A Preclinical Proof of Concept
by Ann-Christin Eder, Jessica Matthias, Francois Lacombe, Lisa-Charlotte Domogalla, Antoine Jacques, Nils Steinacker, Gaetan Christien, Elodie Martin, Aline Criton and Matthias Eder
Pharmaceuticals 2025, 18(6), 841; https://doi.org/10.3390/ph18060841 - 4 Jun 2025
Viewed by 628
Abstract
In prostate cancer (PCa) surgery, precise tumor margin identification remains challenging despite advances in surgical techniques. This study evaluates the combination of tumor-specific near-infrared imaging with the PSMA-targeting molecule PSMA-914 and optical endomicroscopy (NIR-pCLE) for single-cell-level tumor identification in a preclinical proof of [...] Read more.
In prostate cancer (PCa) surgery, precise tumor margin identification remains challenging despite advances in surgical techniques. This study evaluates the combination of tumor-specific near-infrared imaging with the PSMA-targeting molecule PSMA-914 and optical endomicroscopy (NIR-pCLE) for single-cell-level tumor identification in a preclinical proof of concept. Methods: NIR-pCLE imaging of varying PSMA-914 concentrations was performed on PSMA-positive LNCaP and PSMA-negative PC-3 cells using Cellvizio® 100 with pCLE Confocal Miniprobes™. To identify optimal PSMA-914 dosing for in vivo imaging, different doses (0–10 nmol) were evaluated using NIR-pCLE, Odyssey CLx imaging, and confocal microscopy in an LNCaP tumor-bearing xenograft model. A proof of concept mimicking a clinical workflow was performed using 5 nmol [68Ga]Ga-PSMA-914 in LNCaP and PC-3 tumor xenografts, including PET/MRI, in/ex vivo NIR-pCLE imaging, and microscopic/macroscopic imaging. Results: NIR-pCLE detected PSMA-specific fluorescence at concentrations above 30 nM in vitro. The optimal dose was identified as 5 nmol PSMA-914 for NIR-pCLE imaging with cellular resolution in LNCaP xenografts. PET/MRI confirmed high tumor uptake and a favorable distribution profile of PSMA-914. NIR-pCLE imaging enabled real-time, single-cell-level detection of PSMA-positive tissue, visualizing tumor heterogeneity, confirmed by ex vivo microscopy and imaging. Conclusions: This preclinical proof of concept demonstrates the potential of intraoperative PSMA-specific NIR-pCLE imaging to visualize tissue structures in real time at cellular resolution. Clinical implementation could provide surgeons with valuable additional information, potentially advancing PCa patient care through improved surgical precision. Full article
(This article belongs to the Special Issue Past, Present and Future Radiotracer Techniques: Radiopharmaceuticals in Cancer Theranostics)
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30 pages, 2081 KiB  
Review
The Potential of Artificial Intelligence in Pharmaceutical Innovation: From Drug Discovery to Clinical Trials
by Vera Malheiro, Beatriz Santos, Ana Figueiras and Filipa Mascarenhas-Melo
Pharmaceuticals 2025, 18(6), 788; https://doi.org/10.3390/ph18060788 - 25 May 2025
Viewed by 4428
Abstract
Artificial intelligence (AI) is a subfield of computer science focused on developing systems that can execute tasks traditionally associated with human intelligence. AI systems work through algorithms based on rules or instructions that enable the machine to make decisions. With the advancement of [...] Read more.
Artificial intelligence (AI) is a subfield of computer science focused on developing systems that can execute tasks traditionally associated with human intelligence. AI systems work through algorithms based on rules or instructions that enable the machine to make decisions. With the advancement of science, more sophisticated AI techniques, such as machine learning and deep learning, have been developed, allowing machines to learn from large amounts of data and improve their performance over time. The pharmaceutical industry has greatly benefited from the development of this technology. AI has revolutionized drug discovery and development by enabling rapid and effective analysis of vast volumes of biological and chemical data during the identification of new therapeutic compounds. The algorithms developed can predict the efficacy, toxicity, and possible adverse effects of new drugs, optimize the steps involved in clinical trials, reduce associated time and costs, and facilitate the implementation of innovative drugs in the market, making it easier to develop precise therapies tailored to the individual genetic profile of patients. Despite significant advancements, there are still gaps in the application of AI, particularly due to the lack of comprehensive regulation. The constant evolution of this technology requires ongoing and in-depth legislative oversight to ensure its use remains safe, ethical, and free from bias. This review explores the role of AI in drug development, assessing its potential to enhance formulation, accelerate discovery, and repurpose existing medications. It highlights AI’s impact across all stages, from initial research to clinical trials, emphasizing its ability to optimize processes, drive innovation, and improve therapeutic outcomes. Full article
(This article belongs to the Special Issue Computational Methods in Drug Development)
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19 pages, 1294 KiB  
Review
Interferon Lambda: The Next Frontier in Antiviral Therapy?
by Sofia Chronopoulou and Ilias Tsochantaridis
Pharmaceuticals 2025, 18(6), 785; https://doi.org/10.3390/ph18060785 - 24 May 2025
Cited by 1 | Viewed by 1715
Abstract
Type III interferons (IFN-λ) are the most recently identified members of the interferon family, distantly related to type I interferons and members of the interleukin-10 (IL-10). Unlike type I interferons, which have broadly distributed cellular receptors, IFN-λ signals through a heterodimeric receptor complex [...] Read more.
Type III interferons (IFN-λ) are the most recently identified members of the interferon family, distantly related to type I interferons and members of the interleukin-10 (IL-10). Unlike type I interferons, which have broadly distributed cellular receptors, IFN-λ signals through a heterodimeric receptor complex with primary expression on epithelial cells. This restricted receptor distribution makes IFN-λ a favorable candidate for therapeutic and antiviral applications with reduced side effects. In this review, we describe the molecular structure, signaling mechanisms, and the role of IFN-λ in the innate immunity of epithelial tissue, which are its primary sites of action. Moreover, this review will summarize and critically examine the antiviral potential of IFN-λ based on all published clinical trials conducted for the treatment of COVID-19, and hepatitis B, C and D virus. Furthermore, this review suggests IFN-λ as a promising therapeutic recombinant protein, with special emphasis on its potential for production using alternative expression and advanced drug delivery systems. To emphasize its potential as a therapeutic intervention, the design and engineering of recombinant IFN-λ will be presented, with a focus on its lower side-effect profile compared to Type I interferons. Full article
(This article belongs to the Section Biopharmaceuticals)
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13 pages, 1642 KiB  
Article
Efficacy and Safety of a Single Ivy Extract Versus Two Herbal Extract Combinations in Patients with Acute Bronchitis: A Multi-Center, Randomized, Open-Label Clinical Trial
by Peter Kardos, Justus de Zeeuw, Inga Trompetter, Simon Braun and Yuliya Ilieva
Pharmaceuticals 2025, 18(5), 754; https://doi.org/10.3390/ph18050754 - 20 May 2025
Cited by 1 | Viewed by 1653
Abstract
Background: The combination therapy for acute bronchitis with several plant extracts, such as Ivy and Thyme or Primrose and Thyme, is assumed to offer added benefit over single extract preparations. However, no clinical trials have yet demonstrated such a therapeutic advantage. Methods [...] Read more.
Background: The combination therapy for acute bronchitis with several plant extracts, such as Ivy and Thyme or Primrose and Thyme, is assumed to offer added benefit over single extract preparations. However, no clinical trials have yet demonstrated such a therapeutic advantage. Methods: In this three-arm, open-label, randomized clinical trial, patients with acute bronchitis were assigned to groups receiving Ivy extract EA 575 (Prospan® Cough Drops), Ivy/Thyme extract combination (Bronchipret® Drops), or Thyme/Primrose extract combination (Bronchicum® Drops) according to their respective labels. The primary endpoint was the assessment of non-inferiority, and the second endpoint was the assessment of superiority of Ivy vs. each of the two comparators (Ivy/Thyme and Thyme/Primrose) regarding the change in Bronchitis Severity Score between baseline and day 7. In total, 325 adult patients were considered for evaluation. Results: Non-inferiority of Ivy extract was statistically significant against both comparators (both p < 0.0001). Superiority of Ivy extract was statistically significant against Ivy/Thyme extract (p < 0.0001) but missed statistical significance against Thyme/Primrose extract (p < 0.0607). The incidence of adverse events was low and comparable between the groups. All adverse events were non-serious. Conclusions: these data revealed that Ivy extract EA 575 is non-inferior in acute bronchitis treatment compared to both comparators and superior to Ivy/Thyme. Full article
(This article belongs to the Section Natural Products)
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27 pages, 550 KiB  
Systematic Review
Anti-Suicidal Effects of Lithium, Ketamine, and Clozapine—A 10-Year Systematic Review
by Przemyslaw M. Waszak, Jan Opalko, Natalia Olszańska and Paweł Zagożdżon
Pharmaceuticals 2025, 18(5), 742; https://doi.org/10.3390/ph18050742 - 18 May 2025
Viewed by 1890
Abstract
Background/Objectives: Suicide is a complex issue resulting in approximately 700,000 deaths annually. Individuals with mood disorders or schizophrenia are at an increased risk. Pharmacological interventions, such as lithium, clozapine, and ketamine, show promise in reducing suicidality. Methods: A systematic search was conducted across [...] Read more.
Background/Objectives: Suicide is a complex issue resulting in approximately 700,000 deaths annually. Individuals with mood disorders or schizophrenia are at an increased risk. Pharmacological interventions, such as lithium, clozapine, and ketamine, show promise in reducing suicidality. Methods: A systematic search was conducted across Google Scholar, Scopus, and PubMed to identify studies evaluating the effects of lithium, clozapine, and ketamine on suicidality. Peer-reviewed articles published between 2014 and 2024 that focused on adult populations were included. After screening 1297 records, 49 studies met the eligibility criteria: 14 on lithium, 23 on ketamine, and 12 on clozapine. Results: Multiple studies highlight lithium’s significant anti-suicidal effects in patients with bipolar disorder, showing superior suicide risk reduction compared to valproate and other mood stabilizers. Ketamine has been shown to rapidly reduce suicidal ideation, with effects observable within hours and lasting up to a week. While most studies support its short-term efficacy, findings regarding its long-term benefits and the impact of repeated dosing remain inconsistent. Clozapine has consistently demonstrated a reduction in suicide risk for individuals with schizophrenia. Large-scale cohort studies report a significant decrease in suicide attempts and mortality when compared to other antipsychotics. Conclusions: Lithium, ketamine, and clozapine were proven to be effective in reducing suicidality. However, limited data, adherence challenges, and methodological differences across studies highlight the need for more robust, large-scale experimental research. Effective suicide prevention is an extremely complex topic and also requires consideration of healthcare and social system factors. Full article
(This article belongs to the Special Issue Recent Advances in Psychiatric Medications)
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13 pages, 544 KiB  
Systematic Review
The Impact of Methylphenidate on Sexual Functions: A Systematic Review of Benefits and Risks
by Rafał Bieś, Zuzanna Szewczyk, Anna Warchala, Ewa Martyniak and Marek Krzystanek
Pharmaceuticals 2025, 18(5), 718; https://doi.org/10.3390/ph18050718 - 14 May 2025
Viewed by 6784
Abstract
Background: Methylphenidate is a psychostimulant that enhances dopamine and norepinephrine neurotransmission through the mechanism of reuptake inhibition at the synaptic cleft. Studies indicate that sexual dysfunction is prevalent among psychiatric patients. The objective of our study was to assess the impact of methylphenidate [...] Read more.
Background: Methylphenidate is a psychostimulant that enhances dopamine and norepinephrine neurotransmission through the mechanism of reuptake inhibition at the synaptic cleft. Studies indicate that sexual dysfunction is prevalent among psychiatric patients. The objective of our study was to assess the impact of methylphenidate on patients’ sexual health, identify specific types of sexual dysfunction, and analyse the correlations between psychiatric disorders, treatment dosages and durations, and the presence of sexual dysfunction. Additionally, we aimed to evaluate the prevalence of improved sexual function resulting from methylphenidate use. Methods: A systematic literature review was performed using the PubMed database in accordance with PRISMA guidelines. The initial search yielded 186 articles, of which 14 met the inclusion criteria and were analyzed. Clinical studies involving changes in libido, erectile function, ejaculation, semen quality, and sexual behavior due to methylphenidate were reviewed. Results: The findings indicate that methylphenidate can have both negative and positive effects on sexual function. In some patients, particularly those with psychiatric comorbidities, methylphenidate was associated with decreased libido and ejaculation disorders. In other cases, especially in individuals with preexisting dysfunctions or on low doses, it appeared to enhance sexual arousal and performance. Conclusions: Methylphenidate may influence sexual function in complex ways depending on individual patient profiles and treatment variables. Clinicians should be aware of these potential outcomes and consider sexual health as part of the therapeutic discussion when prescribing methylphenidate. Full article
(This article belongs to the Special Issue Toxicological Effects of Drug Abuse and Its Consequences on Health)
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44 pages, 18795 KiB  
Article
Citicoline and Coenzyme Q10: Therapeutic Agents for Glial Activation Reduction in Ocular Hypertension
by José A. Matamoros, Sara Rubio-Casado, José A. Fernández-Albarral, Miguel A. Martínez-López, Ana I. Ramírez, Elena Salobrar-García, Eva M. Marco, Victor Paleo-García, Rosa de Hoz, Inés López-Cuenca, Lorena Elvira-Hurtado, Lidia Sánchez-Puebla, José M. Ramírez, Meritxell López-Gallardo and Juan J. Salazar
Pharmaceuticals 2025, 18(5), 694; https://doi.org/10.3390/ph18050694 - 8 May 2025
Viewed by 2507
Abstract
Background/Objectives: The loss of retinal ganglion cells (RGCs) is a hallmark of glaucoma, a major cause of blindness. Glial cell activation due to increased intraocular pressure (IOP) significantly contributes to RGC death. Therefore, substances with anti-inflammatory properties could help prevent that process. [...] Read more.
Background/Objectives: The loss of retinal ganglion cells (RGCs) is a hallmark of glaucoma, a major cause of blindness. Glial cell activation due to increased intraocular pressure (IOP) significantly contributes to RGC death. Therefore, substances with anti-inflammatory properties could help prevent that process. This study investigated whether combining Citicoline and Coenzyme Q10 (CoQ10) can reduce glial activation in the retina and the rest of the visual pathway, potentially preventing neurodegeneration in a mouse model of unilateral laser-induced ocular hypertension (OHT). Methods: Four groups of mice were used: vehicle (n = 12), CitiQ10 (n = 12), OHT–vehicle (n = 18), and OHT–CitiQ10 (n = 18). The administration of Citicoline and CoQ10 was performed orally once a day, initiated 15 days prior to the laser treatment and maintained post-treatment until sacrifice (3 days for retina or 7 days for the rest of the visual pathway). The retina, dorsolateral geniculate nucleus, superior colliculus, and visual cortex (V1) were immunohistochemically stained and analyzed. Results: In the laser–CitiQ10 group, the Citicoline + CoQ10 compound revealed (1) an IOP decrease at 24 h and 3 days post-laser; and (2) reduced signs of macroglial (decreased GFAP area) and microglial (soma size, arbor area, microglia number, P2RY12 expression) activation in the retina and in the rest of the visual pathway (reduced activated microglial phenotypes and lower GFAP expression). Conclusions: This study shows that oral administration of Citicoline and CoQ10 can reduce glial activation caused by increased IOP in retina and visual pathway in a mouse model of OHT, potentially protecting RGCs from OHT-induced inflammation. Full article
(This article belongs to the Section Pharmacology)
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22 pages, 3787 KiB  
Article
Development of Smart pH-Sensitive Collagen-Hydroxyethylcellulose Films with Naproxen for Burn Wound Healing
by Elena-Emilia Tudoroiu, Mădălina Georgiana Albu Kaya, Cristina Elena Dinu-Pîrvu, Lăcrămioara Popa, Valentina Anuța, Mădălina Ignat, Emilia Visileanu, Durmuș Alpaslan Kaya, Răzvan Mihai Prisada and Mihaela Violeta Ghica
Pharmaceuticals 2025, 18(5), 689; https://doi.org/10.3390/ph18050689 - 7 May 2025
Cited by 1 | Viewed by 892
Abstract
Background: Developing versatile dressings that offer wound protection, maintain a moist environment, and facilitate healing represents an important therapeutic approach for burn patients. Objectives: This study presents the development of new smart pH-sensitive collagen-hydroxyethylcellulose films, incorporating naproxen and phenol red, designed [...] Read more.
Background: Developing versatile dressings that offer wound protection, maintain a moist environment, and facilitate healing represents an important therapeutic approach for burn patients. Objectives: This study presents the development of new smart pH-sensitive collagen-hydroxyethylcellulose films, incorporating naproxen and phenol red, designed to provide controlled drug release while enabling real-time pH monitoring for burn care. Methods: Biopolymeric films were prepared by the solvent-casting method using ethanol and glycerol as plasticizers. Results: Orange-colored films were thin, flexible, and easily peelable, with uniform, smooth, and nonporous morphology. Tensile strength varied from 0.61 N/mm2 to 3.33 N/mm2, indicating improved mechanical properties with increasing collagen content, while wetting analysis indicated a hydrophilic surface with contact angle values between 17.61° and 75.51°. Maximum swelling occurred at pH 7.4, ranging from 5.65 g/g to 9.20 g/g and pH 8.5, with values from 4.74 g/g to 7.92 g/g, suggesting effective exudate absorption. In vitro degradation proved structural stability maintenance for at least one day, with more than 40% weight loss. Films presented a biphasic naproxen release profile with more than 75% of the drug released after 24 h, properly managing inflammation and pain on the first-day post-burn. The pH variation mimicking the stages of the healing process demonstrated the color transition from yellow (pH 5.5) to orange (pH 7.4) and finally to bright fuchsia (pH 8.5), enabling easy visual evaluation of the wound environment. Conclusions: New multifunctional films combine diagnostic and therapeutic functions, providing a promising platform for monitoring wound healing, making them suitable for real-time wound assessment. Full article
(This article belongs to the Special Issue Development of Specific Dosage Form: Wound Dressing)
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35 pages, 19345 KiB  
Review
Natural Antidiabetic Agents: Insights into Ericaceae-Derived Phenolics and Their Role in Metabolic and Oxidative Modulation in Diabetes
by Mihaela Popescu, Kristina Radivojevic, Diana-Maria Trasca, Renata Maria Varut, Irina Enache and Andrei Osman
Pharmaceuticals 2025, 18(5), 682; https://doi.org/10.3390/ph18050682 - 4 May 2025
Viewed by 1614
Abstract
Diabetes mellitus (DM) is a chronic disease with a growing prevalence worldwide, leading to severe health complications. Current treatment relies on antidiabetic medications, which may have adverse effects, highlighting the need for alternative approaches. Natural compounds, such as phenolic compounds, have shown promise [...] Read more.
Diabetes mellitus (DM) is a chronic disease with a growing prevalence worldwide, leading to severe health complications. Current treatment relies on antidiabetic medications, which may have adverse effects, highlighting the need for alternative approaches. Natural compounds, such as phenolic compounds, have shown promise in glucose modulation. The Ericaceae family includes several plants with potential antidiabetic properties. This review examines the pathophysiology of diabetes, chemical composition, and specific Ericaceae species that have demonstrated antidiabetic effects. Studies indicate that Vaccinium species and other Ericaceae plants can lower blood glucose levels and improve insulin sensitivity through mechanisms such as enzyme inhibition. These findings suggest that Ericaceae plants may serve as complementary strategies for diabetes management. Full article
(This article belongs to the Section Natural Products)
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27 pages, 764 KiB  
Article
Effects of Carnosine Supplementation on Cognitive Outcomes in Prediabetes and Well-Controlled Type 2 Diabetes: A Randomised Placebo-Controlled Clinical Trial
by Rohit Hariharan, Aya Mousa, Kirthi Menon, Jack Feehan, Barbara Ukropcová, Jozef Ukropec, Martin Schön, Arshad Majid, Giancarlo Aldini, Maximilian de Courten, James Cameron, Simon M. Bell and Barbora de Courten
Pharmaceuticals 2025, 18(5), 630; https://doi.org/10.3390/ph18050630 - 26 Apr 2025
Viewed by 1220
Abstract
Background: Trends in global ageing underscore the rising burden of age-related cognitive decline and concomitant cardiometabolic diseases, including type 2 diabetes mellitus (T2DM). Carnosine, a naturally occurring dipeptide with anti-inflammatory, antioxidant and anti-glycating properties, has shown promise in animal models and limited human [...] Read more.
Background: Trends in global ageing underscore the rising burden of age-related cognitive decline and concomitant cardiometabolic diseases, including type 2 diabetes mellitus (T2DM). Carnosine, a naturally occurring dipeptide with anti-inflammatory, antioxidant and anti-glycating properties, has shown promise in animal models and limited human studies for improving cognitive function, insulin resistance and T2DM, but its therapeutic effects on cognition remain unclear. The aim of this study is to assess the effects of carnosine on cognitive function in individuals with prediabetes or well-controlled T2DM. Methods: This is a secondary analysis of a double-blind randomised controlled trial (RCT), whereby 49 adults with prediabetes or early-stage well-controlled T2DM were randomised to receive 2 g of carnosine or identical placebo daily for 14 weeks. At baseline and follow-up, cognitive function was assessed as a secondary outcome using the Digit-Symbol Substitution Test, Stroop test, Trail Making Tests A & B, and the Cambridge Automated Neuropsychological Test Battery (CANTAB). Results: In total, 42 adults (23 males and 19 females) completed the trial. There were no differences in participant anthropometry or cognitive functioning between carnosine and placebo groups at baseline (all p > 0.1). After the 14-week supplementation period, there were no differences between carnosine and placebo groups in change and follow-up values for any cognitive measures including Stroop, Digit Symbol Substitution Sest, Trail Making A/B or CANTAB (all p > 0.05). Adjustments for baseline cognitive scores, diabetic status, level of education, age or interaction effects with participants’ sex did not change the results. Conclusions: Carnosine supplementation did not improve cognitive measures in individuals with prediabetes or T2DM in this study. While larger trials may provide further insights, alternative factors—such as the relatively young and healthy profile of our cohort—may have contributed to the lack of observed effect. Future research should examine individuals with existing cognitive impairment or those at higher risk of cognitive decline to better define the therapeutic potential of carnosine in this context. Full article
(This article belongs to the Special Issue Therapeutic Potential of Natural Products in Internal Diseases)
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23 pages, 8189 KiB  
Review
Exploring Macrocyclic Chemical Space: Strategies and Technologies for Drug Discovery
by Taegwan Kim, Eunbee Baek and Jonghoon Kim
Pharmaceuticals 2025, 18(5), 617; https://doi.org/10.3390/ph18050617 - 24 Apr 2025
Viewed by 1938
Abstract
Macrocycles have emerged as significant therapeutic candidates in drug discovery due to their unique capacity to target complex and traditionally inaccessible biological interfaces. Their structurally constrained three-dimensional configurations facilitate high-affinity interactions with challenging targets, notably protein–protein interfaces. However, despite their potential, the synthesis [...] Read more.
Macrocycles have emerged as significant therapeutic candidates in drug discovery due to their unique capacity to target complex and traditionally inaccessible biological interfaces. Their structurally constrained three-dimensional configurations facilitate high-affinity interactions with challenging targets, notably protein–protein interfaces. However, despite their potential, the synthesis and optimization of macrocyclic compounds present considerable challenges related to structural complexity, synthetic accessibility, and the attainment of favorable drug-like properties, particularly cell permeability and oral bioavailability. Recent advancements in synthetic methodologies have expanded the chemical space accessible to macrocycles, enabling the creation of structurally diverse and pharmacologically active compounds. Concurrent developments in computational strategies have further enhanced macrocycle design, providing valuable insights into structural optimization and predicting molecular properties essential for therapeutic efficacy. Additionally, a deeper understanding of macrocycles’ conformational adaptability, especially their ability to internally shield polar functionalities to improve membrane permeability, has significantly informed their rational design. This review discusses recent innovations in synthetic and computational methodologies that have advanced macrocycle drug discovery over the past five years. It emphasizes the importance of integrating these strategies to overcome existing challenges, illustrating how their synergy expands the therapeutic potential and chemical diversity of macrocycles. Selected case studies underscore the practical impact of these integrated approaches, highlighting promising therapeutic applications across diverse biomedical targets. Full article
(This article belongs to the Special Issue Advances in the Synthesis and Application of Heterocyclic Compounds)
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40 pages, 1048 KiB  
Review
Antidiabetic GLP-1 Receptor Agonists Have Neuroprotective Properties in Experimental Animal Models of Alzheimer’s Disease
by Melinda Urkon, Elek Ferencz, József Attila Szász, Monica Iudita Maria Szabo, Károly Orbán-Kis, Szabolcs Szatmári and Előd Ernő Nagy
Pharmaceuticals 2025, 18(5), 614; https://doi.org/10.3390/ph18050614 - 23 Apr 2025
Cited by 3 | Viewed by 1898
Abstract
In addition to the classically accepted pathophysiological features of Alzheimer’s disease (AD), increasing attention is paid to the role of the insulin-resistant state of the central nervous system. Glucagon-like peptide-1 receptor (GLP-1R) agonism demonstrated neuroprotective consequences by mitigating neuroinflammation and oxidative damage. The [...] Read more.
In addition to the classically accepted pathophysiological features of Alzheimer’s disease (AD), increasing attention is paid to the role of the insulin-resistant state of the central nervous system. Glucagon-like peptide-1 receptor (GLP-1R) agonism demonstrated neuroprotective consequences by mitigating neuroinflammation and oxidative damage. The present review aims to offer a comprehensive overview of the neuroprotective properties of GLP-1R agonists (GLP-1RAs), with a particular focus on experimental animal models of AD. Ameliorated amyloid-β plaque and neurofibrillary tangle formation and deposition following exenatide, liraglutide, and lixisenatide treatment was confirmed in several models. The GLP-1RAs studied alleviated central insulin resistance, as evidenced by the decreased serine phosphorylation of insulin receptor substrate 1 (IRS-1) and restored downstream phosphoinositide 3-kinase/RAC serine/threonine–protein kinase (PI3K/Akt) signaling. Furthermore, the GLP-1RAs influenced multiple mitogen-activated protein kinases (extracellular signal-regulated kinase: ERK; c-Jun N-terminal kinase: JNK, p38) positively and suppressed glycogen synthase kinase 3 (GSK-3β) hyperactivation. A lower proportion of reactive microglia and astrocytes was associated with better neuronal preservation following their administration. Finally, restoration of cognitive functions, particularly spatial memory, was also observed for semaglutide and dulaglutide. GLP-1RAs, therefore, hold promising disease-modifying potential in the management of AD. Full article
(This article belongs to the Special Issue Neurodegenerative Disorders: Computer – Aided Drug Design, Еxperimental Аpproaches and Mechanisms)
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17 pages, 294 KiB  
Review
Hormonal Treatment of Endometriosis: A Narrative Review
by Elvin Piriyev, Sven Schiermeier and Thomas Römer
Pharmaceuticals 2025, 18(4), 588; https://doi.org/10.3390/ph18040588 - 17 Apr 2025
Viewed by 3062
Abstract
Background: Endometriosis is one of the most common gynecological diseases, affecting up to 10–15% of women of reproductive age. It is a chronic, estrogen-dependent condition that often presents with heterogeneous symptoms, complicating diagnosis and delaying treatment. Methods: This is a narrative [...] Read more.
Background: Endometriosis is one of the most common gynecological diseases, affecting up to 10–15% of women of reproductive age. It is a chronic, estrogen-dependent condition that often presents with heterogeneous symptoms, complicating diagnosis and delaying treatment. Methods: This is a narrative review based on a comprehensive analysis of recent literature regarding hormonal treatment options for endometriosis, including primary and adjuvant therapies. Results: Combined oral contraceptives (COCs) are effective in reducing dysmenorrhea, but show limited benefit for other symptoms and may not prevent disease progression. Progestins, particularly dienogest, demonstrate superior long-term efficacy with favorable side-effect profiles. GnRH agonists and antagonists are reserved for second-line treatment due to side effects and hypoestrogenism, but can significantly reduce endometriotic lesions. The levonorgestrel intrauterine system (LNG-IUS) is especially effective in patients with adenomyosis. Conclusions: Hormonal therapies are central to the management of endometriosis. Progestins are considered the most suitable long-term option. Despite promising results, evidence quality varies, and further studies are needed to establish long-term efficacy, patient-specific outcomes, and direct comparisons between agents. Full article
(This article belongs to the Special Issue Pharmacotherapy of Endometriosis)
31 pages, 3986 KiB  
Article
GNNSeq: A Sequence-Based Graph Neural Network for Predicting Protein–Ligand Binding Affinity
by Somanath Dandibhotla, Madhav Samudrala, Arjun Kaneriya and Sivanesan Dakshanamurthy
Pharmaceuticals 2025, 18(3), 329; https://doi.org/10.3390/ph18030329 - 26 Feb 2025
Cited by 1 | Viewed by 4468
Abstract
Background/Objectives: Accurately predicting protein–ligand binding affinity is essential in drug discovery for identifying effective compounds. While existing sequence-based machine learning models for binding affinity prediction have shown potential, they lack accuracy and robustness in pattern recognition, which limits their generalizability across diverse and [...] Read more.
Background/Objectives: Accurately predicting protein–ligand binding affinity is essential in drug discovery for identifying effective compounds. While existing sequence-based machine learning models for binding affinity prediction have shown potential, they lack accuracy and robustness in pattern recognition, which limits their generalizability across diverse and novel binding complexes. To overcome these limitations, we developed GNNSeq, a novel hybrid machine learning model that integrates a Graph Neural Network (GNN) with Random Forest (RF) and XGBoost. Methods: GNNSeq predicts ligand binding affinity by extracting molecular characteristics and sequence patterns from protein and ligand sequences. The fully optimized GNNSeq model was trained and tested on subsets of the PDBbind dataset. The novelty of GNNSeq lies in its exclusive reliance on sequence features, a hybrid GNN framework, and an optimized kernel-based context-switching design. By relying exclusively on sequence features, GNNSeq eliminates the need for pre-docked complexes or high-quality structural data, allowing for accurate binding affinity predictions even when interaction-based or structural information is unavailable. The integration of GNN, XGBoost, and RF improves GNNSeq performance by hierarchical sequence learning, handling complex feature interactions, reducing variance, and forming a robust ensemble that improves predictions and mitigates overfitting. The GNNSeq unique kernel-based context switching scheme optimizes model efficiency and runtime, dynamically adjusts feature weighting between sequence and basic structural information, and improves predictive accuracy and model generalization. Results: In benchmarking, GNNSeq performed comparably to several existing sequence-based models and achieved a Pearson correlation coefficient (PCC) of 0.784 on the PDBbind v.2020 refined set and 0.84 on the PDBbind v.2016 core set. During external validation with the DUDE-Z v.2023.06.20 dataset, GNNSeq attained an average area under the curve (AUC) of 0.74, demonstrating its ability to distinguish active ligands from decoys across diverse ligand–receptor pairs. To further evaluate its performance, we combined GNNSeq with two additional specialized models that integrate structural and protein–ligand interaction features. When tested on a curated set of well-characterized drug–target complexes, the hybrid models achieved an average PCC of 0.89, with the top-performing model reaching a PCC of 0.97. GNNSeq was designed with a strong emphasis on computational efficiency, training on 5000+ complexes in 1 h and 32 min, with real-time affinity predictions for test complexes. Conclusions: GNNSeq provides an efficient and scalable approach for binding affinity prediction, offering improved accuracy and generalizability while enabling large-scale virtual screening and cost-effective hit identification. GNNSeq is publicly available in a server-based graphical user interface (GUI) format. Full article
(This article belongs to the Section Biopharmaceuticals)
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85 pages, 24685 KiB  
Review
Adaptogens in Long-Lasting Brain Fatigue: An Insight from Systems Biology and Network Pharmacology
by Alexander Panossian, Terrence Lemerond and Thomas Efferth
Pharmaceuticals 2025, 18(2), 261; https://doi.org/10.3390/ph18020261 - 15 Feb 2025
Cited by 1 | Viewed by 8155
Abstract
Long-lasting brain fatigue is a consequence of stroke or traumatic brain injury associated with emotional, psychological, and physical overload, distress in hypertension, atherosclerosis, viral infection, and aging-related chronic low-grade inflammatory disorders. The pathogenesis of brain fatigue is linked to disrupted neurotransmission, the glutamate-glutamine [...] Read more.
Long-lasting brain fatigue is a consequence of stroke or traumatic brain injury associated with emotional, psychological, and physical overload, distress in hypertension, atherosclerosis, viral infection, and aging-related chronic low-grade inflammatory disorders. The pathogenesis of brain fatigue is linked to disrupted neurotransmission, the glutamate-glutamine cycle imbalance, glucose metabolism, and ATP energy supply, which are associated with multiple molecular targets and signaling pathways in neuroendocrine-immune and blood circulation systems. Regeneration of damaged brain tissue is a long-lasting multistage process, including spontaneously regulating hypothalamus-pituitary (HPA) axis-controlled anabolic–catabolic homeostasis to recover harmonized sympathoadrenal system (SAS)-mediated function, brain energy supply, and deregulated gene expression in rehabilitation. The driving mechanism of spontaneous recovery and regeneration of brain tissue is a cross-talk of mediators of neuronal, microglia, immunocompetent, and endothelial cells collectively involved in neurogenesis and angiogenesis, which plant adaptogens can target. Adaptogens are small molecules of plant origin that increase the adaptability of cells and organisms to stress by interaction with the HPA axis and SAS of the stress system (neuroendocrine-immune and cardiovascular complex), targeting multiple mediators of adaptive GPCR signaling pathways. Two major groups of adaptogens comprise (i) phenolic phenethyl and phenylpropanoid derivatives and (ii) tetracyclic and pentacyclic glycosides, whose chemical structure can be distinguished as related correspondingly to (i) monoamine neurotransmitters of SAS (epinephrine, norepinephrine, and dopamine) and (ii) steroid hormones (cortisol, testosterone, and estradiol). In this narrative review, we discuss (i) the multitarget mechanism of integrated pharmacological activity of botanical adaptogens in stress overload, ischemic stroke, and long-lasting brain fatigue; (ii) the time-dependent dual response of physiological regulatory systems to adaptogens to support homeostasis in chronic stress and overload; and (iii) the dual dose-dependent reversal (hormetic) effect of botanical adaptogens. This narrative review shows that the adaptogenic concept cannot be reduced and rectified to the various effects of adaptogens on selected molecular targets or specific modes of action without estimating their interactions within the networks of mediators of the neuroendocrine-immune complex that, in turn, regulates other pharmacological systems (cardiovascular, gastrointestinal, reproductive systems) due to numerous intra- and extracellular communications and feedback regulations. These interactions result in polyvalent action and the pleiotropic pharmacological activity of adaptogens, which is essential for characterizing adaptogens as distinct types of botanicals. They trigger the defense adaptive stress response that leads to the extension of the limits of resilience to overload, inducing brain fatigue and mental disorders. For the first time, this review justifies the neurogenesis potential of adaptogens, particularly the botanical hybrid preparation (BHP) of Arctic Root and Ashwagandha, providing a rationale for potential use in individuals experiencing long-lasting brain fatigue. The review provided insight into future research on the network pharmacology of adaptogens in preventing and rehabilitating long-lasting brain fatigue following stroke, trauma, and viral infections. Full article
(This article belongs to the Section Natural Products)
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16 pages, 2977 KiB  
Article
Protective Effects of Oleanolic Acid on Human Keratinocytes: A Defense Against Exogenous Damage
by Marzia Vasarri, Maria Camilla Bergonzi, Manuela Leri, Rebecca Castellacci, Monica Bucciantini, Lucia De Marchi and Donatella Degl’Innocenti
Pharmaceuticals 2025, 18(2), 238; https://doi.org/10.3390/ph18020238 - 11 Feb 2025
Cited by 1 | Viewed by 4228
Abstract
Background/objectives: Aging leads to increased oxidative stress and chronic inflammation in the skin, which contribute to various disorders such as dermatitis and cancer. This study explores the cytoprotective effects of oleanolic acid (OA), a natural triterpenoid compound known for its potential in mitigating [...] Read more.
Background/objectives: Aging leads to increased oxidative stress and chronic inflammation in the skin, which contribute to various disorders such as dermatitis and cancer. This study explores the cytoprotective effects of oleanolic acid (OA), a natural triterpenoid compound known for its potential in mitigating oxidative damage, on human keratinocyte (HaCaT) cells exposed to oxidative stress from tert-butyl hydroperoxide (tBHP). Methods: Using in vitro experiments, we assessed cell viability, reactive oxygen species (ROS) levels, nitric oxide (NO) production, and protein expression following OA pre-treatment. Advanced imaging techniques were employed to visualize protein localization. Results: Results demonstrated that OA significantly improved cell viability and reduced intracellular ROS levels compared with those in controls. Additionally, OA inhibited inducible nitric oxide synthase (iNOS) expression and subsequent nitric oxide release, indicating a modulation of inflammatory responses. Notably, while tBHP activated the Nrf2/HO-1 signaling pathway, OA did not enhance this response, suggesting that OA exerts cytoprotective effects through mechanisms independent of Nrf2 activation. Conclusion: OA shows promise in protecting HaCaT cells from tBHP-induced oxidative stress, highlighting its potential role in promoting skin health and addressing aging-related damage. The study proposes that OA operates through pathways distinct from Nrf2 and MAPKs, paving the way for new therapeutic strategies aimed at improving skin health against oxidative stress. Full article
(This article belongs to the Special Issue Natural-Based Skincare Solutions)
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18 pages, 3686 KiB  
Article
Drug Repurposing of Voglibose, a Diabetes Medication for Skin Health
by Hyeon-Mi Kim and Chang-Gu Hyun
Pharmaceuticals 2025, 18(2), 224; https://doi.org/10.3390/ph18020224 - 7 Feb 2025
Cited by 1 | Viewed by 2605
Abstract
Background/Objectives: Voglibose, an α-glucosidase inhibitor commonly prescribed to manage postprandial hyperglycemia in diabetes mellitus, demonstrates potential for repurposing as an anti-melanogenic agent. This study aims to explore the inhibitory effects of voglibose on melanogenesis and elucidate its molecular mechanisms, highlighting its possible applications [...] Read more.
Background/Objectives: Voglibose, an α-glucosidase inhibitor commonly prescribed to manage postprandial hyperglycemia in diabetes mellitus, demonstrates potential for repurposing as an anti-melanogenic agent. This study aims to explore the inhibitory effects of voglibose on melanogenesis and elucidate its molecular mechanisms, highlighting its possible applications in treating hyperpigmentation disorders. Methods: The anti-melanogenic effects of voglibose were investigated using B16F10 melanoma cells. Cell viability, melanin content, and tyrosinase activity were assessed following voglibose treatment. Western blot analysis was performed to examine changes in melanogenic proteins and transcription factors. The role of signaling pathways, including PKA/CREB, MAPK, PI3K/AKT, and GSK3β/β-Catenin, was analyzed. Primary human skin irritation tests were conducted to evaluate the topical safety of voglibose. Results: Voglibose significantly reduced melanin synthesis and tyrosinase activity in B16F10 cells in a dose-dependent manner. Western blot analysis revealed decreased expression of MITF, TRP-1, and TRP-2, indicating the inhibition of melanogenesis. Voglibose modulated key signaling pathways, including the suppression of PKA/CREB, MAPK, and AKT activation, while restoring GSK3β activity to inhibit β-catenin stabilization. Human skin irritation tests confirmed voglibose’s safety for topical application, showing no adverse reactions at 50 and 100 μM concentrations. Conclusions: Voglibose demonstrates anti-melanogenic properties through the modulation of multiple signaling pathways and the inhibition of melanin biosynthesis. Its safety profile and efficacy suggest its potential as a repurposed drug for managing hyperpigmentation and advancing cosmeceutical applications. Full article
(This article belongs to the Special Issue Bioactive Substances and Skin Health: The Role of Pharmacy and Nutrition—Properties and Technology)
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19 pages, 2136 KiB  
Review
Exploring the Therapeutic Potential of Mitragynine and Corynoxeine: Kratom-Derived Indole and Oxindole Alkaloids for Pain Management
by Ahmed S. Alford, Hope L. Moreno, Menny M. Benjamin, Cody F. Dickinson and Mark T. Hamann
Pharmaceuticals 2025, 18(2), 222; https://doi.org/10.3390/ph18020222 - 6 Feb 2025
Cited by 2 | Viewed by 5704
Abstract
The search for effective pain management solutions remains a critical challenge, especially amidst growing concerns over the use of conventional opioids. In the US, opioid-related mortality rates have surged to as many as 80 deaths per 100,000 people in some states, with an [...] Read more.
The search for effective pain management solutions remains a critical challenge, especially amidst growing concerns over the use of conventional opioids. In the US, opioid-related mortality rates have surged to as many as 80 deaths per 100,000 people in some states, with an estimated economic burden of USD 1.5 trillion annually—exceeding the gross domestic product (GDP) of most US industrial sectors. A remarkable breakthrough lies in the discovery that indole and oxindole alkaloids, produced by several genera within the plant Tribe Naucleeae, act on opioid receptors without activating the beta-arrestin-2 pathway, the primary driver of respiratory depression and overdose deaths. This systematic review explores the pharmacological properties, mechanisms of action, dosing considerations, interactions, and long-term effects of mitragynine and corynoxeine, alkaloids from the Southeast Asian plant Mitragyna speciosa (kratom) and others in the Tribe Naucleeae. Mitragynine, a partial opioid receptor agonist, and corynoxeine, known for its anti-inflammatory and neuroprotective effects, demonstrate significant therapeutic potential for managing diverse pain types—including neuropathic, inflammatory, nociceptive, visceral, and central pain syndromes—with a focus on cancer pain. Unlike traditional opioids, these compounds do not recruit beta-arrestin-2, avoiding key adverse effects such as respiratory depression, severe constipation, and rapid tolerance development. Their distinct pharmacological profiles make them innovative candidates for safer, non-lethal pain relief. However, challenges persist, including the unregulated nature of kratom products, inconsistencies in potency due to crude extract variability, potential for misuse, and adverse drug interactions. Addressing these issues requires establishing standardized quality control protocols, such as Good Manufacturing Practices (GMP), to ensure consistent potency and purity. Clear labeling requirements with dosage guidelines and warnings should be mandated to ensure safe use and prevent misuse. Furthermore, the implementation of regulatory oversight to monitor product quality and enforce compliance is essential. This review emphasizes the urgency of focused research to optimize dosing regimens, characterize the pharmacodynamic profiles of these alkaloids, and evaluate long-term safety. By addressing these gaps, the mitragynine- and corynoxeine-related drug classes can transition from promising plant-derived molecules to validated pharmacotherapeutic agents, potentially revolutionizing the field of pain management. Full article
(This article belongs to the Section Natural Products)
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22 pages, 940 KiB  
Review
Multifunctionality and Possible Medical Application of the BPC 157 Peptide—Literature and Patent Review
by Michalina Józwiak, Marta Bauer, Wojciech Kamysz and Patrycja Kleczkowska
Pharmaceuticals 2025, 18(2), 185; https://doi.org/10.3390/ph18020185 - 30 Jan 2025
Cited by 1 | Viewed by 62336
Abstract
BPC 157, known as the “Body Protection Compound”, is a pentadecapeptide isolated from human gastric juice that demonstrated its pleiotropic beneficial effects in various preclinical models mimicking medical conditions, such as tissue injury, inflammatory bowel disease, or even CNS disorders. Unlike many other [...] Read more.
BPC 157, known as the “Body Protection Compound”, is a pentadecapeptide isolated from human gastric juice that demonstrated its pleiotropic beneficial effects in various preclinical models mimicking medical conditions, such as tissue injury, inflammatory bowel disease, or even CNS disorders. Unlike many other drugs, BPC 157 has a desirable safety profile, since only a few side effects have been reported following its administration. Nevertheless, this compound was temporarily banned by the World Anti-Doping Agency (WADA) in 2022 (it is not currently listed as banned by the WADA). However, it has not been approved for use in standard medicine by the FDA and other global regulatory authorities due to the absence of sufficient and comprehensive clinical studies confirming its health benefits in humans. In this review, we summarize information on the biological activities of BPC 157, with particular reference to its mechanism of action and probable toxicity. This generated the attention of experts, as BPC 157 has been offered for sale on many websites. We also present recent interest in BPC 157 as reflected in a number of patent applications and granted patents. Full article
(This article belongs to the Special Issue Recent Advances in the Discovery and Development of Drugs for Civilization Diseases)
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17 pages, 946 KiB  
Review
Diverse Roles of Antibodies in Antibody–Drug Conjugates
by Aiko Yamaguchi and H. Charles Manning
Pharmaceuticals 2025, 18(2), 180; https://doi.org/10.3390/ph18020180 - 29 Jan 2025
Cited by 1 | Viewed by 3449
Abstract
The emergence of antibody–drug conjugates (ADCs) has transformed the treatment landscape of a variety of cancers. ADCs typically consist of three main components: monoclonal antibody, chemical linker, and cytotoxic payload. These integrated therapeutic modalities harness the benefits of each component to provide a [...] Read more.
The emergence of antibody–drug conjugates (ADCs) has transformed the treatment landscape of a variety of cancers. ADCs typically consist of three main components: monoclonal antibody, chemical linker, and cytotoxic payload. These integrated therapeutic modalities harness the benefits of each component to provide a therapeutic response that cannot be achieved by conventional chemotherapy. Antibodies play roles in determining tumor specificity through target-mediated uptake, prolonging the circulation half-life of cytotoxic payloads, and providing additional mechanisms of action inherent to the original antibody, thus significantly contributing to the overall performance of ADCs. However, ADCs have unique safety concerns, such as drug-induced adverse events related to the target-mediated uptake of the ADC in normal tissues (so-called “on-target, off-tumor toxicity”) and platform toxicity, which are partially derived from limited tumor uptake of antibodies. Identifying suitable target antigens thus impacts the clinical success of ADCs and requires careful consideration, given the multifaceted aspects of this unique treatment modality. This review briefly summarizes the representative roles that antibodies play in determining the efficacy and safety of ADCs. Key considerations for selecting suitable cell surface target antigens for ADC therapy are also highlighted. Full article
(This article belongs to the Special Issue Antibody-Based Imaging and Targeted Therapy in Cancer)
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17 pages, 2708 KiB  
Article
HDAC/σ1R Dual-Ligand as a Targeted Melanoma Therapeutic
by Claudia Giovanna Leotta, Carla Barbaraci, Jole Fiorito, Alessandro Coco, Viviana di Giacomo, Emanuele Amata, Agostino Marrazzo and Giovanni Mario Pitari
Pharmaceuticals 2025, 18(2), 179; https://doi.org/10.3390/ph18020179 - 28 Jan 2025
Cited by 2 | Viewed by 2600
Abstract
Background: In melanoma, multiligand drug strategies to disrupt cancer-associated epigenetic alterations and angiogenesis are particularly promising. Here, a novel dual-ligand with a single shared pharmacophore capable of simultaneously targeting histone deacetylases (HDACs) and sigma receptors (σRs) was synthesized and subjected to phenotypic in [...] Read more.
Background: In melanoma, multiligand drug strategies to disrupt cancer-associated epigenetic alterations and angiogenesis are particularly promising. Here, a novel dual-ligand with a single shared pharmacophore capable of simultaneously targeting histone deacetylases (HDACs) and sigma receptors (σRs) was synthesized and subjected to phenotypic in vitro screening. Methods: Tumor cell proliferation and spreading were investigated using immortalized human cancer and normal cell lines. Angiogenesis was also evaluated in mouse endothelial cells using a tube formation assay. Results: The dual-ligand compound exhibited superior potency in suppressing both uveal and cutaneous melanoma cell viability compared to other cancer cell types or normal cells. Melanoma selectivity reflected inhibition of the HDAC-dependent epigenetic regulation of tumor proliferative kinetics, without involvement of σR signaling. In contrast, the bifunctional compound inhibited the formation of capillary-like structures, formed by endothelial cells, and tumor cell spreading through the specific regulation of σ1R signaling, but not HDAC activity. Conclusions: Together, the present findings suggest that dual-targeted HDAC/σ1R ligands might efficiently and simultaneously disrupt tumor growth, dissemination and angiogenesis in melanoma, a strategy amenable to future clinical applications in precision cancer treatment. Full article
(This article belongs to the Section Medicinal Chemistry)
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36 pages, 4971 KiB  
Review
Coffea arabica: An Emerging Active Ingredient in Dermato-Cosmetic Applications
by Grațiana Ruse, Alex-Robert Jîjie, Elena-Alina Moacă, Dalia Pătrașcu, Florina Ardelean, Alina-Arabela Jojic, Simona Ardelean and Diana-Simona Tchiakpe-Antal
Pharmaceuticals 2025, 18(2), 171; https://doi.org/10.3390/ph18020171 - 27 Jan 2025
Cited by 3 | Viewed by 6677
Abstract
Background: Coffea arabica, commonly known as Arabica coffee, has garnered attention in recent years for its potential applications in dermato-cosmetic formulations. This review aims to critically evaluate the emerging role of Coffea arabica as an active ingredient in skin care products, [...] Read more.
Background: Coffea arabica, commonly known as Arabica coffee, has garnered attention in recent years for its potential applications in dermato-cosmetic formulations. This review aims to critically evaluate the emerging role of Coffea arabica as an active ingredient in skin care products, focusing on its bioactive compounds derived from both the leaves and beans, mechanisms of action, and efficacy in dermatological applications. A comparative analysis between the bioactive profiles of the leaves and beans is also presented to elucidate their respective contributions to dermato-cosmetic efficacy. Results: This review synthesizes findings from various studies that highlight the presence of key bioactive compounds in Coffea arabica, including caffeine, chlorogenic acids, and flavonoids. Notably, the leaves exhibit a higher concentration of certain phenolic compounds compared to the beans, suggesting unique properties that may enhance skin health. These compounds have demonstrated significant anticellulite, anti-inflammatory, antioxidant, photoprotective, anti-aging, antibacterial, and moisturizing properties. Discussion: This article delves into the biochemical pathways through which bioactive compounds derived from both the leaves and beans of Coffea arabica exert their beneficial effects on skin and hair health. Furthermore, this review highlights the growing trend of incorporating natural ingredients in cosmetic formulations and the consumer demand for products with scientifically substantiated benefits. Conclusions: The findings of this review underscore the potential of Coffea arabica as a valuable active ingredient in dermato-cosmetic applications. Its multifaceted bioactivity suggests that it can contribute significantly to skin health and cosmetic efficacy. Future research should focus on clinical trials to further validate these benefits and explore optimal formulation strategies for enhanced delivery and stability in cosmetic products. Full article
(This article belongs to the Special Issue Bioactive Substances and Skin Health: The Role of Pharmacy and Nutrition—Properties and Technology)
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19 pages, 2325 KiB  
Article
Development and Blood–Brain Barrier Penetration of Nanovesicles Loaded with Cannabidiol
by Lucia Grifoni, Elisa Landucci, Giuseppe Pieraccini, Costanza Mazzantini, Maria Camilla Bergonzi, Domenico E. Pellegrini-Giampietro and Anna Rita Bilia
Pharmaceuticals 2025, 18(2), 160; https://doi.org/10.3390/ph18020160 - 25 Jan 2025
Cited by 2 | Viewed by 3107
Abstract
Background: Cannabidiol (CBD) is a highly lipophilic compound with potential therapeutic applications in neurological disorders. However, its poor aqueous solubility and bioavailability, coupled with instability in physiological conditions, significantly limit its clinical use. Objectives: This study aimed to develop and characterize nanovesicles [...] Read more.
Background: Cannabidiol (CBD) is a highly lipophilic compound with potential therapeutic applications in neurological disorders. However, its poor aqueous solubility and bioavailability, coupled with instability in physiological conditions, significantly limit its clinical use. Objectives: This study aimed to develop and characterize nanovesicles incorporating Tween 20 to enhance CBD encapsulation, stability, and the performance across the blood–brain barrier (BBB). Methods: Nanovesicles were prepared via thin-film hydration followed by sonication and optimized for size, polydispersity index, and zeta potential. Stability studies were conducted under physiological conditions and during storage at 4 °C. In vitro release studies employed the dialysis bag method, while permeability across the BBB was assessed using PAMPA-BBB and the hCMEC/D3-BBB cell line, characterized for brain endothelial phenotype and largely employed as a model of human blood–brain barrier (BBB) function. Cytotoxicity was evaluated via MTT and LDH assays. Results: The quantification of CBD was carried out by HPLC-DAD and HPLC-MS/MS. Nanovesicles with Tween 20 (VS-CBD) exhibited smaller size (65.27 ± 1.27 nm vs. 90.7 ± 0.2), lower polydispersity (0.230 ± 0.005 vs. 0.295 ± 0.003), and higher stability compared to conventional liposomes (L-CBD). VS-CBD achieved high encapsulation efficiency (96.80 ± 0.96%) and recovery (99.89 ± 0.52%). Release studies showed sustained CBD release with Higuchi model fitting (R2 = 0.9901). Both PAMPA-BBB and hCMEC/D3-BBB cell lines demonstrated an improved controlled permeability of the formulation compared to free CBD. Cytotoxicity tests confirmed the good biocompatibility of VS-CBD formulations. The addition of Tween 20 to nanovesicles enhanced CBD encapsulation, stability, and controlled release. Conclusions: These nanovesicles represent a promising strategy to improve CBD delivery to the brain, offering sustained therapeutic effects and reduced dosing frequency, potentially benefiting the treatment of neurological disorders. Full article
(This article belongs to the Special Issue Therapeutic Potential for Cannabinoid and Its Receptor)
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24 pages, 13681 KiB  
Article
Enhancing Tetrahydrocannabinol’s Therapeutic Efficacy in Inflammatory Bowel Disease: The Roles of Cannabidiol and the Cannabinoid 1 Receptor Allosteric Modulator ZCZ011
by Dinesh Thapa, Mohan Patil, Leon N Warne, Rodrigo Carlessi and Marco Falasca
Pharmaceuticals 2025, 18(2), 148; https://doi.org/10.3390/ph18020148 - 23 Jan 2025
Cited by 2 | Viewed by 4540
Abstract
Background/Objectives: Current inflammatory bowel disease (IBD) treatments focus on symptomatic relief, highlighting the need for innovative approaches. Dysregulation of the cannabinoid 1 (CB1) receptor, part of the endocannabinoid system, is linked to colitis. While tetrahydrocannabinol (THC) alleviates colitis via CB1 activation, its psychotropic [...] Read more.
Background/Objectives: Current inflammatory bowel disease (IBD) treatments focus on symptomatic relief, highlighting the need for innovative approaches. Dysregulation of the cannabinoid 1 (CB1) receptor, part of the endocannabinoid system, is linked to colitis. While tetrahydrocannabinol (THC) alleviates colitis via CB1 activation, its psychotropic effects limit clinical use. ZCZ011, a CB1R allosteric modulator, and cannabidiol (CBD), a non-psychoactive cannabinoid, offer alternatives. This study investigated combining sub-therapeutic THC doses with ZCZ011 or CBD in a murine model of dextran sodium sulphate (DSS)-induced colitis. Methods: Acute colitis was induced with 4% DSS for 7 days, followed by 3 days of water. Chronic colitis was modelled over 24 days with alternating DSS concentrations. The combination of 2.5 mg/kg THC with 20 mg/kg ZCZ011 or 10 mg/kg CBD was evaluated. Key markers were assessed to determine efficacy and safety, including disease activity index (DAI), inflammation, cytokine levels, GLP-1, and organ health. Results: DSS-induced colitis resulted in increased DAI scores, cytokines, organ inflammation and dysregulation of GLP-1 and ammonia. THC at 10 mg/kg significantly improved colitis markers but was ineffective at 2.5 and 5 mg/kg. ZCZ011 alone showed transient effects. However, combining 2.5 mg/kg THC with either 20 mg/kg ZCZ011 or 10 mg/kg CBD significantly alleviated colitis markers, restored colon integrity and reestablished GLP-1 homeostasis. This combination also maintained favourable haematological and biochemical profiles, including a notable reduction in colitis-induced elevated ammonia levels. Conclusions: This study demonstrates the synergistic potential of low-dose THC combined with CBD or ZCZ011 as a novel, effective and safer therapeutic strategy for ulcerative colitis. Full article
(This article belongs to the Special Issue Therapeutic Potential of Cannabinoid Receptors Type 1 and 2—Novel Insights for Enhancing the Chance of Clinical Success)
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22 pages, 2130 KiB  
Review
Dual-Labeled Small Peptides in Cancer Imaging and Fluorescence-Guided Surgery: Progress and Future Perspectives
by Paul Minges, Matthias Eder and Ann-Christin Eder
Pharmaceuticals 2025, 18(2), 143; https://doi.org/10.3390/ph18020143 - 22 Jan 2025
Cited by 2 | Viewed by 2963
Abstract
Dual-labeled compounds that combine radiolabeling and fluorescence labeling represent a significant advancement in precision oncology. Their clinical implementation enhances patient care and outcomes by leveraging the high sensitivity of radioimaging for tumor detection and taking advantage of fluorescence-based optical visualization for surgical guidance. [...] Read more.
Dual-labeled compounds that combine radiolabeling and fluorescence labeling represent a significant advancement in precision oncology. Their clinical implementation enhances patient care and outcomes by leveraging the high sensitivity of radioimaging for tumor detection and taking advantage of fluorescence-based optical visualization for surgical guidance. Non-invasive radioimaging facilitates immediate identification of both primary tumors and metastases, while fluorescence imaging assists in decision-making during surgery by offering a spatial distinction between malignant and non-malignant tissue. These advancements hold promise for enhancing patient outcomes and personalization of cancer treatment. The development of dual-labeled molecular probes targeting various cancer biomarkers is crucial in addressing the heterogeneity inherent in cancer pathology and recent studies had already demonstrated the impact of dual-labeled compounds in surgical decision-making (NCT03699332, NCT03407781). This review focuses on the development and application of small dual-labeled peptides in the imaging and treatment of various cancer types. It summarizes the biomarkers targeted to date, tracing their development from initial discovery to the latest advancements in peptidomimetics. Through comprehensive analysis of recent preclinical and clinical studies, the review demonstrates the potential of these dual-labeled peptides to improve tumor detection, localization, and resection. Additionally, it highlights the evolving landscape of dual-modality imaging, emphasizing its critical role in advancing personalized and effective cancer therapy. This synthesis of current research underscores the promise of dual-labeled peptides in enhancing diagnostic accuracy and therapeutic outcomes in oncology. Full article
(This article belongs to the Special Issue Past, Present and Future Radiotracer Techniques: Radiopharmaceuticals in Cancer Theranostics)
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54 pages, 6031 KiB  
Article
(E)-1-(3-(3-Hydroxy-4-Methoxyphenyl)-1-(3,4,5-Trimethoxyphenyl)allyl)-1H-1,2,4-Triazole and Related Compounds: Their Synthesis and Biological Evaluation as Novel Antimitotic Agents Targeting Breast Cancer
by Gloria Ana, Azizah M. Malebari, Sara Noorani, Darren Fayne, Niamh M. O’Boyle, Daniela M. Zisterer, Elisangela Flavia Pimentel, Denise Coutinho Endringer and Mary J. Meegan
Pharmaceuticals 2025, 18(1), 118; https://doi.org/10.3390/ph18010118 - 17 Jan 2025
Cited by 2 | Viewed by 3803
Abstract
Background/Objectives: The synthesis of (E)-1-(1,3-diphenylallyl)-1H-1,2,4-triazoles and related compounds as anti-mitotic agents with activity in breast cancer was investigated. These compounds were designed as hybrids of the microtubule-targeting chalcones, indanones, and the aromatase inhibitor letrozole. Methods: A panel of [...] Read more.
Background/Objectives: The synthesis of (E)-1-(1,3-diphenylallyl)-1H-1,2,4-triazoles and related compounds as anti-mitotic agents with activity in breast cancer was investigated. These compounds were designed as hybrids of the microtubule-targeting chalcones, indanones, and the aromatase inhibitor letrozole. Methods: A panel of 29 compounds was synthesized and examined by a preliminary screening in estrogen receptor (ER) and progesterone receptor (PR)-positive MCF-7 breast cancer cells together with cell cycle analysis and tubulin polymerization inhibition. Results: (E)-5-(3-(1H-1,2,4-triazol-1-yl)-3-(3,4,5-trimethoxyphenyl)prop-1-en-1-yl)-2-methoxyphenol 22b was identified as a potent antiproliferative compound with an IC50 value of 0.39 mM in MCF-7 breast cancer cells, 0.77 mM in triple-negative MDA-MB-231 breast cancer cells, and 0.37 mM in leukemia HL-60 cells. In addition, compound 22b demonstrated potent activity in the sub-micromolar range against the NCI 60 cancer cell line panel including prostate, melanoma, colon, leukemia, and non-small cell lung cancers. G2/M phase cell cycle arrest and the induction of apoptosis in MCF-7 cells together with inhibition of tubulin polymerization were demonstrated. Immunofluorescence studies confirmed that compound 22b targeted tubulin in MCF-7 cells, while computational docking studies predicted binding conformations for 22b in the colchicine binding site of tubulin. Compound 22b also selectively inhibited aromatase. Conclusions: Based on the results obtained, these novel compounds are suitable candidates for further investigation as antiproliferative microtubule-targeting agents for breast cancer. Full article
(This article belongs to the Special Issue The 20th Anniversary of Pharmaceuticals—Advances in Medicinal Chemistry)
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24 pages, 5476 KiB  
Article
Sustainable Skincare Innovation: Cork Powder Extracts as Active Ingredients for Skin Aging
by Ana Silva, Cláudia Pinto, Sara Cravo, Sandra Mota, Liliana Rego, Smeera Ratanji, Clara Quintas, Joana Rocha e Silva, Carlos Afonso, Maria Elizabeth Tiritan, Honorina Cidade, Teresa Cruz and Isabel F. Almeida
Pharmaceuticals 2025, 18(1), 121; https://doi.org/10.3390/ph18010121 - 17 Jan 2025
Cited by 2 | Viewed by 3383
Abstract
Background: An emerging practice within the concept of circular beauty involves the upcycling of agro-industrial by-products. Cork processing, for instance, yields by-products like cork powder, which presents an opportunity to create value-added cosmetic ingredients. Building upon our previous research, demonstrating the antioxidant [...] Read more.
Background: An emerging practice within the concept of circular beauty involves the upcycling of agro-industrial by-products. Cork processing, for instance, yields by-products like cork powder, which presents an opportunity to create value-added cosmetic ingredients. Building upon our previous research, demonstrating the antioxidant potential of hydroalcoholic extracts derived from two distinct cork powders (P0 and P1), in this work, aqueous extracts were prepared and analyzed. The safety and bioactivities of the newly obtained aqueous extracts, as well as the 30% ethanol extracts, previously reported to be the most promising for skin application, were also evaluated. Methods: Aqueous extracts were obtained from cork powders (P0 and P1) and the identification and quantification of some polyphenols was achieved by liquid chromatography (LC). Antioxidant potential was screened by DPPH method and the bioactivity and safety of extracts were further explored using cell-based assays. Results: All extracts exhibited a reduction in age-related markers, including senescence-associated beta-galactosidase (SA-β-gal) activity. Additionally, they demonstrated a pronounced anti-inflammatory effect by suppressing the production of several pro-inflammatory mediators in macrophages upon lipopolysaccharide stimulation. Moreover, the extracts upregulated genes and proteins associated with antioxidant activity, such as heme oxygenase 1. The aqueous extract from P1 powder was especially active in reducing pro-inflammatory mediators, namely the Nos2 gene, inducible nitric oxide protein levels, and nitric oxide production. Moreover, it did not induce skin irritation, as assessed by the EpiSkin test, in compliance with the OECD Test Guidelines. Conclusions: Overall, our findings underscore the potential of aqueous extracts derived from cork waste streams to mitigate various hallmarks of skin aging, including senescence and inflammaging, and their suitability for incorporation into cosmetics formulations. These results warrant further exploration for their application in the pharmaceutical and cosmetic industries and could foster a sustainable and circular bioeconomy. Full article
(This article belongs to the Special Issue Natural-Based Skincare Solutions)
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35 pages, 7073 KiB  
Review
Anti-Biofilm Agents to Overcome Pseudomonas aeruginosa Antibiotic Resistance
by Marie Hanot, Elodie Lohou and Pascal Sonnet
Pharmaceuticals 2025, 18(1), 92; https://doi.org/10.3390/ph18010092 - 13 Jan 2025
Cited by 2 | Viewed by 3591
Abstract
Pseudomonas aeruginosa is one of world’s most threatening bacteria. In addition to the emerging prevalence of multi-drug resistant (MDR) strains, the bacterium also possesses a wide variety of virulence traits that worsen the course of the infections. Particularly, its ability to form biofilms [...] Read more.
Pseudomonas aeruginosa is one of world’s most threatening bacteria. In addition to the emerging prevalence of multi-drug resistant (MDR) strains, the bacterium also possesses a wide variety of virulence traits that worsen the course of the infections. Particularly, its ability to form biofilms that protect colonies from antimicrobial agents is a major cause of chronic and hard-to-treat infections in immune-compromised patients. This protective barrier also ensures cell growth on abiotic surfaces and thus enables bacterial survival on medical devices. Hence, as the WHO alerted to the need to develop new treatments, the use of anti-biofilm agents (ABAs) appeared as a promising approach. Given the selection pressure imposed by conventional antibiotics, a new therapeutic strategy has emerged that aims at reducing bacterial virulence without inhibiting cell growth. So-called anti-virulence agents (AVAs) would then restore the efficacy of conventional antibiotics (ATBs) or potentiate the effectiveness of the immune system. The last decade has seen the development of ABAs as AVAs against P. aeruginosa. This review aims to highlight the design strategy and critical features of these molecules to pave the way for further discoveries of highly potent compounds. Full article
(This article belongs to the Special Issue New Approaches to Fighting Infectious Diseases: Overcoming the Antimicrobial Resistance in Current Treatments)
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24 pages, 360 KiB  
Review
Antibiotic Resistance of Staphylococcus aureus Strains—Searching for New Antimicrobial Agents—Review
by Michał Michalik, Adrianna Podbielska-Kubera and Agnieszka Dmowska-Koroblewska
Pharmaceuticals 2025, 18(1), 81; https://doi.org/10.3390/ph18010081 - 11 Jan 2025
Cited by 7 | Viewed by 5939
Abstract
Inappropriate and excessive use of antibiotics is responsible for the rapid development of antimicrobial resistance, which is associated with increased patient morbidity and mortality. There is an urgent need to explore new antibiotics or alternative antimicrobial agents. S. aureus a commensal microorganism but [...] Read more.
Inappropriate and excessive use of antibiotics is responsible for the rapid development of antimicrobial resistance, which is associated with increased patient morbidity and mortality. There is an urgent need to explore new antibiotics or alternative antimicrobial agents. S. aureus a commensal microorganism but is also responsible for numerous infections. In addition to innate resistance to β-lactam antibiotics, S. aureus strains resistant to methicillin (MRSA) often show resistance to other classes of antibiotics (multidrug resistance). The advancement of phage therapy against MRSA infections offers a promising alternative in the context of increasing antibiotic resistance. Therapeutic phages are easier to obtain and cheaper to produce than antibiotics. However, there is still a lack of standards to ensure the safe use of phages, including purification, dosage, means of administration, and the quantity of phages used. Some bacteria have developed defense mechanisms against phages. The use of phage cocktails or the combination of antibiotics and phages is preferred. For personalized therapy, it is essential to set up large collections to enable phage selection. In the future, the fight against MRSA strains using phages should be based on a multidisciplinary approach, including molecular biology and medicine. Other therapies in the fight against MRSA strains include the use of endolysin antimicrobial peptides (including defensins and cathelicidins). Researchers’ activities also focus on the potential use of plant extracts, honey, propolis, alkaloids, and essential oils. To date, no vaccine has been approved against S. aureus strains. Full article
(This article belongs to the Section Pharmacology)
17 pages, 9958 KiB  
Article
Spinorphin Molecules as Opportunities for Incorporation into Spinorphin@AuNPs Conjugate Systems for Potential Sustained Targeted Delivery to the Brain
by Stela Georgieva, Petar Todorov and Jana Tchekalarova
Pharmaceuticals 2025, 18(1), 53; https://doi.org/10.3390/ph18010053 - 5 Jan 2025
Viewed by 2050
Abstract
Background: This study explores the potential for the synthesis of peptide nanosystems comprising spinorphin molecules (with rhodamine moiety: Rh-S, Rh-S5, and Rh-S6) conjugated with nanoparticles (AuNPs), specifically peptide Rh-S@AuNPs, peptide Rh-S5@AuNPs, and peptide Rh-S6@AuNPs, alongside a comparative analysis of the biological activities of [...] Read more.
Background: This study explores the potential for the synthesis of peptide nanosystems comprising spinorphin molecules (with rhodamine moiety: Rh-S, Rh-S5, and Rh-S6) conjugated with nanoparticles (AuNPs), specifically peptide Rh-S@AuNPs, peptide Rh-S5@AuNPs, and peptide Rh-S6@AuNPs, alongside a comparative analysis of the biological activities of free and conjugated peptides. The examination of the microstructural characteristics of the obtained peptide systems and their physicochemical properties constitutes a key focus of this study. Methods: Zeta (ζ) potential, Fourier transformation infrared (FTIR) spectroscopy, circular dichroism (CD), scanning electron microscopy (SEM-EDS), transmission electron microscopy (TEM), and UV–Vis spectrophotometry were employed to elucidate the structure–activity correlations of the peptide@nano AuNP systems. Results: The zeta potential values for all the Rh-S@AuNPs demonstrate that the samples are electrically stable and resistant to flocculation and coagulation. The absorption of energy quanta from UV–Vis radiation by the novel nanopeptide systems does not substantially influence the distinctive signal of AuNPs, which is situated at around 531 nm. The FTIR measurements indicate the signals associated with the unique functional groups of the peptides, whereas circular dichroism verifies the synthesis of the conjugated nanocomposites of the spinorphin@AuNP type. An analysis of the SEM and TEM data revealed that most AuNPs have a spherical morphology, with an average diameter of around 21.92 ± 6.89 nm. The results of the in vivo studies showed promising findings regarding the anticonvulsant properties of the nanocompounds, especially the Rh-S@AuNP formulation. Conclusions: All the nanocompounds tested demonstrated the ability to reduce generalized tonic–clonic seizures. This suggests that these formulations may effectively target the underlying neuronal hyperexcitability. In addition, the prepared Rh-S@AuNP formulations also showed anticonvulsant activity in the maximal electroshock test performed in mice, which was evident after systemic (intraperitoneal) administration. The study’s findings indicate that conjugates can be synthesized via a straightforward process, rendering them potential therapeutic agents with biological activity. Full article
(This article belongs to the Special Issue Peptide Drug Conjugates and Their Applications)
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48 pages, 6035 KiB  
Review
Uncovering the Mechanism of Action of Antiprotozoal Agents: A Survey on Photoaffinity Labeling Strategy
by Alessandro Giraudo, Cristiano Bolchi, Marco Pallavicini, Roberto Di Santo, Roberta Costi and Francesco Saccoliti
Pharmaceuticals 2025, 18(1), 28; https://doi.org/10.3390/ph18010028 - 28 Dec 2024
Cited by 1 | Viewed by 3089
Abstract
Plasmodium, Leishmania, and Trypanosoma parasites are responsible for infectious diseases threatening millions of people worldwide. Despite more recent efforts devoted to the search for new antiprotozoal agents, efficacy, safety, and resistance issues still hinder the development of suited therapeutic options. The [...] Read more.
Plasmodium, Leishmania, and Trypanosoma parasites are responsible for infectious diseases threatening millions of people worldwide. Despite more recent efforts devoted to the search for new antiprotozoal agents, efficacy, safety, and resistance issues still hinder the development of suited therapeutic options. The lack of robustly validated targets and the complexity of parasite’s diseases have made phenotypic screening a preferential drug discovery strategy for the identification of new chemical entities. However, via this approach, no information on biological target(s) and mechanisms of action of compounds are provided. Among the target deconvolution strategies useful to fill this gap, photoaffinity labeling (PAL) has emerged as one of most suited to enable investigation in a complex cellular environment. More recently, PAL has been exploited to unravel the molecular basis of bioactive compounds’ function in live parasites, allowing elucidation of the mechanism of action of both approved drugs and new chemical entities. Besides highlighting new potential drug targets, PAL can provide valuable information on efficacy and liabilities of small molecules at the molecular level, which could be exploited to greatly facilitate the rational optimization of compounds in terms of potency and safety. In this review, we will report the most recent studies that have leveraged PAL to disclose the biological targets and mechanism of action of phenotypically active compounds targeting kinetoplastid diseases (i.e., human African trypanosomiasis, leishmaniasis, and Chagas disease) and malaria. Moreover, we will comment on potential perspectives that this innovative approach can provide in aiding the discovery and development of new antiprotozoal drugs. Full article
(This article belongs to the Special Issue Recent Advancements in the Development of Antiprotozoal Agents)
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29 pages, 2268 KiB  
Review
Research and Clinical Practice Involving the Use of Cannabis Products, with Emphasis on Cannabidiol: A Narrative Review
by João Luís Q. Simei, José Diogo R. Souza, João Francisco Pedrazzi, Francisco S. Guimarães, Alline Cristina Campos, Antônio Zuardi, Jaime Eduardo C. Hallak and José Alexandre S. Crippa
Pharmaceuticals 2024, 17(12), 1644; https://doi.org/10.3390/ph17121644 - 6 Dec 2024
Cited by 6 | Viewed by 7074
Abstract
Background: Emerging evidence supports cannabidiol (CBD) as a promising therapeutic compound for various health conditions, despite its approval as a medication (product for medical purposes) remaining restricted to a limited range of clinical indications. Simultaneously, the regulation of cannabis-derived products for medicinal and [...] Read more.
Background: Emerging evidence supports cannabidiol (CBD) as a promising therapeutic compound for various health conditions, despite its approval as a medication (product for medical purposes) remaining restricted to a limited range of clinical indications. Simultaneously, the regulation of cannabis-derived products for medicinal and recreational use has expanded their global market availability to meet local community demands. This scenario presents a complex challenge for clinicians, researchers, and industry, as the global appeal of therapeutic uses of CBD is growing more rapidly than the scientific evidence supporting its safety and effectiveness. Outcomes: A narrative review was conducted to discuss the best evidence regarding the pharmacological profile of CBD, its efficacy, and safety within the context of regulation and perspectives on the development of new cannabinoid-based drugs. Key articles addressing the various facets of this issue were selected for comprehensive analysis. Conclusions: Clinicians and researchers may face unique challenges in understanding the pharmacological profile of CBD and the prospects for developing its clinical indications, given the heterogeneity of clinical terminologies and the quality and composition of cannabis-based medical products available on the market. More basic and clinical research that complies with regulatory agencies’ testing guidelines, such as good manufacturing practices (GMPs), good laboratory practices (GLPs), and good clinical practices (GCPs), is needed to obtain approval for CBD or any other cannabinoid as a therapeutic for broader clinical indications. Full article
(This article belongs to the Special Issue Innovative Applications and Therapeutic Potential of Cannabinoids)
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24 pages, 3016 KiB  
Article
Safety and Efficacy of Loading Doses of Vitamin D: Recommendations for Effective Repletion
by Béla E. Tóth, István Takács, Kristóf Kádár, Sara Mirani, Miklós Vecsernyés and Péter Lakatos
Pharmaceuticals 2024, 17(12), 1620; https://doi.org/10.3390/ph17121620 - 30 Nov 2024
Cited by 1 | Viewed by 6538
Abstract
Background/Objectives: Epidemiological data on vitamin D status revealed that, despite various dosage and durations of supplementation, the effectiveness often fails to achieve optimal outcomes. The need for higher doses than previously recommended was suggested, but several modifying factors should be considered, including the [...] Read more.
Background/Objectives: Epidemiological data on vitamin D status revealed that, despite various dosage and durations of supplementation, the effectiveness often fails to achieve optimal outcomes. The need for higher doses than previously recommended was suggested, but several modifying factors should be considered, including the level of deficiency, and BMI. The objectives of this post hoc evaluation are to characterize treatment effectiveness based on the applied dose, duration and BMI; and to assess the safety aspects associated with rapid repletion of vitamin D. Methods: Vitamin D deficient subjects selected in the post-hoc analysis: seventy patients included from a combined loading-maintenance supplementation (300,000 IU followed by 60,000 IU) protocol and 62 deficient subjects who received a low-dose maintenance (1000 IU/day) therapy. The risk of overload and the incidence of hypercalciuria and hypercalcemia resulting from loading or post-loading maintenance were investigated. Results: The moderate–fast-loading schedule of 60,000 IU per week for 5 weeks, effectively achieves the target in 25(OH)D levels over 30 ng/mL for all deficient subjects, regardless of their BMI. Slower loading with lower weekly doses confirms the safety of supplementation, but the effectiveness is dependent on the subjects’ BMI; overweight and obese patients require higher doses to reach the same vitamin D levels. No difference in safety parameters observed compared to low-dose therapies. Conclusions: The loading treatment involving a total dose of 300,000 IU administered over 5 or 10 weeks is effective for repletion, does not lead to 25(OH)D overload, and poses no additional risks of hypercalcemia or hypercalciuria. Furthermore, there are no safety concerns regarding changes in bone resorption markers. A combination of the loading treatment with a subsequent maintenance dose of 2000 IU daily is adequate to achieve the target vitamin D levels. Full article
(This article belongs to the Special Issue Drug Insights: Vitamin D and Its Analogs 2023)
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16 pages, 561 KiB  
Review
A Comprehensive Review and Update on Cannabis Hyperemesis Syndrome
by Priyadarshini Loganathan, Mahesh Gajendran and Hemant Goyal
Pharmaceuticals 2024, 17(11), 1549; https://doi.org/10.3390/ph17111549 - 18 Nov 2024
Cited by 4 | Viewed by 6736
Abstract
Cannabis, derived from Cannabis sativa plants, is a prevalent illicit substance in the United States, containing over 400 chemicals, including 100 cannabinoids, each affecting the body’s organs differently upon ingestion. Cannabis hyperemesis syndrome (CHS) is a gut–brain axis disorder characterized by recurring nausea [...] Read more.
Cannabis, derived from Cannabis sativa plants, is a prevalent illicit substance in the United States, containing over 400 chemicals, including 100 cannabinoids, each affecting the body’s organs differently upon ingestion. Cannabis hyperemesis syndrome (CHS) is a gut–brain axis disorder characterized by recurring nausea and vomiting intensified by excessive cannabis consumption. CHS often goes undiagnosed due to inconsistent criteria, subjective symptoms, and similarity to cyclical vomiting syndrome (CVS). Understanding the endocannabinoid system (ECS) and its dual response (pro-emetic at higher doses and anti-emetic at lower doses) is crucial in the pathophysiology of CHS. Recent research noted that type 1 cannabinoid receptors in the intestinal nerve plexus exhibit an inhibitory effect on gastrointestinal motility. At the same time, the thermoregulatory function of endocannabinoids might explain compulsive hot bathing in CHS patients. The prevalence of cannabis CHS is expected to rise as legal restrictions on its recreational use decrease in several states. Education and awareness are vital in diagnosing and treating CHS as its prevalence increases. This comprehensive review explores the ECS’s involvement, CHS management approaches, and knowledge gaps to enhance understanding of this syndrome. Full article
(This article belongs to the Special Issue Medical Cannabis and Its Derivatives)
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14 pages, 2191 KiB  
Article
Prunella vulgaris Extract Ameliorates Testosterone-Induced Benign Prostatic Hyperplasia by Regulating Androgen Levels, Cell Proliferation, and Apoptosis
by Poornima Kumbukgahadeniya, Eun-Bok Baek, Eun-Ju Hong, Jun-Yeop Song, Youn-Gil Kwak, Mi-Ran Jang, Hyo-Seong Ji and Hyo-Jung Kwun
Pharmaceuticals 2024, 17(11), 1516; https://doi.org/10.3390/ph17111516 - 11 Nov 2024
Cited by 3 | Viewed by 1948
Abstract
Background/Objectives: Benign prostatic hyperplasia (BPH) is a prevalent urological condition affecting elderly men. Prunella vulgaris L. (PV), a perennial herbaceous plant native to Europe and Asia, has anti-inflammatory, antioxidant, and antimicrobial effects. In this study, we determined the effect of PV extract on [...] Read more.
Background/Objectives: Benign prostatic hyperplasia (BPH) is a prevalent urological condition affecting elderly men. Prunella vulgaris L. (PV), a perennial herbaceous plant native to Europe and Asia, has anti-inflammatory, antioxidant, and antimicrobial effects. In this study, we determined the effect of PV extract on the development of BPH. Methods: Rats were treated via a daily hypodermic injection of testosterone propionate (TP; 3 mg/kg) for 4 weeks. Groups of BPH rats were treated with or without PV (60 or 80 mg/kg) by oral gavage. Results: In BPH model rats, PV considerably reduced their relative prostate weight and serum concentrations of dihydrotestosterone (DHT) and testosterone. The TP-induced increases in epithelial thickness in the prostate, proliferating cell nuclear antigen (PCNA) expression, and cyclin D1 expression were remarkably reduced, whereas terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive cells and cleaved caspase-3 levels were increased, in PV-treated rats compared to BPH rats. The mRNA expression levels of growth factors, such as transforming growth factor-β (TGF-β), fibroblast growth factor (FGF), and insulin-like growth factor (IGF-2), were significantly reduced in PV-treated rats. Mechanistically, the TP-induced activation of c-Jun N-terminal kinase (JNK) was reduced by PV administration. Conclusions: These results designate that PV effectively ameliorates the development of testosterone-induced BPH through anti-androgenic, anti-proliferative, and pro-apoptotic activities, suggesting that it could be a potential therapeutic substance for BPH. Full article
(This article belongs to the Special Issue The 20th Anniversary of Pharmaceuticals — Multi-Targeted Natural Products as Therapeutics)
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19 pages, 8091 KiB  
Article
The Role of Freeze-Drying as a Multifunctional Process in Improving the Properties of Hydrogels for Medical Use
by Kacper Odziomek, Anna K. Drabczyk, Paulina Kościelniak, Patryk Konieczny, Mateusz Barczewski and Katarzyna Bialik-Wąs
Pharmaceuticals 2024, 17(11), 1512; https://doi.org/10.3390/ph17111512 - 10 Nov 2024
Cited by 8 | Viewed by 4354
Abstract
Background/Objectives: Freeze-drying is a dehydration method that extends the shelf life and stability of drugs, vaccines, and biologics. Recently, its role has expanded beyond preservation to improve novel pharmaceuticals and their carriers, such as hydrogels, which are widely studied for both drug delivery [...] Read more.
Background/Objectives: Freeze-drying is a dehydration method that extends the shelf life and stability of drugs, vaccines, and biologics. Recently, its role has expanded beyond preservation to improve novel pharmaceuticals and their carriers, such as hydrogels, which are widely studied for both drug delivery and wound healing. The main aim of this study was to explore the multifunctional role of freeze-drying in improving the physicochemical properties of sodium alginate/poly(vinyl alcohol)-based hydrogels for medical applications. Methods: The base matrix and hydrogels containing a nanocarrier-drug system, were prepared by chemical cross-linking and then freeze-dried for 24 h at −53 °C under 0.2 mBa. Key analyses included determination of gel fraction, swelling ratio, FT-IR, SEM, TG/DTG, in vitro drug release and kinetics, and cytotoxicity assessment. Results: Freeze-drying caused an increase in the gel fraction of the hydrogel with the dual drug delivery system from 55 ± 1.6% to 72 ± 0.5%. Swelling ability was pH-dependent and remained in the same range (175–282%). Thermogravimetric analysis showed that freeze-dried hydrogels exhibited higher thermal stability than their non-freeze-dried equivalents. The temperature at 10% weight loss increased from 194.0 °C to 198.9 °C for the freeze-dried drug-loaded matrix, and from 188.4 °C to 203.1 °C for the freeze-dried drug-free matrix. The average pore size of the freeze-dried hydrogels was in the range of 1.07 µm ± 0.54 to 1.74 µm ± 0.92. In vitro drug release revealed that active substances were released in a controlled and prolonged way, according to the Korsmeyer–Peppas model. The cumulative amount of salicylic acid released at pH = 9.0 after 96 h was 63%, while that of fluocinolone acetonide reached 73%. Both hydrogels were non-toxic to human fibroblast cells, maintaining over 90% cell viability after 48 h of incubation. Conclusions: The results show a high potential for commercialisation of the obtained hydrogels as medical dressings. Full article
(This article belongs to the Special Issue Progress of Hydrogel Applications in Novel Drug Delivery Platforms)
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21 pages, 6227 KiB  
Article
Synthesis and Evaluation of Glucosyl-, Acyl- and Silyl- Resveratrol Derivatives as Retinoprotective Agents: Piceid Octanoate Notably Delays Photoreceptor Degeneration in a Retinitis Pigmentosa Mouse Model
by Lourdes Valdés-Sánchez, Seyed Mohamadmehdi Moshtaghion, Estefanía Caballano-Infantes, Pablo Peñalver, Rosario Rodríguez-Ruiz, José Luis González-Alfonso, Francisco José Plou, Tom Desmet, Juan C. Morales and Francisco J. Díaz-Corrales
Pharmaceuticals 2024, 17(11), 1482; https://doi.org/10.3390/ph17111482 - 5 Nov 2024
Cited by 1 | Viewed by 1740
Abstract
Background: Retinitis pigmentosa (RP), the leading cause of inherited blindness in adults, is marked by the progressive degeneration of rod photoreceptors in the retina. While gene therapy has shown promise in treating RP in patients with specific mutations, no effective therapies currently exist [...] Read more.
Background: Retinitis pigmentosa (RP), the leading cause of inherited blindness in adults, is marked by the progressive degeneration of rod photoreceptors in the retina. While gene therapy has shown promise in treating RP in patients with specific mutations, no effective therapies currently exist for the majority of patients with diverse genetic backgrounds. Additionally, no intervention can yet prevent or delay photoreceptor loss across the broader RP patient population. Resveratrol (RES), a naturally occurring polyphenol, has shown cytoprotective effects in various neurodegenerative disease models; however, its therapeutic potential is limited by low bioavailability. Methods: In this study, we synthesized novel RES derivatives and assessed their retinoprotective effects in a murine model of RP (rd10 mice). Results: Among these derivatives, piceid octanoate (PIC-OCT) significantly delayed photoreceptor degeneration in the RP model, demonstrating superior efficacy compared to RES. Conclusions: PIC-OCT shows strong potential as a leading candidate for developing new therapeutic strategies for RP. Full article
(This article belongs to the Special Issue The 20th Anniversary of Pharmaceuticals—Emerging Trends in Biopharmaceuticals)
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24 pages, 10379 KiB  
Review
Theranostics Nuclear Medicine in Prostate Cancer
by Helena Lima, Marina Etchebehere, Mateos Bogoni, Caroline Torricelli, Ellen Nogueira-Lima, Victor M. Deflon, Mariana Lima and Elba Etchebehere
Pharmaceuticals 2024, 17(11), 1483; https://doi.org/10.3390/ph17111483 - 5 Nov 2024
Cited by 1 | Viewed by 3448
Abstract
Theranostic Nuclear Medicine is based on the idea of combining the same molecule (or drug) with different radioisotopes for both diagnosis and treatment, a concept that emerged in the early 1940s with the use of radioactive iodine for thyroid diseases. Theranostic Nuclear Medicine [...] Read more.
Theranostic Nuclear Medicine is based on the idea of combining the same molecule (or drug) with different radioisotopes for both diagnosis and treatment, a concept that emerged in the early 1940s with the use of radioactive iodine for thyroid diseases. Theranostic Nuclear Medicine has since expanded to diseases of higher incidence, such as prostate cancer, with several imaging methods used to assess the extent of the disease and the corresponding radiopharmaceuticals used for treatment. For example, by detecting osteoblastic metastases by bone scintigraphy, corresponding radiopharmaceuticals with therapeutic properties can be administered to eliminate or reduce pain associated with metastases and/or determine overall survival gain. The purpose of this review is to discuss the role of Theranostic Nuclear Medicine in prostate cancer, addressing the main diagnostic imaging studies with their corresponding treatments in the Theranostic model. Full article
(This article belongs to the Special Issue Past, Present and Future Radiotracer Techniques: Radiopharmaceuticals in Cancer Theranostics)
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19 pages, 1952 KiB  
Review
The MET Oncogene: An Update on Targeting Strategies
by Simona Gallo, Consolata Beatrice Folco and Tiziana Crepaldi
Pharmaceuticals 2024, 17(11), 1473; https://doi.org/10.3390/ph17111473 - 2 Nov 2024
Cited by 2 | Viewed by 2792
Abstract
The MET receptor, commonly known as HGF (hepatocyte growth factor) receptor, is a focus of extensive scientific research. MET has been linked to embryonic development, tissue regeneration following injury, tumorigenesis, and cancer metastasis. These functions underscore its involvement in numerous cellular processes, including [...] Read more.
The MET receptor, commonly known as HGF (hepatocyte growth factor) receptor, is a focus of extensive scientific research. MET has been linked to embryonic development, tissue regeneration following injury, tumorigenesis, and cancer metastasis. These functions underscore its involvement in numerous cellular processes, including stemness, proliferation, motility, cell dissociation, and survival. However, the enigmatic nature of MET becomes apparent in the context of cancer. When MET remains persistently activated, since its gene undergoes genetic alterations, it initiates a complex signaling cascade setting in motion an aggressive and metastatic program that is characteristic of malignant cells and is known as “invasive growth”. The expanding knowledge of MET signaling has opened up numerous opportunities for therapeutic interventions, particularly in the realm of oncology. Targeting MET presents a promising strategy for developing novel anti-cancer treatments. In this review, we provide an updated overview of drugs designed to modulate MET signaling, highlighting MET kinase inhibitors, degraders, anti-MET/HGF monoclonal antibodies, and MET-targeted antibody–drug conjugates. Through this review, we aim to contribute to the ongoing advancement of therapeutic strategies targeting MET signaling. Full article
(This article belongs to the Section Pharmacology)
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24 pages, 2487 KiB  
Article
[68Ga]Ga-FAPI-46 PET/CT for Staging Suspected/Confirmed Lung Cancer: Results on the Surgical Cohort Within a Monocentric Prospective Trial
by Lucia Zanoni, Emilia Fortunati, Giulia Cuzzani, Claudio Malizia, Filippo Lodi, Veronica Serena Cabitza, Irene Brusa, Stefano Emiliani, Marta Assenza, Filippo Antonacci, Francesca Giunchi, Alessio Degiovanni, Marco Ferrari, Filippo Natali, Thomas Galasso, Gian Piero Bandelli, Simona Civollani, Piero Candoli, Antonietta D’Errico, Piergiorgio Solli, Stefano Fanti and Cristina Nanniadd Show full author list remove Hide full author list
Pharmaceuticals 2024, 17(11), 1468; https://doi.org/10.3390/ph17111468 - 1 Nov 2024
Cited by 4 | Viewed by 2038
Abstract
Background/Objectives. To evaluate T&N-staging diagnostic performance of [68Ga]Ga-FAPI-46 PET/CT (FAPI) in a suspected/confirmed lung cancer surgical cohort. Methods: Patients were enrolled in a prospective monocentric trial (EudraCT: 2021-006570-23) to perform FAPI, in addition to conventional-staging-flow-chart (including [18F]F-FDG PET/CT-FDG). For the current purpose, only [...] Read more.
Background/Objectives. To evaluate T&N-staging diagnostic performance of [68Ga]Ga-FAPI-46 PET/CT (FAPI) in a suspected/confirmed lung cancer surgical cohort. Methods: Patients were enrolled in a prospective monocentric trial (EudraCT: 2021-006570-23) to perform FAPI, in addition to conventional-staging-flow-chart (including [18F]F-FDG PET/CT-FDG). For the current purpose, only surgical patients were included. PET-semiquantitative parameters were measured for T&N: SUVmax, target-to-background-ratios (using mediastinal blood pool-MBP, liver-L and pulmonary-parenchyma-P). Visual and semiquantitative T&N PET/CT performances were analysed per patient and per region for both tracers, with surgical histopathology as standard-of-truth. Results: 63 FAPI scans were performed in 64 patients enrolled (26 May 2022–30 November 2023). A total of 50/63 patients underwent surgery and were included. Agreement (%) with histopathological-T&N-StagingAJCC8thEdition was slightly in favour of FAPI (T-66% vs. 58%, N-78% vs. 70%), increasing when T&N dichotomised (T-92% vs. 80%, N-78% vs. 72%). The performance of Visual-Criteria for T-per patient (n = 50) resulted higher FAPI than FDG. For N-per patient (n = 46), sensitivity and NPV were slightly lower with FAPI. Among 59 T-regions surgically examined, malignancy was excluded in 6/59 (10%). FAPI showed (vs. FDG): sensitivity 85% (vs. 72%), specificity 67% (vs. 50%), PPV 96% (vs. 93%), NPV 33% (vs. 17%), accuracy 83% (vs. 69%). Among 217 N-stations surgically assessed (overall 746 ln removed), only 15/217 (7%) resulted malignant; FAPI showed (vs. FDG): sensitivity 53% (vs. 60%), PPV 53% (vs. 26%), NPV 97% (vs. 97%), and significantly higher specificity (97% vs. 88%, p = 0.001) and accuracy (94% vs. 86%, p = 0.018). Semiquantitative-PET parameters performed similarly, better for N (p < 0.001) than for T, slightly in favour (although not significantly) of FAPI over FDG. Conclusions: In a suspected/confirmed lung cancer surgical cohort, PET/CT performances for preoperative T&Nstaging were slightly in favour of FAPI than FDG (except for suboptimal N-sensitivity), significantly better only for N (region-based) specificity and accuracy using visual assessment. The trial’s conventional follow-up is still ongoing; future analyses are pending, including non-surgical findings and theoretical impact on patient management. Full article
(This article belongs to the Special Issue Past, Present and Future Radiotracer Techniques: Radiopharmaceuticals in Cancer Theranostics)
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17 pages, 2709 KiB  
Article
Antidepressant-like Effects of Cannabis sativa L. Extract in an Lipopolysaccharide Model: Modulation of Mast Cell Activation in Deep Cervical Lymph Nodes and Dura Mater
by Joonyoung Shin, Dong-Uk Kim, Gi-Sang Bae, Ji-Ye Han, Do-Won Lim, Young-Mi Lee, Eunjae Kim, Eunjeong Kwon, Dongwoon Han and Sungchul Kim
Pharmaceuticals 2024, 17(10), 1409; https://doi.org/10.3390/ph17101409 - 21 Oct 2024
Cited by 2 | Viewed by 2535
Abstract
Background: Lipopolysaccharide (LPS)-induced neuroinflammation is a well-established model for studying depression-like behavior, driven by pro-inflammatory cytokines such as TNF-α and IL-1β. Mast cells (MCs) contribute to neuroinflammation by releasing mediators that exacerbate depressive-like symptoms. This study evaluates the antidepressant-like and anti-inflammatory effects of [...] Read more.
Background: Lipopolysaccharide (LPS)-induced neuroinflammation is a well-established model for studying depression-like behavior, driven by pro-inflammatory cytokines such as TNF-α and IL-1β. Mast cells (MCs) contribute to neuroinflammation by releasing mediators that exacerbate depressive-like symptoms. This study evaluates the antidepressant-like and anti-inflammatory effects of Cannabis sativa L. inflorescence extract (CSL) in an LPS-induced neuroinflammation model. Methods: Male C57BL/6 mice were intraperitoneally injected with CSL at doses of 10, 20, and 30 mg/kg, 30 min prior to LPS (0.83 mg/kg) administration. Depressive behaviors were assessed using the sucrose preference test (SPT), tail suspension test (TST), and forced swimming test (FST). The neutrophil-to-lymphocyte ratio (NLR) was measured to assess systemic inflammation. Cytokine levels in the prefrontal cortex (PFC) were measured, and mast cell degranulation in the lymph nodes and dura mater was analyzed histologically (approval number: WKU24-64). Results: CSL significantly improved depressive-like behaviors and decreased the NLR, indicating reduced systemic inflammation. CSL also significantly reduced TNF-α and IL-1β levels in the PFC. Furthermore, CSL inhibited MC degranulation in the deep cervical lymph nodes and dura mater, with the strongest effects observed at 30 mg/kg. Conclusions: CSL demonstrated antidepressant-like and anti-inflammatory effects in an LPS-induced neuroinflammation model, likely through the modulation of cytokine expression and mast cell activity. These results suggest the potential of CSL as a therapeutic option for treating inflammation-related depression. Full article
(This article belongs to the Special Issue The 20th Anniversary of Pharmaceuticals — Multi-Targeted Natural Products as Therapeutics)
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25 pages, 6428 KiB  
Article
Hydrogel Containing Propolis: Physical Characterization and Evaluation of Biological Activities for Potential Use in the Treatment of Skin Lesions
by Lindalva Maria de Meneses Costa Ferreira, Naila Ferreira da Cruz, Desireé Gyles Lynch, Patrícia Fagundes da Costa, Claudio Guedes Salgado, José Otávio Carréra Silva-Júnior, Alessandra Rossi and Roseane Maria Ribeiro-Costa
Pharmaceuticals 2024, 17(10), 1400; https://doi.org/10.3390/ph17101400 - 20 Oct 2024
Cited by 3 | Viewed by 2175
Abstract
Background: Skin injury affects the integrity of the skin structure and induces the wound healing process, which is defined by a well-coordinated series of cellular and molecular reactions that aim to recover or replace the injured tissue. Hydrogels are a group of promising [...] Read more.
Background: Skin injury affects the integrity of the skin structure and induces the wound healing process, which is defined by a well-coordinated series of cellular and molecular reactions that aim to recover or replace the injured tissue. Hydrogels are a group of promising biomaterials that are able to incorporate active ingredients for use as dressings. This study aimed to synthesize hydrogels with and without propolis extract and evaluate their physical characteristics and biological activities in vitro for potential use as active dressings in the treatment of skin lesions. Methods: The antifungal [Candida albicans (C. albicans) and Candida tropicalis (C. tropicalis)] and antibacterial [Staphylococcus aureus (S. aureus), Pseudomonas aeruginosas (P. aeruginosas) and Escherichia coli (E. coli)] activity was assessed by the microdilution method in plates and antioxidant potential by the reduction of the phosphomolybdate complex. Results: The hydrogels showed good water absorption capacity, high solubility, and high gel fraction, as well as good porosity, water retention, and vapor transmission rates. They revealed a totally amorphous structure. The extract and the hydrogels containing the propolis extract (1.0% and 2.5%) did not inhibit fungal growth. However, they showed antibacterial activity against strains of S. aureus and P. aeruginosas. Regarding the E. coli strain, only the extract inhibited its growth. It showed good antioxidant activity by the evaluation method used. Conclusions: Therefore, the hydrogels containing propolis extract can be a promising alternative with antibacterial and antioxidant action for use as dressings for the treatment of skin lesions. Full article
(This article belongs to the Section Medicinal Chemistry)
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27 pages, 6049 KiB  
Review
Ponatinib: A Review of the History of Medicinal Chemistry behind Its Development
by Mayara Nascimento, Stefany Moura, Lidia Parra, Valeska Vasconcellos, Gabriela Costa, Debora Leite, Maria Dias, Tácio Vinício Amorim Fernandes, Lucas Hoelz, Luiz Pimentel, Monica Bastos and Nubia Boechat
Pharmaceuticals 2024, 17(10), 1361; https://doi.org/10.3390/ph17101361 - 11 Oct 2024
Cited by 3 | Viewed by 3736
Abstract
The primary treatment for chronic myeloid leukemia (CML) involves first- and second-generation tyrosine kinase inhibitors (TKIs), such as imatinib, nilotinib, bosutinib, and dasatinib. However, these medications are ineffective against mutations in the kinase domain of the ABL1 protein, particularly in the protein with [...] Read more.
The primary treatment for chronic myeloid leukemia (CML) involves first- and second-generation tyrosine kinase inhibitors (TKIs), such as imatinib, nilotinib, bosutinib, and dasatinib. However, these medications are ineffective against mutations in the kinase domain of the ABL1 protein, particularly in the protein with the T315I mutation. To address this, ponatinib (PNT), a third-generation inhibitor, was developed. Despite its efficacy in treating the BCR-ABL1T315I mutation, the use of PNT was briefly suspended in 2013 due to serious adverse effects but was subsequently reintroduced to the market. During the drug discovery and development process, it is rare to consolidate all information into a single article, as is the case with ponatinib. This review aims to compile and chronologically organize the research on the discovery of ponatinib using medicinal chemistry tools and computational methods. It includes in silico calculations, such as the octanol/water partition coefficient (cLogP) via SwissAdme, and 2D maps of intermolecular interactions through molecular docking. This approach enhances understanding for both specialists and those interested in medicinal chemistry and pharmacology, while also contextualizing future directions for further optimizations of ponatinib, facilitating the development of new analogs of this crucial inhibitor for the treatment of CML and Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL). Full article
(This article belongs to the Special Issue The 20th Anniversary of Pharmaceuticals—Heterocyclic Compounds and Their Application in Therapy)
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50 pages, 8706 KiB  
Review
Metabolic-Associated Fatty Liver Disease: The Influence of Oxidative Stress, Inflammation, Mitochondrial Dysfunctions, and the Role of Polyphenols
by Raissa Bulaty Tauil, Paula Takano Golono, Enzo Pereira de Lima, Ricardo de Alvares Goulart, Elen Landgraf Guiguer, Marcelo Dib Bechara, Claudia C. T. Nicolau, José Luiz Yanaguizawa Junior, Adriana M. R. Fiorini, Nahum Méndez-Sánchez, Ludovico Abenavoli, Rosa Direito, Vitor Engrácia Valente, Lucas Fornari Laurindo and Sandra Maria Barbalho
Pharmaceuticals 2024, 17(10), 1354; https://doi.org/10.3390/ph17101354 - 10 Oct 2024
Cited by 17 | Viewed by 5019
Abstract
Metabolic-Associated Fatty Liver Disease (MAFLD) is a clinical–pathological scenario that occurs due to the accumulation of triglycerides in hepatocytes which is considered a significant cause of liver conditions and contributes to an increased risk of death worldwide. Even though the possible causes of [...] Read more.
Metabolic-Associated Fatty Liver Disease (MAFLD) is a clinical–pathological scenario that occurs due to the accumulation of triglycerides in hepatocytes which is considered a significant cause of liver conditions and contributes to an increased risk of death worldwide. Even though the possible causes of MAFLD can involve the interaction of genetics, hormones, and nutrition, lifestyle (diet and sedentary lifestyle) is the most influential factor in developing this condition. Polyphenols comprise many natural chemical compounds that can be helpful in managing metabolic diseases. Therefore, the aim of this review was to investigate the impact of oxidative stress, inflammation, mitochondrial dysfunction, and the role of polyphenols in managing MAFLD. Some polyphenols can reverse part of the liver damage related to inflammation, oxidative stress, or mitochondrial dysfunction, and among them are anthocyanin, baicalin, catechin, curcumin, chlorogenic acid, didymin, epigallocatechin-3-gallate, luteolin, mangiferin, puerarin, punicalagin, resveratrol, and silymarin. These compounds have actions in reducing plasma liver enzymes, body mass index, waist circumference, adipose visceral indices, lipids, glycated hemoglobin, insulin resistance, and the HOMA index. They also reduce nuclear factor-KB (NF-KB), interleukin (IL)-1β, IL-6, tumor necrosis factor-α (TNF-α), blood pressure, liver fat content, steatosis index, and fibrosis. On the other hand, they can improve HDL-c, adiponectin levels, and fibrogenesis markers. These results show that polyphenols are promising in the prevention and treatment of MAFLD. Full article
(This article belongs to the Special Issue Medicinal Plants: A Natural Approach to Inflammatory Diseases and Conditions Related to Oxidative Stress)
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22 pages, 1556 KiB  
Review
Present Scenario and Future Landscape of Payloads for ADCs: Focus on DNA-Interacting Agents
by Barbara Valsasina, Paolo Orsini, Chiara Terenghi and Alberto Ocana
Pharmaceuticals 2024, 17(10), 1338; https://doi.org/10.3390/ph17101338 - 7 Oct 2024
Viewed by 5791
Abstract
ADCs have emerged as a promising class of therapeutics, combining the targeting specificity of monoclonal antibodies with the cytotoxic potency of small-molecule drugs. Although the majority of approved ADCs are still based on microtubule binder payloads, the recent success of topoisomerase I inhibitors [...] Read more.
ADCs have emerged as a promising class of therapeutics, combining the targeting specificity of monoclonal antibodies with the cytotoxic potency of small-molecule drugs. Although the majority of approved ADCs are still based on microtubule binder payloads, the recent success of topoisomerase I inhibitors has revitalized interest in the identification of novel agents overcoming present limitations in the field including narrow therapeutic window and chemoresistance. The success of DNA binders as payload for ADCs has been very limited, up to now, due, among other factors, to high hydrophobicity and planar chemical structures resulting in most cases in ADCs with a strong tendency to aggregate, poor plasma stability, and limited therapeutic index. Some of these molecules, however, continue to be of interest due to their favorable properties in terms of cytotoxic potency even in chemoresistant settings, bystander and immunogenic cell death effects, and known combinability with approved drugs. We critically evaluated several clinically tested ADCs containing DNA binders, focusing on payload physicochemical properties, cytotoxic potency, and obtained clinical results. Our analysis suggests that further exploration of certain chemical classes, specifically anthracyclines and duocarmycins, based on the optimization of physicochemical parameters, reduction of cytotoxic potency, and careful design of targeting molecules is warranted. This approach will possibly result in a novel generation of payloads overcoming the limitations of clinically validated ADCs. Full article
(This article belongs to the Special Issue Evaluation of the Antitumor Mechanism of Armed Antibodies: 2nd Edition)
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12 pages, 1677 KiB  
Article
Inhibitory Effects of Decursin Derivative against Lipopolysaccharide-Induced Inflammation
by Jinhee Lee, Jong-Beom Heo, Sanghee Cho, Chang-Woo Ryu, Hae-Joon Heo, Mi-Young Yun, Gaewon Nam, Gyu-Yong Song and Jong-Sup Bae
Pharmaceuticals 2024, 17(10), 1337; https://doi.org/10.3390/ph17101337 - 7 Oct 2024
Cited by 2 | Viewed by 1404
Abstract
Background: This study aims to explore the protective role of JB-V-60—a novel synthetic derivative of decur-sin—against lipopolysaccharide (LPS)-induced inflammation. Methods: We examined the effects of JB-V-60 on heme oxygenase (HO)-1, cyclooxygenase (COX)-2, and inducible nitric oxide synthase (iNOS) in LPS-activated human pulmonary artery [...] Read more.
Background: This study aims to explore the protective role of JB-V-60—a novel synthetic derivative of decur-sin—against lipopolysaccharide (LPS)-induced inflammation. Methods: We examined the effects of JB-V-60 on heme oxygenase (HO)-1, cyclooxygenase (COX)-2, and inducible nitric oxide synthase (iNOS) in LPS-activated human pulmonary artery endothelial cells (HPAECs). Additionally, we assessed its effects on iNOS, tumor necrosis factor (TNF)-α, and interleukin (IL)-1β in LPS-exposed mice. Results: JB-V-60 enhanced HO-1 levels, inhibited NF-κB activation, reduced COX-2/PGE2 and iNOS/NO concentra-tions, and lowered phosphorylation of signal transducer and activator of transcription 1. It also promoted the translocation of Nrf2 into the nucleus, allowing its binding to antioxidant response elements and resulting in reduced IL-1β in LPS-stimulated HPAECs. The reduction in iNOS/NO levels by JB-V-60 was reversed when HO-1 was inhibited via RNAi. In the animal model, JB-V-60 sig-nificantly decreased iNOS expression in lung tissues and TNF-α levels in bronchoalveolar lavage fluid. Conclusions: These findings highlight the anti-inflammatory effects of JB-V-60 and its potential as a treat-ment for inflammatory disorders. Full article
(This article belongs to the Section Pharmacology)
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