Pharmaceuticals

29 pages, 9454 KB

Open AccessArticle

Pfaffia glomerata Ameliorates BPA-Induced Reproductive Impairments in Mice by Suppressing Apoptosis via PI3K/AKT Signaling Activation

by Hongwei Xue, Shuyan Zhang, Juan Lu, Jia Liu, Yihang Li and Xi Chen

Pharmaceuticals 2025, 18(11), 1614; https://doi.org/10.3390/ph18111614 (registering DOI) - 25 Oct 2025

Abstract

Objectives: Bisphenol A (BPA), a prototypical environmental endocrine-disrupting chemical (EDC), is ubiquitously present in environmental matrices and biological fluids. Dietary ingestion and inhalation exposure to BPA can induce testicular oxidative stress and apoptosis. This study aimed to investigate the protective effects and underlying [...] Read more.

Objectives: Bisphenol A (BPA), a prototypical environmental endocrine-disrupting chemical (EDC), is ubiquitously present in environmental matrices and biological fluids. Dietary ingestion and inhalation exposure to BPA can induce testicular oxidative stress and apoptosis. This study aimed to investigate the protective effects and underlying mechanisms of Pfaffia glomerata (Pg), a perennial herb of the Amaranthaceae family, against BPA-induced reproductive system injury. Methods: Potential targets and molecular mechanisms were predicted through network pharmacology. Physiological indicators, histopathological changes, serum biochemical parameters, and Western blot analysis were used to systematically evaluate the ameliorative effects of Pg and elucidate its mechanisms. Results: Our network pharmacology analysis identified core targets of Pg in attenuating reproductive system injury, including PTPN11, PIK3CA, JAK2, PIK3R1, PDGFRB, and others. GO enrichment and KEGG pathway analysis indicated that these key targets primarily regulate steroid metabolism, enhance antioxidant capacity, and modulate signaling pathways such as PI3K-AKT, Fc epsilon RI, and cAMP. In vivo studies demonstrated that all Pg dose groups showed significant improvement in BPA-induced histopathological injury to testicular tissues. BPA exposure increased serum levels of follicle-stimulating hormone (FSH) while decreasing testosterone (T), estradiol (E2), and progesterone (PROG) levels. Furthermore, BPA elevated serum levels of the testicular marker enzymes acid phosphatase (ACP) and lactate dehydrogenase (LDH) but reduced alkaline phosphatase (ALP) levels; all these effects were significantly reversed with Pg treatment. Western blot results showed that compared with the model group, high-dose Pg significantly upregulated the expression of phosphorylated AKT (p-AKT), phosphorylated PI3K (p-PI3K), and Bcl-2, while downregulating Cleaved Caspase-3 and Bax. Conclusions: Our findings indicate that Pg may attenuate BPA-induced reproductive system injury by activating the PI3K/AKT signaling pathway, upregulating the anti-apoptotic protein Bcl-2, and inhibiting the activation of the apoptotic effector Caspase-3. The study provides a new theoretical basis for the development of novel natural drugs or health products. Full article

(This article belongs to the Section Pharmacology)

► Show Figures

Figure 1

15 pages, 4423 KB

Open AccessArticle

A Multi-Laboratory, Multi-Platform Analysis of the Multi-Attribute Method

by Joshua Shipman, Mercy Oyugi, Tim Andres Marzan, Ilan Geerlof-Vidavsky, Douglas Kirkpatrick, Hongbin Zhu, Milani Rasangika and Sarah Rogstad

Pharmaceuticals 2025, 18(11), 1613; https://doi.org/10.3390/ph18111613 (registering DOI) - 25 Oct 2025

Abstract

Background/Objectives: The multi-attribute method (MAM) has found diverse use in the analytical characterization of therapeutic protein products during their development and production. As the MAM matures it has the potential to enter quality control (QC) laboratories, consolidating and replacing many less informative [...] Read more.

Background/Objectives: The multi-attribute method (MAM) has found diverse use in the analytical characterization of therapeutic protein products during their development and production. As the MAM matures it has the potential to enter quality control (QC) laboratories, consolidating and replacing many less informative chromatographic techniques; however, this requires an appropriate risk assessment and understanding of method capability. Methods: A validated MAM approach was used to quantify product quality attributes (PQAs) using three different mass spectrometers across two laboratories; the results were compared to conventional hydrophilic interaction chromatography–fluorescence detection (HILIC-FLD) and cation exchange chromatography–ultraviolet (CEX-UV) techniques. Results: Stressed, long-term, and accelerated stability studies were performed, and their effects on glycosylation, deamidation, oxidation and N- and C-termini were quantified. Conclusions: Overall, the inter-instrument inter-laboratory data provided here showed important considerations for transferring methods between laboratories and establishing the correlation between the MAM and conventional data, elements which are necessary to transition the MAM to the QC environment and ultimately achieving the goal of replacing orthogonal QC methods. Full article

(This article belongs to the Special Issue Characterization and Quality Control of Biopharmaceuticals Using the Multi-Attribute Method (MAM): Advantages and Challenges)

► Show Figures

Figure 1

22 pages, 955 KB

Open AccessReview

Targeting Inflammatory Pathways in Chronic Low Back Pain: Opportunities for Novel Therapeutics

by Panagiota Anyfanti, Paschalis Evangelidis, Konstantinos Tragiannidis, Christina Antza, Dimitrios Poulis, Theodoros Dimitroulas and Vasilios Kotsis

Pharmaceuticals 2025, 18(11), 1612; https://doi.org/10.3390/ph18111612 (registering DOI) - 24 Oct 2025

Abstract

Low back pain (LBP) is a highly prevalent musculoskeletal problem and a leading cause of disability worldwide. From a pathophysiological perspective, the contribution of inflammation to LBP is being increasingly recognized. In this literature review, we aim to provide an overview of the [...] Read more.

Low back pain (LBP) is a highly prevalent musculoskeletal problem and a leading cause of disability worldwide. From a pathophysiological perspective, the contribution of inflammation to LBP is being increasingly recognized. In this literature review, we aim to provide an overview of the role of inflammation as a mediator of LBP while summarizing clinical studies investigating the potential role of anti-inflammatory treatments in the management of LBP. Although often controversial, the available evidence suggests an important role of inflammation in the pathogenesis of LBP, which can be further translated into novel therapeutic targets. Both anti-tumor necrosis factor (anti-TNF) and anti-nerve growth factor (anti-NGF) agents hold the potential of blocking inflammation and pain pathways in patients with chronic LBP. TNF inhibitors have been tested mostly in small trials with mixed results, and their long-term efficacy remains to be proven. Anti-NGF agents have demonstrated stronger and consistent efficacy in randomized controlled trials, but safety concerns compromise their widespread use. The potential role of other anti-inflammatory molecules is currently under investigation. Presently, the routine use of TNF or NGF inhibitors is not supported in radiculopathy or chronic LBP. However, novel anti-inflammatory therapies introduced in the rheumatology field appear to be promising for specific subsets of patients suffering from chronic, refractory LBP, with a complementary role as therapeutic tools, after the unsuccessful outcome of the conservative approach. Full article

(This article belongs to the Section Pharmacology)

► Show Figures

Figure 1

25 pages, 6630 KB

Open AccessReview

Clinical Studies on Topical Anesthesia in Dentistry: A Bibliometric Analysis

by Helena Carla Gonçalves dos Santos, Iago Torres Cortês de Sousa, Aylla Mesquita Pestana, Arthur Antunes Costa Bezerra, Ana Luiza Martins Lucas, Paulo Antônio Martins-Júnior and Michelle Franz-Montan

Pharmaceuticals 2025, 18(11), 1611; https://doi.org/10.3390/ph18111611 (registering DOI) - 24 Oct 2025

Abstract

Topical anesthesia is widely used in dentistry. However, its clinical effectiveness remains controversial. This study conducted a bibliometric analysis of the most cited clinical dentistry articles on topical anesthesia, identifying the most studied drugs, research trends, leading authors, geographic distribution, funding sources, and [...] Read more.

Topical anesthesia is widely used in dentistry. However, its clinical effectiveness remains controversial. This study conducted a bibliometric analysis of the most cited clinical dentistry articles on topical anesthesia, identifying the most studied drugs, research trends, leading authors, geographic distribution, funding sources, and study characteristics. A structured search was conducted in the Web of Science using defined descriptors and Boolean operators, with citation comparisons in Scopus and Google Scholar. The search, conducted without language or publication year restrictions, extended until October 2023. Out of 4892 articles, the 30 most cited were selected, collectively accumulating 953 citations between 1992 and 2017. Most highly cited and funded studies originated from the United States. Journals focusing on periodontics, general dentistry, and oral surgery published the majority of these articles, with lidocaine being the most studied anesthetic. Despite their widespread use, topical anesthetics have garnered relatively few citations. Our findings suggest a research preference for studies with immediate clinical impact over those focusing on pain management, particularly in the field of topical dental anesthesia. This highlights the need for further research and progress in this important field. Full article

(This article belongs to the Special Issue Dental Medication)

► Show Figures

Graphical abstract

17 pages, 2315 KB

Open AccessArticle

Enhancing the Solubility of Indomethacin: A Breakthrough with Cocrystal Formation

by Hugo Pardo, Víctor Guarnizo-Herrero, Borja Martínez-Alonso and Mª Ángeles Peña Fernández

Pharmaceuticals 2025, 18(11), 1610; https://doi.org/10.3390/ph18111610 (registering DOI) - 24 Oct 2025

Abstract

Background/objectives: Pharmaceutical cocrystals have emerged as a promising strategy to enhance the solubility and bioavailability of poorly water-soluble drugs. Indomethacin (IND), classified as a Biopharmaceutics Classification System (BCS) Class II drug, exhibits low solubility but high permeability. This study aims to develop a [...] Read more.

Background/objectives: Pharmaceutical cocrystals have emerged as a promising strategy to enhance the solubility and bioavailability of poorly water-soluble drugs. Indomethacin (IND), classified as a Biopharmaceutics Classification System (BCS) Class II drug, exhibits low solubility but high permeability. This study aims to develop a synthesis method, evaluate cocrystal solubility/stability and the physicochemical properties of the pure components, and describe cocrystal solubility using a mathematical model. Methods: Cocrystals were synthesized via solvent evaporation, using ethanol, methanol, and ethyl acetate. The pure components, IND and benzoic acid (AcBz) were dissolved in each solvent and maintained in a thermostabilizer for 24 h. Cocrystal formation was confirmed by UV-V spectroscopy, differential scanning calorimetry (DSC), and infrared (IR) spectroscopy. Results: The results showed that the solubility of the cocrystals decreased with increasing benzoic acid concentration. Mathematical modelling revealed that solubility can be expressed as the product of the solubilities of the individual components and the stability constant of the solution complex. Among the solvents tested, ethanol exhibited the highest solubility and equilibrium constant (K_eq) for IND–AcBz cocrystals, suggesting a greater molecular affinity and enhanced cocrystal formation. Conclusions: These findings demonstrate that the formation of the novel INDAcBz cocrystal significantly enhances Indomethacin solubility and thermodynamic stability. These results validate benzoic acid as an effective coformer and establish phase solubility diagrams (PSD) as predictive tools for rational cocrystal design, supporting the future development of optimized pharmaceutical formulations. Full article

(This article belongs to the Special Issue Drug Formulation: Solubilization and Controlled-Release Strategies)

► Show Figures

Figure 1

18 pages, 3908 KB

Open AccessArticle

Repurposed Drugs for Heterotopic Ossification Management: Revitalizing Therapeutic Strategies

by Ana Alonso-Pérez, Eloi Franco-Trepat, María Guillán-Fresco, Miriam López-Fagúndez, Andrés Pazos-Pérez, Verónica López, Antonio Salas, Federico Martinón-Torres, Alberto A. Jorge-Mora and Rodolfo Gómez

Pharmaceuticals 2025, 18(11), 1609; https://doi.org/10.3390/ph18111609 (registering DOI) - 24 Oct 2025

Abstract

Background and Objectives: Heterotopic ossification (HO) involves abnormal bone growth in soft tissues. Current treatments are ineffective and prone to adverse effects, suggesting the need for new HO therapies. Intramembranous bone growth is led by osteoblasts. Since osteoblastogenesis and adipogenesis are opposed [...] Read more.

Background and Objectives: Heterotopic ossification (HO) involves abnormal bone growth in soft tissues. Current treatments are ineffective and prone to adverse effects, suggesting the need for new HO therapies. Intramembranous bone growth is led by osteoblasts. Since osteoblastogenesis and adipogenesis are opposed and mutually controlled processes, this study aims to identify a new repurposed therapeutic tool to inhibit osteoblastogenesis through adipogenesis promotion. Methods: We performed docking experiments between peroxisome proliferator-activated receptor-γ and bone metabolism-affecting drugs, namely, thiazolidinediones (rosiglitazone, pioglitazone), indomethacin, and dexamethasone, to test tritherapy antiosteoblastogenic effect. Mouse mesenchymal stem cells (C3H10T1/2), human osteoblast-like cells (SaOS2 and primary preosteoblasts), and mouse chondrocytes (ATDC5) were differentiated in the presence of these compounds. The effects on osteoblastogenesis, adipogenesis, and endochondral ossification were analysed through marker gene expression via RT–qPCR. Additionally, primary human HO cells and a congenital HO patient were treated with the selected drug combination (P-tritherapy). Results: Tritherapy significantly and synergistically promoted the expression of an adipogenic marker (fatty acid-binding protein 4) and decreased the expression of an osteoblastogenic marker (osteopontin). In an endochondral ossification model, it reduced ossification markers (collagen-2α1) expression, and in HO cells, it increased adipogenesis markers’ expression. Clinically, P-tritherapy administration prompted bone resorption in a patient with progressive osseous heteroplasia. Conclusions: Tritherapy induced adipogenesis while inhibiting osteoblastogenesis and endochondral ossification, demonstrating its potential as a new therapeutic tool to prevent abnormal bone growth. These results were consistent with bone turnover modification observed in a congenital HO patient. This concordance underscores tritherapy potential for rapid and safe translation to prevent HO. Full article

(This article belongs to the Section Pharmacology)

► Show Figures

Figure 1

22 pages, 1723 KB

Open AccessReview

Clinical Experience with Targeted Alpha-Emitter Peptide Receptor Radionuclide Therapy (α-PRRT) for Somatostatin Receptor-Positive Neuroendocrine Tumors

by Hannes Leupe, Merel Cauwenbergh, Frederik Cleeren, Jeroen Dekervel, Chris Verslype and Christophe M. Deroose

Pharmaceuticals 2025, 18(11), 1608; https://doi.org/10.3390/ph18111608 (registering DOI) - 24 Oct 2025

Abstract

Background: α-emitting Peptide Receptor Radionuclide Therapy (α-PRRT) is emerging as a promising new generation of PRRT for neuroendocrine tumors (NETs), providing enhanced tumor cell cytotoxicity and reduced irradiation of adjacent healthy tissues due to its high linear energy transfer (LET) and short particle [...] Read more.

Background: α-emitting Peptide Receptor Radionuclide Therapy (α-PRRT) is emerging as a promising new generation of PRRT for neuroendocrine tumors (NETs), providing enhanced tumor cell cytotoxicity and reduced irradiation of adjacent healthy tissues due to its high linear energy transfer (LET) and short particle range. This review summarizes available clinical evidence on α-PRRT using different α-emitting isotopes, including actinium-225, lead-212, and bismuth-213, in somatostatin receptor (SSTR)-positive NETs. Methods: A comprehensive literature search was conducted across PubMed, Embase, Cochrane Library, Scopus, Web of Science, and ClinicalTrials.gov, as well as major oncology congress abstracts (ENETS, ESMO, ASCO). Eligible studies included clinical trials evaluating α-PRRT in patients with advanced SSTR-positive NETs, reporting therapeutic response and adverse events. The primary endpoint was the objective response rate (ORR); secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Results: Seven studies encompassing 150 patients were included. Treatment with [²²⁵Ac]Ac-DOTATATE yielded a pooled ORR of 50% and a DCR of 81.3% across 121 evaluable patients. The best responses were observed in patients who had previously responded to β-PRRT (ORR 70.4%, DCR 96.3%), while one-third of β-PRRT–refractory patients achieved partial or complete responses. [²¹²Pb]Pb-DOTAMTATE demonstrated an ORR of 56.8% and DCR of 100% in preliminary phase II results, though dysphagia was noted in 34% of patients. [²¹³Bi]Bi-DOTATOC and [²¹²Pb]Pb-VMT-α-NET studies also showed promising disease control with minimal grade ≥ 3 hematologic or renal toxicities. Across all studies, α-PRRT was well tolerated, with predominantly low-grade hematologic adverse events and no significant hepatic or renal toxicity. Conclusions: Clinical data to date indicate that α-PRRT offers meaningful therapeutic benefit in patients with metastatic or treatment-refractory NETs, achieving favorable response rates with manageable toxicity. Early results support α-PRRT as a potential first- or second-line therapeutic option. Ongoing phase III trials will be critical to confirm its long-term safety, survival outcomes, and role in routine clinical practice. Full article

(This article belongs to the Collection Will (Radio)Theranostics Hold Up in the 21st Century—and Why?)

► Show Figures

Figure 1

27 pages, 3467 KB

Open AccessArticle

A Novel Workflow for Non-Animal PBK Modelling of UV Filters: Oxybenzone as a Case Study

by Nazanin Golbamaki, Anne Moustié, Nicola J. Hewitt, Guillaume Lereaux, Matthew Burbank, El Mehdi Ben Yahya, Sébastien Grégoire and Laurène Roussel-Berlier

Pharmaceuticals 2025, 18(11), 1607; https://doi.org/10.3390/ph18111607 (registering DOI) - 24 Oct 2025

Abstract

Background/Objectives: Physiologically based kinetics (PBK) modelling provides (internal) exposure concentrations. We used a PBK model parameterized exclusively with in silico and in vitro data in a bottom-up approach to predict the pharmacokinetics of oxybenzone, a UV filter, present in two formulations (for which [...] Read more.

Background/Objectives: Physiologically based kinetics (PBK) modelling provides (internal) exposure concentrations. We used a PBK model parameterized exclusively with in silico and in vitro data in a bottom-up approach to predict the pharmacokinetics of oxybenzone, a UV filter, present in two formulations (for which dose-normalized C_max and AUC from clinical studies were different). Methods: Skin absorption data were used to refine chemical-specific dermal absorption parameters for oxybenzone in a lotion and spray. The Transdermal Compartmental Absorption and Transit (TCAT) model in GastroPlus^® 9.9 was used to estimate vehicle and skin layer diffusion and partitioning and then used to simulate systemic exposure. The model was validated according to the OECD 331 guideline. Results: PK profiles simulated for both formulations after single and repeated applications correlated with clinical data profiles (used only to validate our approach), with a deviation from the C_max and AUC of <2-fold. Sensitivity and uncertainty analyses indicated that most input parameters had a medium to high reliability, whereas only a few parameters related to dermal delivery had a low reliability: the partition coefficient between vehicle and water for spray and the diffusion coefficient in stratum corneum for lotion. In vitro skin absorption results suggested that absorption kinetics were not statistically different between the formulations; however, parameters such as vehicle evaporation time were different. The fine-tuned TCAT model containing the absorption data suggested that the variability in clinical data might be due to other factors, e.g., the small number of subjects. Conclusions: These results demonstrate how formulation-dependent absorption kinetics improve confidence in estimated exposure, thanks to the PBK model with its bottom-up approach for nonanimal-based safety assessments. Full article

(This article belongs to the Section Pharmacology)

► Show Figures

Graphical abstract

21 pages, 4531 KB

Open AccessArticle

Structure-Based Insights into Stefin-Mediated Targeting of Fowlerpain-1: Towards Novel Therapeutics for Naegleria fowleri Infections

by Pablo A. Madero-Ayala, Rosa E. Mares-Alejandre, Patricia L. A. Muñoz-Muñoz, Samuel G. Meléndez-López and Marco A. Ramos-Ibarra

Pharmaceuticals 2025, 18(11), 1606; https://doi.org/10.3390/ph18111606 - 23 Oct 2025

Abstract

Background/Objectives: Naegleria fowleri is a free-living protozoan that causes primary amoebic meningoencephalitis, a rapidly progressing central nervous system infection with high mortality rates and limited treatment options. Targeting virulence-associated proteins is essential for effective drug development. Fowlerpain-1 (FWP1), a papain-like cysteine protease [...] Read more.

Background/Objectives: Naegleria fowleri is a free-living protozoan that causes primary amoebic meningoencephalitis, a rapidly progressing central nervous system infection with high mortality rates and limited treatment options. Targeting virulence-associated proteins is essential for effective drug development. Fowlerpain-1 (FWP1), a papain-like cysteine protease (CP) implicated in extracellular matrix degradation and host–cell cytotoxicity, has been investigated as a therapeutic target. This study aimed to evaluate the FWP1 pocket geometry and stefin binding using an integrated in silico structural biology approach. Methods: A computational pipeline was used, including AlphaFold2-Multimer modeling of FWP1–stefin complexes, 20-ns molecular dynamics simulations under NPT conditions for conformational sampling, and molecular mechanics Poisson–Boltzmann surface area free energy calculations. Three natural CP inhibitors (stefins) were investigated. Structural stability was assessed using root mean square deviations, and binding profiles were characterized using protein–protein interaction analysis. Results: Stable FWP1–stefin interaction interfaces were predicted, with human stefin A showing favorable binding free energy. Two conserved motifs (PG and QVVAG) were identified as critical mediators of active-site recognition. Druggability analysis revealed a concave pocket with both hydrophobic and polar characteristics, consistent with a high-affinity ligand-binding site. Conclusions: This computational study supports a structural hypothesis for selective FWP1 inhibition and identifies stefins as promising scaffolds for developing structure-guided protease-targeted therapeutics against N. fowleri. Full article

(This article belongs to the Special Issue Recent Advancements in the Development of Antiprotozoal Agents)

► Show Figures

Figure 1

33 pages, 1907 KB

Open AccessReview

Topical β-Caryophyllene for Dermatologic Disorders: Mechanisms, Human Evidence, and Clinical Translation

by Amina M. Bagher

Pharmaceuticals 2025, 18(11), 1605; https://doi.org/10.3390/ph18111605 - 23 Oct 2025

Abstract

Background: Chronic inflammatory skin disorders, including atopic dermatitis, psoriasis, acne, and chronic wounds, affect nearly two billion people worldwide, impose substantial morbidity and economic burden, and remain only partially controlled by existing therapies. The cutaneous endocannabinoid system (ECS), comprising cannabinoid receptors, endocannabinoids, and [...] Read more.

Background: Chronic inflammatory skin disorders, including atopic dermatitis, psoriasis, acne, and chronic wounds, affect nearly two billion people worldwide, impose substantial morbidity and economic burden, and remain only partially controlled by existing therapies. The cutaneous endocannabinoid system (ECS), comprising cannabinoid receptors, endocannabinoids, and their metabolic enzymes, regulates inflammation, pruritus, barrier integrity, and tissue repair; cannabinoid receptor type 2 (CB₂) has emerged as a particularly relevant target. β-Caryophyllene (BCP), a dietary sesquiterpene and highly selective CB₂ agonist with favorable safety and pharmacokinetic attributes, has attracted attention as a promising topical candidate. Methods: We systematically searched PubMed, Embase, and Web of Science (inception–30 July 2025) for studies on “β-caryophyllene” and dermatological outcomes, prioritizing purified BCP and analytically characterized BCP-rich fractions. Quantitative parameters, including tested concentration ranges (0.5 µM–10%) and principal mechanistic outcomes, were extracted to provide a translational context. Results: BCP penetrates the stratum corneum, suppresses NF-κB/MAPK and IL-4/TSLP pathways, enhances Nrf2-driven antioxidant defenses, and accelerates re-epithelialization and collagen remodeling. Across in vitro, in vivo, and formulation studies, BCP produced consistent anti-inflammatory and barrier-restorative effects within this concentration range. CB₂ antagonism attenuated these responses, confirming receptor specificity. BCP’s volatility and autoxidation to β-caryophyllene oxide (BCPO) necessitate stability-by-design strategies using antioxidants, low-oxygen processing, and protective packaging. Human evidence, limited to BCP-rich botanicals such as Copaifera oleoresins, suggests benefits for scars, wounds, and acne but lacks compound-specific validation. Conclusions: BCP exhibits coherent CB₂-mediated anti-inflammatory, antipruritic, antioxidant, and reparative actions with a favorable safety profile. Dose-defined, oxidation-controlled clinical trials of purified BCP are warranted to establish its potential as a steroid-sparing topical therapy. 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, 2nd Edition)

► Show Figures

Graphical abstract

21 pages, 325 KB

Open AccessReview

Emerging Strategies for the Prevention of Chemotherapy-Induced Cardiotoxicity in Paediatric Cancer Patients: Advances and Future Perspectives

by Alice Pozza, Angela Di Candia, Luca Zanella, Emil Joly Stefors, Elena Bennati, Camilla Somigli, Elena Poli, Emmanuelle Fournier, Raphael Joye, Rossella Mura, Franca Fagioli and Nicoletta Bertorello

Pharmaceuticals 2025, 18(11), 1604; https://doi.org/10.3390/ph18111604 - 23 Oct 2025

Abstract

Chemotherapy-induced cardiotoxicity (CIC) represents a major long-term complication in paediatric oncology patients, with conventional cardioprotective agents providing only limited efficacy. As survival rates improve, preserving cardiac function has become essential for ensuring quality of life in childhood cancer survivors (CCS). A multi-modal approach [...] Read more.

Chemotherapy-induced cardiotoxicity (CIC) represents a major long-term complication in paediatric oncology patients, with conventional cardioprotective agents providing only limited efficacy. As survival rates improve, preserving cardiac function has become essential for ensuring quality of life in childhood cancer survivors (CCS). A multi-modal approach combining pharmacological agents, gene- and RNA-based technologies, cell therapies, and immune modulation holds great potential for long-term cardiac preservation. As paediatric-specific research advances, successful integration of these emerging strategies into standard care will require multidisciplinary collaboration, long-term monitoring, and ethical safeguards tailored to children. This narrative review aims to provide a comprehensive overview of both established and novel strategies for preventing or reducing CIC in paediatric cancer patients, critically examining recent progress, assessing their efficacy and safety, and outlining key priorities for future research and clinical application. Full article

(This article belongs to the Special Issue Emerging Therapeutics for the Prevention of Chemotherapy-Induced Cardiotoxicity: Advances and Future Perspectives)

► Show Figures

Graphical abstract

14 pages, 2654 KB

Open AccessArticle

Screening Novel Furoxan Derivatives as Potential Inhibitors Targeting Thioredoxin Glutathione Reductase of Fasciola gigantica

by Yanhui Han, Yuting He, Qingqing Guo, Gongming Li, Huan Chen, Wenjiao Zhao, Yan Zhou, Zhiqiang Fu, Oyetunde T. Oyeyemi, Huili Zhu, Qiangqiang Wang, Dequn Sun and Yang Hong

Pharmaceuticals 2025, 18(11), 1603; https://doi.org/10.3390/ph18111603 - 23 Oct 2025

Abstract

Background: Fascioliasis, caused by Fasciola species, is a significant public health concern affecting over 250 million people globally and causing annual economic losses exceeding USD 6 billion. The sole FDA-approved treatment, triclabendazole (TCZ), faces increasing resistance due to extensive use, highlighting the urgent [...] Read more.

Background: Fascioliasis, caused by Fasciola species, is a significant public health concern affecting over 250 million people globally and causing annual economic losses exceeding USD 6 billion. The sole FDA-approved treatment, triclabendazole (TCZ), faces increasing resistance due to extensive use, highlighting the urgent need for alternative therapeutic targets. A promising candidate is thioredoxin glutathione reductase (TGR), a multifunctional enzyme unique to platyhelminths, essential for redox balance and parasite survival. Methods: This study investigated the antioxidant and enzymatic activities of recombinant Fasciola gigantica TGR (FgTGR), its localization within the parasite, and its inhibition by furoxan derivatives. FgTGRsec (FgTGR containing selenocysteine) was expressed and purified, and its enzymatic activities, including thioredoxin reductase (TrxR), glutathione reductase (GR), and glutaredoxin (Grx), were characterized. Results: Immunolocalization studies revealed FgTGR’s presence in critical tissues, underscoring its functional significance. Antioxidant assays demonstrated the protein’s role in protecting against oxidative damage. Inhibition assays with furoxan derivatives identified potential inhibitors targeting TGR activity. Sequence and phylogenetic analyses showed FgTGR’s evolutionary conservation among trematodes, confirming its potential as a drug target. Conclusions: The study’s findings establish FgTGR as a critical enzyme for parasite survival and a promising target for developing novel therapeutics. These results pave the way for the further screening and optimization of TGR inhibitors, offering a strategic approach to overcoming TCZ resistance and improving fascioliasis control. Full article

(This article belongs to the Section Medicinal Chemistry)

► Show Figures

Figure 1

4 pages, 140 KB

Open AccessEditorial

Recent Advances in Psychopharmacology

by Roos van Westrhenen and Allan H. Young

Pharmaceuticals 2025, 18(11), 1602; https://doi.org/10.3390/ph18111602 - 23 Oct 2025

Abstract

Delivering clinical trials is a challenge, most notably due to recruitment, especially among individuals with psychiatric disorders [...] Full article

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

20 pages, 1246 KB

Open AccessReview

Fluid Therapy in Acute Pancreatitis—Current Knowledge and Future Perspectives

by Miłosz Caban, Hubert Zatorski and Ewa Małecka-Wojciesko

Pharmaceuticals 2025, 18(11), 1601; https://doi.org/10.3390/ph18111601 - 23 Oct 2025

Viewed by 20

Abstract

Acute pancreatitis (AP) is one of the most frequent diseases requiring hospitalization in gastroenterology or intensive care unit departments. Its incidence and hospitalization rates have steadily increased over the last few years, contributing to high costs of medical care. This disease is associated [...] Read more.

Acute pancreatitis (AP) is one of the most frequent diseases requiring hospitalization in gastroenterology or intensive care unit departments. Its incidence and hospitalization rates have steadily increased over the last few years, contributing to high costs of medical care. This disease is associated with relevant mortality and morbidity rates. Fluid therapy in the first 48–72 h has an important role in the clinical course and complications; however, it has been raising numerous controversies recently. We present a review article summarizing the current knowledge about fluid therapy in AP. The demonstrated results are based on the most recent clinical studies published in the last five years. Data confirms that the therapy should be individualized along with the amount of fluids adapted to body mass, concomitant diseases, critical signs, and laboratory markers. A relevant issue in the context of fluid therapy of AP is fluid resuscitation that should be implemented in some patients upon hospital admission to maintain organ perfusion and substrate delivery. Ringer’s lactate should be preferred in the vast majority of AP cases over normal saline solution. Its use is associated with lowered risk of intensive care unit admission and local complications development, reduced hospital stay, and decreased mortality. Colloids, mainly hydroxyethyl starch, should not be recommended. Moderate-rate fluid infusion seems to be an advantage over high-rate infusion. Relying on presented results, fluid therapy has a key therapeutic role in AP management. Full article

(This article belongs to the Special Issue New and Emerging Treatment Strategies for Gastrointestinal Diseases)

► Show Figures

Figure 1

25 pages, 4241 KB

Open AccessArticle

VDAC1 Intervention Alleviates Bisphenol AF-Induced Succinate Metabolism Dysregulation and Inflammatory Responses

by Xinyu Hong, Ning Wang, Jing Leng, Jing Xu, Kelei Qian, Zhiqing Zheng, Gonghua Tao and Ping Xiao

Pharmaceuticals 2025, 18(11), 1600; https://doi.org/10.3390/ph18111600 - 22 Oct 2025

Viewed by 169

Abstract

Background/Objectives: Bisphenol AF (BPAF) is a prevalent environmental contaminant with demonstrated metabolic and immunological toxicity. This study aimed to investigate whether VDAC1 (Voltage-Dependent Anion Channel 1) mediates BPAF-induced succinate dysmetabolism and inflammatory responses in macrophages, and to evaluate the therapeutic potential of [...] Read more.

Background/Objectives: Bisphenol AF (BPAF) is a prevalent environmental contaminant with demonstrated metabolic and immunological toxicity. This study aimed to investigate whether VDAC1 (Voltage-Dependent Anion Channel 1) mediates BPAF-induced succinate dysmetabolism and inflammatory responses in macrophages, and to evaluate the therapeutic potential of VDAC1 silencing. Methods: RAW264.7 macrophages were exposed to BPAF (0–2500 nM, 24 h) with or without VDAC1 siRNA transfection. Succinate levels, SDH activity, mitochondrial function (complexes I–V, ATP, membrane potential), and inflammatory markers (TNF-α, IL-6, IL-1β, ROS, MDA) were quantified. A 90-day oral toxicity study in C57BL/6J mice (0–32 mg kg⁻¹) assessed systemic inflammation and hepatic ultrastructure. p38 MAPK/NF-κB signaling was evaluated by Western blot and immunofluorescence. Results: BPAF elevated succinate 2.3-fold and decreased SDH activity by 48%, coinciding with reduced mitochondrial membrane potential and ATP synthesis (p < 0.01). Inflammatory cytokines and ROS were markedly increased. VDAC1 siRNA reversed these perturbations, restored complex II activity, and blunted p38 MAPK/NF-κB activation. In vivo, BPAF dose-dependently increased serum TNF-α, IL-6 and IL-1β, promoted NF-κB nuclear translocation and mitochondrial swelling, without altering body or liver weight; VDAC1 knockdown mitigated these effects. Conclusions: VDAC1 orchestrates BPAF-elicited succinate accumulation and macrophage inflammation via p38 MAPK/NF-κB signaling. Targeted VDAC1 silencing alleviates metabolic and inflammatory injury, offering a promising therapeutic strategy against BPAF-related diseases. Full article

(This article belongs to the Special Issue Dysregulation of Cyclic AMP and Cyclic PIP Synthesis: Implications for Disease and Advances in Therapeutic Development)

► Show Figures

Figure 1

28 pages, 4904 KB

Open AccessArticle

Synthesis of Novel Chloro-Benzo [d]imidazole Regioisomers as Selective CB₂ Receptor Agonists: Indirect Functional Evaluation and Molecular Insights

by Valeria Zuñiga Salazar, Renato Burgos Ravanal, Jonathan Soto-Flores, Gianfranco Sabadini, José Vicente González, Jaime Mella and Javier Romero-Parra

Pharmaceuticals 2025, 18(11), 1599; https://doi.org/10.3390/ph18111599 - 22 Oct 2025

Viewed by 111

Abstract

Background/Objectives: The cannabinoid type 2 receptor (CB₂ receptor) has been extensively studied in recent years due to the benefits associated with its modulation, including the regulation of the inflammatory response, neuroimmunomodulatory properties, and antitumor effects, all with the advantage of lacking significant [...] Read more.

Background/Objectives: The cannabinoid type 2 receptor (CB₂ receptor) has been extensively studied in recent years due to the benefits associated with its modulation, including the regulation of the inflammatory response, neuroimmunomodulatory properties, and antitumor effects, all with the advantage of lacking significant psychoactive effects. Herein, we report the design, synthesis, characterization, biological assays, and molecular modelling analyses of novel (5/6-chloro-2-aryl-1H-benzo [d]imidazol-1-yl)(4-methoxyphenyl)methanone and 5/6-chloro-1-(4-methoxybenzyl)-2-aryl-1H-benzo [d]imidazole regioisomers as potential cannabinoid type 2 receptor ligands. Methods: The compounds were evaluated for their presumed CB₂ agonist activity using an indirect receptor-dependent apoptotic cell death assay exerted by cannabinoids, using the cell lines HEK293 (low CB₁/CB₂ expression), U-87 MG (high CB₁ expression), and HL-60 (exclusive CB₂ expression), and including the known cannabinoid ligands WIN-55,212-2 and AM630 as reference ligands. Flow cytometry was performed to assess apoptosis. Molecular docking and molecular dynamics simulations were used to explore ligand-receptor interactions at the CB₂ active site. Results: Compounds 3a, 3b’, 3c, and 4b selectively reduced HL-60 cell viability, similar to WIN-55,212-2, while showing no toxicity toward HEK293 or U-87 MG cells. Flow cytometry indicated that compounds 3a and 3c induced apoptosis in HL-60 cells comparable to WIN-55,212-2. Computational studies suggested that both compounds bind within the CB₂ receptor active site predominantly through π–π and hydrophobic interactions involving their benzo [d]imidazole cores, 2-aryl moieties, and 4-methoxybenzoyl scaffolds, resembling the binding patterns of established CB₂ ligands. Conclusions: Compounds 3a and 3c exert selective cytotoxicity against HL-60 cells, likely via a CB₂ agonist-mediated apoptotic mechanism. The applied combined experimental and computational approach provides a rapid, informative strategy for preliminary evaluation of CB₂ ligands and guides subsequent detailed pharmacological studies. Full article

(This article belongs to the Section Medicinal Chemistry)

► Show Figures

Graphical abstract

26 pages, 7000 KB

Open AccessArticle

Synthesis and Anticancer Activity Evaluation of New 5-((5-Nitrofuran-2-yl)allylidene)-2-thioxo-4-thiazolidinones

by Magdalena Podolak, Volodymyr Horishny, Rostyslav Dudchak, Agnieszka Gornowicz, Robert Czarnomysy, Dmytro Mural, Serhii Holota, Krzysztof Bielawski, Roman Lesyk and Anna Bielawska

Pharmaceuticals 2025, 18(11), 1598; https://doi.org/10.3390/ph18111598 - 22 Oct 2025

Viewed by 155

Abstract

Background/Objectives: Cancer persists as a leading concern in the current medical field. As such, scientists are continuously researching new compounds with anticancer potential. In this study, we explored fifteen new 4-thiazolidinone derivatives as potential anticancer compounds. 4-Thiazolidinones are a well-established group of [...] Read more.

Background/Objectives: Cancer persists as a leading concern in the current medical field. As such, scientists are continuously researching new compounds with anticancer potential. In this study, we explored fifteen new 4-thiazolidinone derivatives as potential anticancer compounds. 4-Thiazolidinones are a well-established group of active structures, most commonly applied for the treatment of Parkinson’s disease and diabetic neuropathy. However, they are actively researched as potential anticancer agents. A number of derivatives have qualified for Phase II and III clinical trials as antitumor agents. Methods: MTT cytotoxicity assay was applied to identify the most active compounds. Three out of the fifteen tested structures displayed a significant inhibitory effect on the MCF-7 and MDA-MB-231 cell lines. To further investigate the influence of compounds on breast cancer cells, we analyzed their capability to induce apoptosis using flow cytometry assessment with Annexin V and propidium iodide dyes. Next, flow cytometry analysis of JC-1 dye was utilized to research their capability to affect mitochondrial membrane. Afterwards, concentrations of important proapoptotic proteins such as Bax and cytochrome C were assessed with a highly sensitive ELISA method. Results: Further analysis with a fluorescent microscope displayed that novel compounds significantly increase the generation of reactive oxygen species. Conclusions: The results represented in this article displayed that the most active compounds positively affected the activation of the intrinsic apoptotic pathway in the tested breast cancer cells. Full article

(This article belongs to the Section Medicinal Chemistry)

► Show Figures

Graphical abstract

15 pages, 2092 KB

Open AccessArticle

A Chlorhexidine Nanocarrier Strategy to Combat Oral Candidiasis Microcosm Biofilms

by Leandro Pimentel Cabral, Juliano Pelim Pessan, Caio Sampaio, Rosana Leal do Prado, Thayse Yumi Hosida, Celso Koogi Sonoda and Douglas Roberto Monteiro

Pharmaceuticals 2025, 18(11), 1597; https://doi.org/10.3390/ph18111597 - 22 Oct 2025

Viewed by 148

Abstract

Background/Objectives: Nanotherapies are a strategy to combat Candida resistance. This study analyzed the impacts of iron oxide nanoparticles (IONPs) functionalized with a chitosan (CS) layer acting as carriers of chlorhexidine (CHX) on an oral candidiasis microcosm biofilm. Methods: Saliva samples from [...] Read more.

Background/Objectives: Nanotherapies are a strategy to combat Candida resistance. This study analyzed the impacts of iron oxide nanoparticles (IONPs) functionalized with a chitosan (CS) layer acting as carriers of chlorhexidine (CHX) on an oral candidiasis microcosm biofilm. Methods: Saliva samples from three healthy donors were used to form biofilms, to which Candida species were added to reproduce an oral candidiasis microcosm. Biofilms were cultivated for 72 h on glass coverslips using an active adhesion model. Biofilms without Candida served as a control model. The nanocarrier loaded with CHX at 78 (IONPs-CS-CHX78) or 156 µg/mL (IONPs-CS-CHX156) was co-incubated with the biofilms for 24 h. Controls included isolated IONPs, CS, and CHX, in addition to an untreated group (NC). Assays for biomass production, metabolism, microbial load, and lactic acid production were conducted to assess antibiofilm effects. Biofilm structure, viability, and thickness were also examined by confocal microscopy. Statistical analysis was performed using one-way ANOVA or Kruskal–Wallis, subsequently accompanied by the Student–Newman–Keuls post hoc test (p < 0.05). Results: CHX and IONPs-CS-CHX156 were the most effective agents against all tested biofilm models, significantly reducing metabolism, microbial load (bacterial and fungal), and viability. For the oral candidiasis biofilm, the nanocarrier did not affect biomass or biofilm thickness but led to a significant increase in lactic acid levels compared to NC. Conclusions: It is concluded that the nanocarrier of CHX exhibits a significant reducing effect on oral candidiasis microcosm biofilms at half the concentration required for non-carried CHX. This nanostructure can be explored in the development of antiseptic or disinfectant solutions for managing oral candidiasis. Full article

(This article belongs to the Section Pharmaceutical Technology)

► Show Figures

Graphical abstract

20 pages, 4371 KB

Open AccessArticle

Inhibitory Effects of Syringic Acid on Endometrial Cancer Cell Growth and Migration and Its Synergistic Suppression with Doxorubicin

by Yi-Ting Kuo, Chi-Chang Chang, Yu Chang, Chin-Feng Hsuan, Tzu-Hsien Chang, Ya-Ling Chen, Hsin-Ya Houng, Yu-Chieh Su and Jer-Yiing Houng

Pharmaceuticals 2025, 18(11), 1596; https://doi.org/10.3390/ph18111596 - 22 Oct 2025

Viewed by 125

Abstract

Background/Objectives: Endometrial cancer (EC), a malignancy arising from the uterine lining, is a leading gynecological cancer in developed countries. Syringic acid (SA), a naturally occurring phenolic compound, possesses various bioactivities including antioxidant, anti-inflammatory, chemoprotective, and anti-angiogenic properties. This study aimed to investigate [...] Read more.

Background/Objectives: Endometrial cancer (EC), a malignancy arising from the uterine lining, is a leading gynecological cancer in developed countries. Syringic acid (SA), a naturally occurring phenolic compound, possesses various bioactivities including antioxidant, anti-inflammatory, chemoprotective, and anti-angiogenic properties. This study aimed to investigate the effects of SA on the proliferation and migration of RL95-2 EC cells, its protective role in normal endometrial stromal cells (HESCs), and the underlying molecular mechanisms. Furthermore, the potential synergistic anticancer effects of SA in combination with chemotherapeutic agents against EC were evaluated. Methods: Cell viability was assessed using nuclear fluorescence staining, the MTT assay, and clonogenic survival assay. Cell migration was evaluated through wound closure and Transwell migration assays. Gene expression levels were analyzed by the RT-PCR method. Results: SA significantly inhibited the proliferation of RL95-2 EC cells, with an IC₅₀ value of 27.22 μM. Co-treatment with SA and the chemotherapeutic agent doxorubicin (Dox) demonstrated an additive inhibitory effect. Mechanistically, both SA and the SA-Dox combination induced apoptosis by upregulating the expression of caspases-3, -8, and -9, increasing the expression of pro-apoptotic genes (Bax and Bad), and downregulating anti-apoptotic genes (Bcl-XL and Bcl-2). Cell cycle analysis revealed the downregulation of cyclin D and the upregulation of tumor suppressors p21 and p27, contributing to growth arrest. In addition, both SA and the combination treatment effectively suppressed cell migration by downregulating matrix metalloproteinases (MMPs) and β-catenin. SA treatment also induced the expression of pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) and activated NF-κB signaling, leading to an elevated expression of inflammatory mediators such as COX-2 and iNOS. Furthermore, SA promoted oxidative stress in RL95-2 cells by inhibiting the Nrf2 pathway and reducing the expression and activities of antioxidant enzymes including catalase, glutathione peroxidase, and superoxide dismutase, thereby enhancing reactive oxygen species (ROS) accumulation. In contrast, in lipopolysaccharide-stimulated HESC cells, SA attenuated inflammation and ROS generation, indicating its selective cytoprotective role in normal endometrial cells. Conclusions: SA may serve as a promising adjuvant candidate to enhance chemotherapeutic efficacy while protecting normal cells by mitigating inflammation and oxidative stress. Full article

(This article belongs to the Topic Advances in Anti-Cancer Drugs: 2nd Edition)

► Show Figures

Graphical abstract

19 pages, 4823 KB

Open AccessArticle

From Bench to Bioactivity: An Integrated Medicinal Development Based on Kinetic and Simulation Assessment of Pyrazolone-Oxadiazole Coupled Benzamide as Promising Inhibitors of Diabetes Mellitus

by Manal M. Khowdiary and Shifa Felemban

Pharmaceuticals 2025, 18(11), 1595; https://doi.org/10.3390/ph18111595 - 22 Oct 2025

Viewed by 162

Abstract

Background: In this research work, novel pyrazolone-derived oxadiazole-based benzamide derivatives (1–10) were synthesized through unique and facile synthetic routes. Introduction: These scaffolds were designed to be therapeutically more effective and have fewer side effects. Methods: To confirm the structure of analogs [...] Read more.

Background: In this research work, novel pyrazolone-derived oxadiazole-based benzamide derivatives (1–10) were synthesized through unique and facile synthetic routes. Introduction: These scaffolds were designed to be therapeutically more effective and have fewer side effects. Methods: To confirm the structure of analogs in detail, we employed ¹HNMR, ¹³CNMR, and HREI-MS spectroscopy. The potential of all derivatives was tested by screening them against alpha-amylase and alpha-glucosidase in comparison with reference anti-diabetic drug acarbose (4.50 ± 0.20 µM and 4.90 ± 0.30 µM). Results & Discussion: Among all tested analogs and standard drugs, derivative 3 proved to be the most promising candidate. It exhibited the most powerful inhibitory effect (IC₅₀ = 3.20 ± 0.20 µM and 3.60 ± 0.10 µM). To further investigate its activity, the experimental results were supported by in silico investigations. Molecular docking demonstrated strong and viable interactions between enzymes and the most potent compound. DFT calculations validated the electronic configuration, stability, and reactivity of lead molecules. Furthermore, the ADMET profile predicted the favorable drug likeness properties and low toxicity. The results of docking were further confirmed via molecular dynamics analysis, whereas the pharmacophore model of analog 3 supports the formation of a stable hydrogen bond network of derivatives with the receptor site of the enzyme. Conclusions: Collectively in silico and in vitro results underscore the therapeutic potential of these derivatives for the effective treatment of diabetes in the future. Full article

(This article belongs to the Section Medicinal Chemistry)

► Show Figures