Pharmaceuticals

22 pages, 4768 KB

Open AccessArticle

Interactions of Linalool and Linalyl Acetate with Selected Dog Cytochrome P450 (CYP) Proteins Identified by In Silico Drug Discovery Followed by Molecular Docking Analysis

by Raquel Rodrigues Soares-Santos, Arun Kumar Jaiswal, Renata Cristina Mendes Ferreira, Vasco Ariston de Carvalho Azevedo, Flávia Figueira Aburjaile and Benito Soto-Blanco

Pharmaceuticals 2025, 18(10), 1499; https://doi.org/10.3390/ph18101499 - 6 Oct 2025

Abstract

Background: Cytochrome P450 (CYP450) enzymes play a central role in the metabolism of xenobiotics, including plant-derived compounds such as terpenoids. Objectives: This study aimed to predict the molecular interactions of linalool (LIN) and linalyl acetate (LINAct), major constituents of lavender essential oil, [...] Read more.

Background: Cytochrome P450 (CYP450) enzymes play a central role in the metabolism of xenobiotics, including plant-derived compounds such as terpenoids. Objectives: This study aimed to predict the molecular interactions of linalool (LIN) and linalyl acetate (LINAct), major constituents of lavender essential oil, with the canine CYP2B11, CYP2C21, and CYP2D15 isoforms, using in silico approaches. Methods: Three-dimensional (3D) models of the target enzymes were generated through homology modeling using SWISS-MODEL and validated based on global model quality estimate (GMQE) and QMEAN Z-score metrics. Ligand structures were optimized in the Molecular Operating Environment (MOE), and pharmacophoric features were analyzed. Molecular docking simulations were performed using AutoDock Vina, followed by visualization of interactions in MOE. Results: LIN and LINAct exhibit favorable binding affinities with all three isoforms, suggesting their potential as substrates or modulators. Hydrogen bonding and hydrophobic interactions were the predominant forces stabilizing the ligand–enzyme complexes. Conclusions: These findings provide a computational basis for understanding the hepatic metabolism of LIN and LINAct in dogs, offering preliminary insights into the role of specific CYP isoforms in their biotransformation. Full article

(This article belongs to the Special Issue Computational (In Silico) Approaches for Drug Target Discovery and Disposition)

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15 pages, 2015 KB

Open AccessCommunication

Combined Effect of Size and Charge on the Interaction of Nanoparticles with Mucus-Mimicking Mucin Hydrogels

by Natalia N. Porfiryeva, Ivan Zlotver and Alejandro Sosnik

Pharmaceuticals 2025, 18(10), 1498; https://doi.org/10.3390/ph18101498 - 5 Oct 2025

Abstract

Background/Objectives: Understanding the interactions between nanoparticles and mucosal tissues is crucial for the development of advanced drug delivery systems, as the diffusion behavior of nanoparticles through mucus is strongly influenced by their size and surface properties, and the viscoelastic nature of the hydrogel [...] Read more.

Background/Objectives: Understanding the interactions between nanoparticles and mucosal tissues is crucial for the development of advanced drug delivery systems, as the diffusion behavior of nanoparticles through mucus is strongly influenced by their size and surface properties, and the viscoelastic nature of the hydrogel matrix. In this study, we investigated the impact of nanoparticle size, surface charge, and hydrogel crosslinking density on nanoparticle diffusion in a mucus model in vitro. Method: Citrate-stabilized and PEGylated 30 and 100 nm gold nanoparticles were used as a model of nanoparticle and their diffusion through mucus-mimicking mucin-based hydrogels of two different crosslinking densities was assessed. Results: Citrate-stabilized 30 nm nanoparticles demonstrated greater diffusion in hydrogels mimicking native mucus compared to more densely crosslinked ones, reaching approximately 50.3 ± 0.2% diffusion within the first 5 min of the assay. This size-dependent effect was not observed for the 100 nm citrate-stabilized nanoparticles, which showed limited diffusion in both hydrogel types. To confer different surface charge, gold nanoparticles were functionalized by the conjugation of poly(ethylene glycol) (PEG) derivatives of identical molecular weight with different terminal moieties (neutral, and positively and negatively charged) to modulate the surface charge and assess their interaction with the negatively charged mucin matrix. PEGylated particles exhibited significantly greater mobility than their citrate-stabilized counterparts, regardless of size or hydrogel density owing to the muco-penetration effect of PEG. Among PEGylated particles, the neutral and negatively charged 30 nm variants demonstrated higher diffusion than the positively charged ones due to weaker interactions with the negatively charged mucin hydrogel. For the 100 nm particles, the neutral PEGylated nanoparticles exhibited greater diffusion than their positively charged counterparts. Conclusions: Overall findings could provide valuable insights into the more rational design of nanoparticle-based drug delivery systems targeting mucosal tissues. Full article

(This article belongs to the Section Pharmaceutical Technology)

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26 pages, 1113 KB

Open AccessArticle

Folic Acid as a Molecule Protecting Cells from the Negative Effects of Ultraviolet Radiation—An In Vitro Study

by Magdalena Jurzak, Paweł Ramos, Barbara Pilawa and Ilona Anna Bednarek

Pharmaceuticals 2025, 18(10), 1497; https://doi.org/10.3390/ph18101497 - 5 Oct 2025

Abstract

Background: Folic acid (FA), also known as vitamin B9, functions as a co-factor in many cellular processes. Ultraviolet radiation (UV) has been shown to cause the formation of free radicals, and chronic exposure of the skin to UV radiation has been demonstrated to [...] Read more.

Background: Folic acid (FA), also known as vitamin B9, functions as a co-factor in many cellular processes. Ultraviolet radiation (UV) has been shown to cause the formation of free radicals, and chronic exposure of the skin to UV radiation has been demonstrated to result in many adverse effects. Skin protection against harmful environmental factors is one of the aims of cosmetic products. One such substance is folic acid. However, aqueous FA solutions decompose after exposure to UV radiation, and the decomposition products can exhibit variable pro/anti-oxidative roles depending on the cell type and its environment. Objectives: The objective of the present study was to demonstrate the effectiveness of folic acid as a UV-protective agent in vitro cell culture model. Methods: The experimental model comprised an in vitro culture of normal human fibroblasts derived from adult skin (NHDF-Ad). Paramagnetic electron resonance (EPR) was used to assess the interaction of folic acid with free radicals after exposure to UV radiation. RT-qPCR was utilized to evaluate the impact of ultraviolet (UV) radiation on the expression of selected cell cycle regulatory genes (CCND1, P53, BAX, and BCL-2) in vitro cultured fibroblasts that were protected by folic acid. Results: EPR studies revealed the antioxidant properties of folic acid. Free radical forms of folic acid are induced during UV irradiation. The strong effect of UV irradiation on interactions of folic acid with free radicals was observed. The interaction was found to be weaker for the irradiated samples. Molecular studies have demonstrated a decline in the BAX/BCL-2 ratio in cells that have been treated with folic acid and exposed to UV radiation in comparison to the BAX/BCL-2 ratio observed in cells that have been exposed exclusively to UV radiation and not treated with folic acid. Conclusions: Whilst molecular and EPR studies both confirm the effectiveness of folic acid as a UV-protective ingredient in cosmetics and pharmaceutical products, further research in this area is required. Full article

(This article belongs to the Section Biopharmaceuticals)

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15 pages, 2257 KB

Open AccessArticle

The Development and Characterization of Layered Pellets Containing a Combination of Amorphized Amlodipine Besylate and Hydrochlorothiazide Using a High-Shear Granulator

by Azza A. K. Mahmoud, Krisztina Ludasi, Dorina Gabriella Dobó, Dániel Sebők, Ákos Kukovecz, Viktória Hornok, Kadosa Sajdik, Tamás Szabó, Tamás Sovány, Géza Regdon, Jr. and Katalin Kristó

Pharmaceuticals 2025, 18(10), 1496; https://doi.org/10.3390/ph18101496 - 5 Oct 2025

Abstract

Background/Objective: The high-shear granulator is considered an effective piece of equipment for layering pelletization because it enhances drug amorphization and improves drug dissolution. This study aimed to apply a high-shear granulator to prepare layered pellets containing a combination of hydrochlorothiazide and amlodipine besylate [...] Read more.

Background/Objective: The high-shear granulator is considered an effective piece of equipment for layering pelletization because it enhances drug amorphization and improves drug dissolution. This study aimed to apply a high-shear granulator to prepare layered pellets containing a combination of hydrochlorothiazide and amlodipine besylate with improved physicochemical properties. Methods: Different molar ratios (2:1, 1:1, and 1:2) of the hydrochlorothiazide and amlodipine besylate mixture were deposited on the surface of the inert spheres of the microcrystalline cellulose (MCC) core by the mechanical effect of the high impeller speed. The resulting layered pellets were characterized using X-ray powder diffractometry (XRPD) and differential scanning calorimetry (DSC) to estimate the degree of the drug amorphization, and consequently a dissolution test was performed to determine the degree of the enhancement of the percentage of release. Additionally, micro-computed tomography (micro-CT) and a texture analyzer were used to determine the morphological characteristics and hardness of the resulting pellets, and then a stability study was performed. Results: On the basis of the micro-CT images, the MCC core was successfully loaded with a uniform layer of the drug combination at the pellet surface, which exhibited higher diameters than pure cellets. Furthermore, the drug combination in layered pellets was partially amorphized with a lower crystallinity percentage, a lower intensity, a broadening of the hydrochlorothiazide melting peak, and a higher cumulative release of both drugs with good stability, except pellets with a molar ratio of 1:2 that were recrystallized with a higher crystallinity percentage of 79.9%. Conclusions: Modifying the physical form and dissolution behavior of the hydrochlorothiazide and amlodipine besylate combination was achieved by single-step layering pelletization. Full article

(This article belongs to the Section Pharmaceutical Technology)

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17 pages, 1730 KB

Open AccessArticle

Surface-Modified Nanocarriers Encapsulating Brucine and Nigella Sativa Oil: A Novel Approach to Solid Tumor Therapy

by Heba S. Elsewedy and Tamer M. Shehata

Pharmaceuticals 2025, 18(10), 1495; https://doi.org/10.3390/ph18101495 - 4 Oct 2025

Abstract

Background: Using natural substances for cancer therapy has attracted considerable interest due to their safety and reduced systemic toxicity. Nigella sativa (NS) oil, a traditional natural oil rich in bioactive compounds, possesses significant therapeutic potential. Brucine (BR), an alkaloid, exhibits potent cytotoxicity against [...] Read more.

Background: Using natural substances for cancer therapy has attracted considerable interest due to their safety and reduced systemic toxicity. Nigella sativa (NS) oil, a traditional natural oil rich in bioactive compounds, possesses significant therapeutic potential. Brucine (BR), an alkaloid, exhibits potent cytotoxicity against various cancer cell lines; however, its poor selectivity and high systemic toxicity limit its clinical application. Objective: To overcome these challenges, this study aimed to enhance drug delivery and improve therapeutic efficacy. Method: A PEGylated nanoemulsion (NE) incorporating NS and BR was developed and characterized for particle size, size distribution, zeta potential, viscosity, and drug content. The in vitro release of BR was evaluated both with and without serum incubation. A quantitative amount of serum protein associated with the surface of the NE was estimated, and a hemolytic safety assay was carried out. Finally, an in vitro cytotoxicity study was conducted, and the in vivo anti-tumor effect of the developed PEGylated BR-loaded NE was evaluated and compared with its naked counterpart. Result: The developed PEGylated BR-loaded NE possessed favorable characteristics as a nanocarrier for parenteral administration, with a particle size of 188.5 nm, a zeta potential of −1.61, a viscosity of 3.4 cP, and 99% drug content uniformity. It released up to 60.4% of BR over 12 h, while only 18.4 µg/µmol of the total lipids were adsorbed on the surface of the formulation, compared with 54.5 µg/µmol for the naked counterpart. The PEGylated NE was safe, inducing less than 5% of hemolysis, and displayed substantial inhibition of MDA cell growth. Conclusions: The PEGylated NE achieved a significant reduction in tumor volume, suggesting that PEGylated NE may serve as a promising platform for enhancing anti-tumor activity. Full article

(This article belongs to the Section Pharmaceutical Technology)

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29 pages, 15230 KB

Open AccessArticle

Harpagide Confers Protection Against Acute Lung Injury Through Multi-Omics Dissection of Immune–Microenvironmental Crosstalk and Convergent Therapeutic Mechanisms

by Hong Wang, Jicheng Yang, Yusheng Zhang, Jie Wang, Shaoqi Song, Longhui Gao, Mei Liu, Zhiliang Chen and Xianyu Li

Pharmaceuticals 2025, 18(10), 1494; https://doi.org/10.3390/ph18101494 - 4 Oct 2025

Abstract

Background: Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), remain major causes of morbidity and mortality, yet no targeted pharmacological therapy is available. Excessive neutrophil and macrophage infiltration drives reactive oxygen species (ROS) production and cytokine release, leading [...] Read more.

Background: Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), remain major causes of morbidity and mortality, yet no targeted pharmacological therapy is available. Excessive neutrophil and macrophage infiltration drives reactive oxygen species (ROS) production and cytokine release, leading to alveolar–capillary barrier disruption and fatal respiratory failure. Methods: We applied an integrative multi-omics strategy combining single-cell transcriptomics, peripheral blood proteomics, and lung tissue proteomics in a lipopolysaccharide (LPS, 10 mg/kg)-induced mouse ALI model to identify key signaling pathways. Harpagide, an iridoid glycoside identified from our natural compound screen, was evaluated in vivo (40 and 80 mg/kg) and in vitro (0.1–1 mg/mL). Histopathology, oxidative stress markers (SOD, GSH, and MDA), cytokine levels (IL-6 and IL-1β), and signaling proteins (HIF-1α, p-PI3K, p-AKT, Nrf2, and HO-1) were quantitatively assessed. Direct target engagement was probed using surface plasmon resonance (SPR), the cellular thermal shift assay (CETSA), and 100 ns molecular dynamics (MD) simulations. Results: Multi-omics profiling revealed robust activation of HIF-1, PI3K/AKT, and glutathione-metabolism pathways following the LPS challenge, with HIF-1α, VEGFA, and AKT as core regulators. Harpagide treatment significantly reduced lung injury scores by ~45% (p < 0.01), collagen deposition by ~50%, and ROS accumulation by >60% relative to LPS (n = 6). The pro-inflammatory cytokines IL-6 and IL-1β were reduced by 55–70% at the protein level (p < 0.01). Harpagide dose-dependently suppressed HIF-1α and p-AKT expression while enhancing Nrf2 and HO-1 levels (p < 0.05). SPR confirmed direct binding of Harpagide to HIF-1α (KD = 8.73 µM), and the CETSA demonstrated enhanced thermal stability of HIF-1α. MD simulations revealed a stable binding conformation within the inhibitory/C-TAD region after 50 ns. Conclusions: This study reveals convergent immune–microenvironmental regulatory mechanisms across cellular and tissue levels in ALI and demonstrates the protective effects of Harpagide through multi-pathway modulation. These findings offer new insights into the pathogenesis of ALI and support the development of “one-drug, multilayer co-regulation” strategies for systemic inflammatory diseases. Full article

(This article belongs to the Section Pharmacology)

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23 pages, 5881 KB

Open AccessArticle

Bioactive Constituents and Antihypertensive Mechanisms of Zhengan Xifeng Decoction: Insights from Plasma UPLC–MS, Network Pharmacology and Molecular Dynamics Simulations

by Yu Wang, Yiyi Li, Zhuoying Lin, Niping Li, Qiuju Zhang, Shuangfang Liu, Meilong Si and Hua Jin

Pharmaceuticals 2025, 18(10), 1493; https://doi.org/10.3390/ph18101493 - 4 Oct 2025

Abstract

Background/Objectives: Hypertension is a global health challenge. Zhengan Xifeng Decoction (ZXD), a classical traditional Chinese medicine, has shown clinical efficacy against hypertension. This study aimed to identify the bioactive constituents of ZXD and elucidate its antihypertensive mechanisms by integrating plasma UPLC–MS (ultra-performance liquid [...] Read more.

Background/Objectives: Hypertension is a global health challenge. Zhengan Xifeng Decoction (ZXD), a classical traditional Chinese medicine, has shown clinical efficacy against hypertension. This study aimed to identify the bioactive constituents of ZXD and elucidate its antihypertensive mechanisms by integrating plasma UPLC–MS (ultra-performance liquid chromatography–mass spectrometry) analysis, network pharmacology, and molecular dynamics (MD) simulations. Methods: ZXD constituents and plasma-absorbed compounds were characterized by UPLC–MS. Putative targets (TCMSP, SwissTargetPrediction) were cross-referenced with hypertension targets (GeneCards, OMIM) and analyzed in a STRING protein–protein interaction network (Cytoscape) to define hub targets, followed by GO/KEGG enrichment. Selected protein–ligand complexes underwent docking, Prime MM-GBSA calculation, and MD validation. Results: A total of 72 absorbed components were identified, including 14 prototype compounds and 58 metabolites. Network pharmacology identified ten key bioactive compounds (e.g., liquiritigenin, isoliquiritigenin, and caffeic acid), 149 hypertension-related targets, and ten core targets such as SRC, PIK3CA, PIK3CB, EGFR, and IGF1R. Functional enrichment implicated cardiovascular, metabolic, and stress-response pathways in the antihypertensive effects of ZXD. Molecular docking demonstrated strong interactions between key compounds, including liquiritigenin, caffeic acid, and isoliquiritigenin, and core targets, supported by the MM-GBSA binding free energy estimation. Subsequent MD simulations confirmed the docking poses and validated the stability of the protein–ligand complexes over time. Conclusions: These findings provide mechanistic insights into the multi-component, multi-target, and multi-pathway therapeutic effects of ZXD, offering a scientific basis for its clinical use and potential guidance for future drug development in hypertension management. Full article

(This article belongs to the Section Pharmacology)

21 pages, 2466 KB

Open AccessArticle

Single-Cell Transcriptomics Reveals a Multi-Compartmental Cellular Cascade Underlying Elahere-Induced Ocular Toxicity in Rats

by Jialing Zhang, Meng Li, Yuxuan Yang, Peng Guo, Weiyu Li, Hongxin An, Yongfei Cui, Luyun Guo, Maoqin Duan, Ye Lu, Chuanfei Yu and Lan Wang

Pharmaceuticals 2025, 18(10), 1492; https://doi.org/10.3390/ph18101492 - 4 Oct 2025

Abstract

Background: Antibody-drug conjugates (ADCs) have ushered in a new era of precision oncology by combining the targeting specificity of monoclonal antibodies with the potent cytotoxicity of chemotherapeutic drugs. However, the cellular and molecular mechanisms underlying their dose-limiting ocular toxicity remain unclear. Elahere™, the [...] Read more.

Background: Antibody-drug conjugates (ADCs) have ushered in a new era of precision oncology by combining the targeting specificity of monoclonal antibodies with the potent cytotoxicity of chemotherapeutic drugs. However, the cellular and molecular mechanisms underlying their dose-limiting ocular toxicity remain unclear. Elahere™, the first FDA-approved ADC targeting folate receptor α (FRα), demonstrates remarkable efficacy in platinum-resistant ovarian cancer but causes keratitis and other ocular toxicities in some patients. Notably, FRα is not expressed in the corneal epithelium—the primary site of damage—highlighting the urgent need to elucidate its underlying mechanisms. The aim of this study was to identify the cell-type-specific molecular mechanisms underlying Elahere-induced ocular toxicity. Methods: Sprague-Dawley rats were treated with intravenous Elahere (20 mg/kg) or vehicle weekly for five weeks. Ocular toxicity was determined by clinical examination and histopathology. Corneal single-cell suspensions were analyzed using the BD Rhapsody single-cell RNA sequencing (scRNA-seq) platform. Bioinformatic analyses to characterize changes in corneal cell populations, gene expression, and signaling pathways included cell clustering, differential gene expression, pseudotime trajectory inference, and cell-cell interaction modeling. Results: scRNA-seq profiling of 47,606 corneal cells revealed significant damage to the ocular surface and corneal epithelia in the Elahere group. Twenty distinct cell types were identified. Elahere depleted myeloid immune cells; in particular, homeostatic gene expression was suppressed in phagocytic macrophages. Progenitor populations (limbal stem cells and basal cells) accumulated (e.g., a ~2.6-fold expansion of limbal stem cells), while terminally differentiated cells decreased in corneal epithelium, indicating differentiation blockade. Endothelial cells exhibited signs of injury and inflammation, including reduced angiogenic subtypes and heightened stress responses. Folate receptor alpha, the target of Elahere, was expressed in endothelial and stromal cells, potentially driving stromal cells toward a pro-fibrotic phenotype. Fc receptor genes were predominantly expressed in myeloid cells, suggesting a potential mechanism underlying their depletion. Conclusions: Elahere induces complex, multi-compartmental ocular toxicity characterized by initial perturbations in vascular endothelial and immune cell populations followed by the arrest of epithelial differentiation and stromal remodeling. These findings reveal a cascade of cellular disruptions and provide mechanistic insights into mitigating Elahere-associated ocular side effects. Full article

(This article belongs to the Section Biopharmaceuticals)

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24 pages, 2653 KB

Open AccessArticle

Assessment of Carrier-Free Metallacarboranes for Targeted Radiation Therapies PBFT and BNCT: Comparative Cellular Effects and Dosimetry Studies with [o-FESAN]⁻ in Breast Cancer Cells

by Salvatore Di Maria, Teresa Pinheiro, Luís Cerqueira Alves, Valeria Bitonto, Nicoletta Protti, Simonetta Geninatti Crich, Kai Nishimura, Hiroyuki Nakamura, António P. Matos, Catarina I. G. Pinto, Filipa Mendes, Francesc Teixidor, Clara Viñas and Fernanda Marques

Pharmaceuticals 2025, 18(10), 1491; https://doi.org/10.3390/ph18101491 - 3 Oct 2025

Abstract

Background: Ferrabis(dicarbollide) ([o-FESAN]⁻) in combination with proton–boron fusion therapy (PBFT) or boron neutron capture therapy (BNCT) are promising alternative radiation modalities for the treatment of breast cancer. The aim of this study was to explore the underlying effects of [...] Read more.

Background: Ferrabis(dicarbollide) ([o-FESAN]⁻) in combination with proton–boron fusion therapy (PBFT) or boron neutron capture therapy (BNCT) are promising alternative radiation modalities for the treatment of breast cancer. The aim of this study was to explore the underlying effects of [o-FESAN]⁻ radio enhancement on breast cancer cells in vitro and in vivo, and to perform comparative dosimetry calculations. Methods: The cellular effects on SKBR-3 and MDA-MB-231 breast cancer cells and MDA-MB-231 xenograft-bearing nude mice induced by carrier-free [o-FESAN]⁻ after BNCT or PBFT were evaluated following recommended protocols. Monte Carlo (MC) dosimetry calculations were performed at the cellular scale for both radiation modalities. Results: Selective retention of [o-FESAN]⁻ within the cytoplasm and nucleus of SKBR-3 and MDA-MB-231 breast cancer cells is demonstrated. Moreover, in vivo studies with MDA-MB-231 xenograft-bearing nude mice show appreciable accumulation of [o-FESAN]⁻ in the tumor. Both radiation modalities induce loss of cellular viability and survival. Comparative dosimetry studies between proton and neutron irradiation agree with the viability data, showing a good correlation between absorbed dose vs. cellular effects. In the case of PBFT, cell structural changes are likely due to necrosis caused by the production of reactive oxygen species (ROS). To explain the radio enhancement effects in more detail, other mechanisms should be taken into consideration. Conclusions: Our results validate the effectiveness of both PBFT and BNCT therapeutic modalities, warranting further studies on carrier-free [o-FESAN]⁻ as a candidate drug for potential clinical translation of radio enhancers in binary radiation therapies. Full article

(This article belongs to the Section Radiopharmaceutical Sciences)

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14 pages, 1893 KB

Open AccessArticle

Anti-Photoaging Effects of a Standardized Hot Water Extract of Petasites japonicus Leaves in Ultraviolet B-Exposed Hairless Mice

by Hyeon-A Song, Min-Ji Park, Chae-Won Lee, Sangsu Park, Jong Kil Lee, Kyung-Sook Chung and Kyung-Tae Lee

Pharmaceuticals 2025, 18(10), 1490; https://doi.org/10.3390/ph18101490 - 3 Oct 2025

Abstract

Background: Ultraviolet B (UVB) radiation accelerates skin aging by inducing oxidative stress, collagen degradation, and cellular senescence. Although Petasites japonicus is known for its antioxidant properties, its anti-photoaging potential remains underexplored. This research explored the protective properties of a hot water extract from [...] Read more.

Background: Ultraviolet B (UVB) radiation accelerates skin aging by inducing oxidative stress, collagen degradation, and cellular senescence. Although Petasites japonicus is known for its antioxidant properties, its anti-photoaging potential remains underexplored. This research explored the protective properties of a hot water extract from P. japonicus leaves (KP-1) against photoaging caused by UVB exposure. Methods: Hairless mice were exposed to UVB three times per week and orally administered KP-1 for 13 weeks. Wrinkle formation, epidermal thickness, skin hydration, and collagen content were assessed. Protein expression related to MAPK/AP-1, TGF-β/Smad2/3, and p53/p21 pathways was analyzed by Western blotting. Results: KP-1 significantly reduced UVB-induced wrinkle area, epidermal and dermal thickening, and transepidermal water loss while restoring collagen density and skin hydration. KP-1 inhibited MMP-1 expression, enhanced COL1A1 levels, suppressed MAPK/AP-1 activation, and activated TGF-β/Smad2/3 signaling. It also balanced p53/p21 expression and restored cyclin D1 and CDK4 levels, thereby preventing UVB-induced senescence. Conclusions: The findings of this research revealed that KP-1 can serve as a promising natural substance for safeguarding the skin from damage and aging caused by UVB exposure. Full article

(This article belongs to the Topic Bioactive Phytochemicals from Plant Essential Oils and Extracts, 2nd Edition)

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16 pages, 1159 KB

Open AccessArticle

Computational Investigation of the Potential Antileishmanial Mechanism of the Nitroindazole Derivative VATR131

by Omar Casanova-Alvarez, Niurka Mollineda-Diogo, Aliuska Morales-Helguera, Vicente Arán-Redó, Reinaldo Molina-Ruiz, Norberto Sánchez-Cruz, Yendrek Velásquez-López and Yunierkis Perez-Castillo

Pharmaceuticals 2025, 18(10), 1489; https://doi.org/10.3390/ph18101489 - 3 Oct 2025

Abstract

Background: Neglected tropical diseases (NTDs) significantly impact global health, particularly affecting impoverished communities. Among these diseases, leishmaniasis, caused by protozoan parasites of the genus Leishmania and transmitted through sandfly vectors, remains a challenge due to limited therapeutic options. Current treatments often suffer from [...] Read more.

Background: Neglected tropical diseases (NTDs) significantly impact global health, particularly affecting impoverished communities. Among these diseases, leishmaniasis, caused by protozoan parasites of the genus Leishmania and transmitted through sandfly vectors, remains a challenge due to limited therapeutic options. Current treatments often suffer from significant limitations, such as high toxicity, limited efficacy, and the emergence of drug resistance. Objectives: This study investigates the potential antileishmanial mechanism of action of nitroindazole derivatives, specifically evaluating the compound VATR131, a molecule with notable selectivity and potency against Leishmania infantum. Methods: We employed computational methodologies, including target fishing, molecular docking, and atomistic molecular dynamics simulations, to identify and characterize potential molecular targets of VATR131. Results: The analysis revealed cysteine peptidase A as a promising target potentially mediating the antileishmanial activity of VATR131. Molecular dynamics simulations suggest critical hydrophobic interactions and hydrogen bonds between the compound and its most likely receptor, thus offering deeper insights into its potential mechanism of action. Conclusions: These findings contribute to the development of novel and effective therapies for leishmaniasis, highlighting the need for experimental validation and continued investigation of nitroindazole derivatives as promising therapeutic candidates. Full article

(This article belongs to the Special Issue Computational (In Silico) Approaches for Drug Target Discovery and Disposition)

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16 pages, 1152 KB

Open AccessArticle

Tacrolimus-Associated Tremor in Renal Transplant Patients: Potential Impact of the Galenic Formulation

by Jordi Rovira, Olga Millán, Pedro Ventura-Aguiar, Mercè Brunet and Fritz Diekmann

Pharmaceuticals 2025, 18(10), 1488; https://doi.org/10.3390/ph18101488 - 3 Oct 2025

Abstract

Background/Objectives: Tacrolimus is the most used immunosuppressive agent in solid organ transplantation due to its efficacy in preventing acute rejection, but it has a narrow therapeutic range, and overexposure often leads to toxicities, including neurological side effects like tremors. Tremor affects up to [...] Read more.

Background/Objectives: Tacrolimus is the most used immunosuppressive agent in solid organ transplantation due to its efficacy in preventing acute rejection, but it has a narrow therapeutic range, and overexposure often leads to toxicities, including neurological side effects like tremors. Tremor affects up to 54% of renal transplant patients under tacrolimus. Extended-release tacrolimus (LCPT) has demonstrated efficacy in reducing tremor severity, as evidenced by studies employing quality of life (QoL) questionnaires, the Fahn–Tolosa–Marin (FTM) scale, and Accelerometer devices. The objectives of this study were to evaluate the benefits of the conversion to LCPT formulation in kidney transplant recipients experiencing tremors on prolonged-release tacrolimus (PR-TAC) treatment and to validate the DyCare device, a wearable wireless sensor for tremors. Results: The DyCare device measured tremor frequencies of 8.74 ± 0.11 Hz and 1.36 ± 0.08° and 17.38 ± 1.16°, as root mean square (RMSx100 for accelerometer and Gyroscope, respectively) in PR-TAC patients. After switching ten patients to LCPT, tremor severity significantly decreased, as confirmed by DyCare and the QoL in the Essential Tremor Questionnaire (QUEST). Additionally, LCPT allowed a 34% reduction in tacrolimus dosage while maintaining therapeutic trough concentrations. Immunological and pharmacodynamic biomarkers (p-miR-210-3p, p-IL10, p-IL12p70, p-IFNγ uCXCL10, NFAT-regulated gene expression) confirmed stable immunosuppression post-conversion. Conclusions: The conversion to the LCPT formulation significantly reduced tremors in kidney transplant recipients without altering their immunological status, as confirmed through a panel of immunologic and pharmacodynamic biomarkers. The DyCare device enables a precise quantification of tremors in transplant recipients, allowing physicians to optimize treatment strategies. Full article

(This article belongs to the Section Pharmaceutical Technology)

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26 pages, 1645 KB

Open AccessReview

Mechanotransduction-Epigenetic Coupling in Pulmonary Regeneration: Multifunctional Bioscaffolds as Emerging Tools

by Jing Wang and Anmin Xu

Pharmaceuticals 2025, 18(10), 1487; https://doi.org/10.3390/ph18101487 - 2 Oct 2025

Abstract

Pulmonary fibrosis (PF) is a progressive and fatal lung disease characterized by irreversible alveolar destruction and pathological extracellular matrix (ECM) deposition. Currently approved agents (pirfenidone and nintedanib) slow functional decline but do not reverse established fibrosis or restore functional alveoli. Multifunctional bioscaffolds present [...] Read more.

Pulmonary fibrosis (PF) is a progressive and fatal lung disease characterized by irreversible alveolar destruction and pathological extracellular matrix (ECM) deposition. Currently approved agents (pirfenidone and nintedanib) slow functional decline but do not reverse established fibrosis or restore functional alveoli. Multifunctional bioscaffolds present a promising therapeutic strategy through targeted modulation of critical cellular processes, including proliferation, migration, and differentiation. This review synthesizes recent advances in scaffold-based interventions for PF, with a focus on their dual mechano-epigenetic regulatory functions. We delineate how scaffold properties (elastic modulus, stiffness gradients, dynamic mechanical cues) direct cell fate decisions via mechanotransduction pathways, exemplified by focal adhesion–cytoskeleton coupling. Critically, we highlight how pathological mechanical inputs establish and perpetuate self-reinforcing epigenetic barriers to regeneration through aberrant chromatin states. Furthermore, we examine scaffolds as platforms for precision epigenetic drug delivery, particularly controlled release of inhibitors targeting DNA methyltransferases (DNMTi) and histone deacetylases (HDACi) to disrupt this mechano-reinforced barrier. Evidence from PF murine models and ex vivo lung slice cultures demonstrate scaffold-mediated remodeling of the fibrotic niche, with key studies reporting substantial reductions in collagen deposition and significant increases in alveolar epithelial cell markers following intervention. These quantitative outcomes highlight enhanced alveolar epithelial plasticity and upregulating antifibrotic gene networks. Emerging integration of stimuli-responsive biomaterials, CRISPR/dCas9-based epigenetic editors, and AI-driven design to enhance scaffold functionality is discussed. Collectively, multifunctional bioscaffolds hold significant potential for clinical translation by uniquely co-targeting mechanotransduction and epigenetic reprogramming. Future work will need to resolve persistent challenges, including the erasure of pathological mechanical memory and precise spatiotemporal control of epigenetic modifiers in vivo, to unlock their full therapeutic potential. Full article

(This article belongs to the Section Pharmacology)

41 pages, 3113 KB

Open AccessReview

Flavonoid-Based Combination Therapies and Nano-Formulations: An Emerging Frontier in Breast Cancer Treatment

by Priyanka Uniyal, Ansab Akhtar and Ravi Rawat

Pharmaceuticals 2025, 18(10), 1486; https://doi.org/10.3390/ph18101486 - 2 Oct 2025

Abstract

Cancer has remained a major global health challenge, with around 20 million new cases and 9.7 million fatalities recorded each year. Even though there has been recent progress in therapies such as radiotherapy, chemotherapy, immunotherapy, and gene therapy, cancer remains a major treatment [...] Read more.

Cancer has remained a major global health challenge, with around 20 million new cases and 9.7 million fatalities recorded each year. Even though there has been recent progress in therapies such as radiotherapy, chemotherapy, immunotherapy, and gene therapy, cancer remains a major treatment challenge due to late diagnosis and difficulties in therapeutic effectiveness. Flavonoids, a substantial category of naturally occurring polyphenols, have received considerable interest in recent years for their potential involvement in cancer management and prevention, especially concerning breast cancer. These bioactive compounds, abundant in vegetables, fruits, and herbs, exhibit various therapeutic actions, including antioxidant, anti-inflammatory, and antimutagenic effects. The advanced therapeutic potential of flavonoids, when combined with FDA-approved medicines, offers synergistic effects and enhanced clinical results. Additionally, flavonoid-loaded nano-formulations, involving co-delivery systems, are being explored to increase solubility, stability, and bioavailability, enabling targeted delivery to cancer cells while reducing off-target adverse effects. This review examines the role of flavonoids in the prevention and management of breast cancer, focusing on their dietary sources, metabolism, and pharmacokinetic properties. Furthermore, we explore novel strategies, such as combination therapies with FDA-approved drugs and the application of flavonoid-based nanoformulations, which have the potential to enhance therapeutic outcomes. The clinical application of these strategies has the potential to improve breast cancer treatment and create new opportunities for the advancement of flavonoid-based therapies. Full article

(This article belongs to the Section Medicinal Chemistry)

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26 pages, 2925 KB

Open AccessArticle

Novel Dual 5-HT₇ Antagonists and Sodium Channel Inhibitors as Potential Therapeutic Agents with Antidepressant and Anxiolytic Activities

by Anna Czopek, Paulina Koczurkiewicz-Adamczyk, Katarzyna Wójcik-Pszczoła, Daria Kornas, Wojciech Sitko, Adam Bucki, Michał Sapa, Krzysztof Kamiński, Grzegorz Satała, Beata Duszyńska, Andrzej J. Bojarski, Gniewomir Latacz, Jacek Czopek, Joanna Szpor, Pola Dryja and Kinga Sałat

Pharmaceuticals 2025, 18(10), 1485; https://doi.org/10.3390/ph18101485 - 2 Oct 2025

Abstract

Background/Objectives: The study aimed to pharmacologically evaluate dually acting ligands, 5-HT₇ antagonists and sodium channel inhibitors, as potential therapeutic agents for the treatment of depression, anxiety, and neuropathic pain. The designed dual ligands combined structural fragments of LP-12 (a 5-HT₇ receptor [...] Read more.

Background/Objectives: The study aimed to pharmacologically evaluate dually acting ligands, 5-HT₇ antagonists and sodium channel inhibitors, as potential therapeutic agents for the treatment of depression, anxiety, and neuropathic pain. The designed dual ligands combined structural fragments of LP-12 (a 5-HT₇ receptor ligand) and phenytoin (a sodium channel blocker). Methods: A series of 1-(2-biphenyl)piperazine derivatives with a hydantoin core was synthesized and evaluated for 5-HT₇ receptor affinity and sodium channel inhibition. The most potent ligands were further analyzed using molecular docking, cytotoxicity assays (MTT, LDH), and in vitro metabolism studies, including microsomal stability and CYP450 inhibition. In vivo pharmacological effects were assessed in behavioral models: forced swim test, four-plate test, and a streptozotocin (STZ)-induced diabetic neuropathy model in mice. Results: Compounds 10 and 20 exhibited high 5-HT₇ receptor affinity (K_i < 10 nM) and potent sodium channel inhibition (>80% at 1 µM). Docking studies revealed binding modes consistent with established 5-HT₇ ligands. Compound 10 showed lower cytotoxicity than compound 20 in both HepG2 and SH-SY5Y cells and was therefore selected for further evaluation. Metabolic profiling indicated improved microsomal stability relative to verapamil and a low risk of CYP-mediated drug–drug interactions. In vivo, compound 10 produced significant antidepressant- and anxiolytic-like effects, though it failed to reduce neuropathic pain symptoms in the STZ-induced model. Conclusions: Compound 10 shows potential for mood disorder treatment, but further refinement may be needed to improve analgesic efficacy. Full article

(This article belongs to the Special Issue Multitargeted Compounds: A Promising Approach in Medicinal Chemistry)

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40 pages, 3660 KB

Open AccessReview

Anti-Inflammatory Activity of 1,2-Benzothiazine 1,1-Dioxide Derivatives

by Berenika M. Szczęśniak-Sięga and Izabela Topolska

Pharmaceuticals 2025, 18(10), 1484; https://doi.org/10.3390/ph18101484 - 2 Oct 2025

Abstract

There is an urgent need to develop new anti-inflammatory compounds due to the versatility of their applications and the side effects associated with currently used nonsteroidal anti-inflammatory drugs (NSAIDs). Compounds containing the 1,2-benzothiazine 1,1-dioxide moiety in their structure have demonstrated a broad range [...] Read more.

There is an urgent need to develop new anti-inflammatory compounds due to the versatility of their applications and the side effects associated with currently used nonsteroidal anti-inflammatory drugs (NSAIDs). Compounds containing the 1,2-benzothiazine 1,1-dioxide moiety in their structure have demonstrated a broad range of pharmacological activities, among which the anti-inflammatory effect is the most well-documented. Numerous in vivo studies have confirmed the effectiveness of these compounds in alleviating pain and inflammation. In turn, in vitro studies have shown that 1,2-benzothiazine derivatives exhibit anti-inflammatory activity not only through the classical mechanism involving the inhibition of cyclooxygenase (COX) but also through modern, more complex mechanisms. These innovative mechanisms include inhibition of microsomal prostaglandin E₂ synthase-1 (mPGES-1) or 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), suppression of pro-inflammatory cytokines, and modulation of kinase activity involved in inflammatory processes. Importantly, many studies have shown that some new 1,2-benzothiazine 1,1-dioxide derivatives exhibit even stronger anti-inflammatory activity than traditional NSAIDs, making them promising candidates for new drugs targeting inflammation-related diseases. This paper presents a review of 1,2-benzothiazine 1,1-dioxide derivatives investigated for their anti-inflammatory activity in both in vivo and in vitro models, taking into account their various mechanisms of action and potential directions for further research. Full article

(This article belongs to the Special Issue Medicinal Chemistry of Thiazine and Oxazine Derivatives: Trends and Future Directions as Therapeutic Drugs)

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24 pages, 3937 KB

Open AccessArticle

Chronic Administration of Calendula officinalis Ethanolic Extract Mitigates Anxiety-like Behavior and Cognitive Impairment Induced by Acute Scopolamine Exposure in Zebrafish

by Lucia-Florina Popovici, Ion Brinza, Simona Oancea and Lucian Hritcu

Pharmaceuticals 2025, 18(10), 1483; https://doi.org/10.3390/ph18101483 - 2 Oct 2025

Abstract

Background/Objectives: Scopolamine (SCO) is widely employed as a pharmacological model of anxiety and amnesia in both rodents and zebrafish, the latter representing a valuable translational model in neuropsychopharmacology. The present study aimed to evaluate the neuroprotective and antioxidant potential of chronic administration of [...] Read more.

Background/Objectives: Scopolamine (SCO) is widely employed as a pharmacological model of anxiety and amnesia in both rodents and zebrafish, the latter representing a valuable translational model in neuropsychopharmacology. The present study aimed to evaluate the neuroprotective and antioxidant potential of chronic administration of an ethanolic extract from Calendula officinalis flowers (CEE). Methods: Adult zebrafish (n = 10/group, both sexes) were exposed to CEE at concentrations of 1, 3, and 10 mg/L, administered daily for 22 consecutive days. After the initial 7-day pretreatment period, fish were challenged with SCO (100 μM, immersion for 30 min) followed by behavioral testing, including the Novel Tank Diving Test, Light/Dark Test, Novel Approach Test, Y-Maze, and Novel Object Recognition. Subsequently, brain homogenates were analyzed for acetylcholinesterase (AChE) activity, antioxidant enzymes (superoxide dismutase—SOD, catalase—CAT, glutathione peroxidase—GPx), reduced glutathione (GSH), protein carbonyls, and malondialdehyde (MDA). Results: Chronic CEE administration significantly attenuated scopolamine-induced anxiety-like behaviors and improved spatial memory (Y-maze) and recognition memory (NOR), as well as reduced anxiety-like behavior in the SCO-induced zebrafish model. Biochemical analyses revealed that CEE restored AChE activity, enhanced the activity of SOD, CAT, and GPx, and increased GSH levels, while concomitantly reducing protein oxidation and lipid peroxidation. The most pronounced effects were observed at 3 mg/L, which nearly normalized both behavioral and biochemical parameters. Conclusions: The CEE exerted anxiolytic and procognitive effects in zebrafish through combined cholinergic and antioxidant mechanisms. These findings highlight its translational potential as a promising candidate for the prevention and treatment of anxiety-related and cognitive disorders. Full article

(This article belongs to the Special Issue Unveiling Nature's Pharmacy: Exploring Drug Discovery Through Medicinal Plants)

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23 pages, 2822 KB

Open AccessSystematic Review

Therapeutic Potential of Astaxanthin for Body Weight Regulation: A Systematic Review and Meta-Analysis with Dose–Response Assessment

by Lucas Fornari Laurindo, Victória Dogani Rodrigues, Mauro Audi, Tereza Lais Menegucci Zutin, Mayara Longui Cabrini, Cláudio José Rubira, Cristiano Machado Galhardi, Jesselina Francisco dos Santos Haber, Lidiane Indiani, Maria Angélica Miglino, Vitor Engrácia Valenti, Eduardo Federighi Baisi Chagas and Sandra Maria Barbalho

Pharmaceuticals 2025, 18(10), 1482; https://doi.org/10.3390/ph18101482 - 1 Oct 2025

Abstract

Background/Objectives: Astaxanthin, a naturally occurring carotenoid renowned for its potent antioxidant properties, has been proposed as a dietary supplement for weight management due to its potential effects on adipose tissue and skeletal muscle metabolism, as well as its anti-inflammatory properties. This meta-analysis systematically [...] Read more.

Background/Objectives: Astaxanthin, a naturally occurring carotenoid renowned for its potent antioxidant properties, has been proposed as a dietary supplement for weight management due to its potential effects on adipose tissue and skeletal muscle metabolism, as well as its anti-inflammatory properties. This meta-analysis systematically evaluated the impact of astaxanthin supplementation on body mass index (BMI) and body weight in adult populations. Methods: Comprehensive searches of reputable databases were conducted, adhering to the PRISMA guidelines, with statistical analyses performed using Jamovi. Results: The study incorporated data from nine clinical trials. Pooled results indicated no significant reduction in the context of BMI (−0.2162; 95% CI: −0.4697 to 0.0374) and a non-significant decrease in body weight (0.0230; 95% CI: −0.4534 to 0.4994) relative to control groups. The heterogeneity observed across studies was 30.1251% (p = 0.1593) for BMI and 73.3885% (p = 0.0002) for body weight management. The dose–response analysis showed no statistically significant association between astaxanthin dosage and outcomes related to BMI and body weight management. Additionally, statistical assessment of funnel plot asymmetry indicated no evidence of publication bias. Conclusions: The findings indicate that astaxanthin does not provide benefits in BMI regulation nor in weight control management, highlighting the need for additional large-scale and long-term clinical trials. This study contributes to the growing body of evidence on the role of nutraceuticals in metabolic health, providing a foundation for future clinical recommendations. Full article

(This article belongs to the Section Natural Products)

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20 pages, 3134 KB

Open AccessArticle

Crinis Carbonisatus-Derived Carbon Dot Suspension Alleviates Temporal Lobe Epilepsy

by Yan Huang, Menghan Li, Liyang Dong, Chenxin He, Peng Zou, Minlong Xia, Bilin Jin, Siqi Wang, Zixuan Lu, Huihua Qu, Yue Zhang and Hui Kong

Pharmaceuticals 2025, 18(10), 1481; https://doi.org/10.3390/ph18101481 - 1 Oct 2025

Abstract

Background: Temporal lobe epilepsy (TLE), a prevalent refractory focal epilepsy frequently complicated by comorbid anxiety and depression, poses significant therapeutic challenges due to the inadequate efficacy of current antiepileptic drugs in seizure control. Carbon dots (CDs) demonstrate notable biological activities and represent a [...] Read more.

Background: Temporal lobe epilepsy (TLE), a prevalent refractory focal epilepsy frequently complicated by comorbid anxiety and depression, poses significant therapeutic challenges due to the inadequate efficacy of current antiepileptic drugs in seizure control. Carbon dots (CDs) demonstrate notable biological activities and represent a promising class of nanomedicines for TLE intervention. Methods: This study established an eco-friendly calcination protocol to synthesize a novel suspension of Crinis Carbonisatus-derived carbon dots (CC-CDs) as a candidate therapeutic for TLE. Results: In a TLE mouse model, the CC-CDs suspension significantly inhibited phosphorylation of the MAPK pathway (p-JNK, p-ERK, p-p38; p < 0.01, p < 0.05), leading to reduced levels of pro-inflammatory cytokines (IL-6, IL-1β, TNF-α; p < 0.01, p < 0.05), upregulation of TGF-β1 (p < 0.01, p < 0.05), and restoration of antioxidant enzyme activities (SOD, GSH, CAT; p < 0.01, p < 0.05). These modifications subsequently regulated the Glu/GABA balance, alleviating excitotoxicity (p < 0.05), attenuating neuronal damage and Nissl body loss in hippocampal CA1/CA3 regions, and improving cognitive function alongside reducing anxiety-like behaviors (p < 0.01, p < 0.05). In vitro, the CC-CDs suspension suppressed LPS-induced apoptosis in BV2 cells. Conclusions: The CC-CDs suspension ameliorates TLE by inhibiting MAPK signaling, thereby reducing neuroinflammation and oxidative stress, rectifying Glu/GABA imbalance, attenuating excitotoxicity, and ultimately improving behavioral deficits. These findings underscore the therapeutic potential of CC-CDs suspension for TLE treatment. Full article

(This article belongs to the Section Pharmacology)

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