Pharmaceuticals

16 pages, 1166 KB

Open AccessArticle

Evaluation of Daughter Radionuclide Release from the ¹⁰³Pd/^103mRh In Vivo Generator for Targeted Auger Therapy

by Aicha Nour Laouameria, Cathryn H. S. Driver, Monika Buys, Elena Sergeevna Kurakina, Mátyás Hunyadi, Jan Rijn Zeevaart and Zoltan Szucs

Pharmaceuticals 2026, 19(1), 126; https://doi.org/10.3390/ph19010126 (registering DOI) - 11 Jan 2026

Abstract

Background/Objectives: The ¹⁰³Pd/^103mRh in vivo generator represents a promising Auger electron-emitting system, in which both parent and daughter radionuclides emit predominantly Auger electrons with minimal accompanying radiation. This study investigates the release dynamics of daughter radionuclides from the ¹⁰³ [...] Read more.

Background/Objectives: The ¹⁰³Pd/^103mRh in vivo generator represents a promising Auger electron-emitting system, in which both parent and daughter radionuclides emit predominantly Auger electrons with minimal accompanying radiation. This study investigates the release dynamics of daughter radionuclides from the ¹⁰³Pd/^103mRh in vivo generator and evaluates the underlying mechanisms governing bond rupture and daughter retention. Methods: Cyclotron irradiation of rhodium foils was performed in two separate batches, followed by radionuclide separation using conventional wet chemistry and a novel dry distillation technique. The purified ¹⁰³Pd radionuclide was used to radiolabel DOTA-TATE, phthalocyanine-TATE, and DOTA-TOC chelators. The resulting complexes were immobilized on Strata-X and Strata-C18 solid-phase extraction columns. Scheduled elution experiments were conducted to quantify the release of the ^103mRh daughter radionuclide. Results: The measured ^103mRh release rates were 9.8 ± 3.0% and 9.6 ± 2.7% from Strata-X columns with DOTA-TATE and phthalocyanine-TATE, respectively, and 10.5 ± 2.7% and 12.0 ± 0.5% from Strata-X and Strata-C18 columns, respectively, with DOTA-TOC. These values are significantly lower than the ~100% release predicted based on the reported Auger electron yield of 186%. One explanation for this difference could be potential inconsistencies in decay data that may require correction; this needs further investigation. The results further demonstrated that delocalized π-electrons, introduced via phthalocyanine-based chelation, did not mitigate daughter release. Conclusions: The low observed daughter nuclide release represents a favorable characteristic for the future clinical translation of the ¹⁰³Pd/^103mRh Auger emitter pair. The findings support the conclusion that Auger electron cascades, rather than nuclear recoil energy, dominate bond rupture processes. Full article

(This article belongs to the Special Issue Advances in Theranostic Radiopharmaceuticals)

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18 pages, 991 KB

Open AccessArticle

Toward Personalized Withdrawal of TNF-α Inhibitors in Non-Systemic Juvenile Idiopathic Arthritis: Predictors of Biologic-Free Remission and Flare

by Ekaterina I. Alexeeva, Irina T. Tsulukiya, Tatyana M. Dvoryakovskaya, Ivan A. Kriulin, Dmitry A. Kudlay, Anna N. Fetisova, Maria S. Botova, Tatyana Y. Kriulina, Elizaveta A. Krekhova, Natalya M. Kondratyeva, Meiri Sh. Shingarova, Maria Y. Kokina, Alyona N. Shilova and Mikhail M. Kostik

Pharmaceuticals 2026, 19(1), 125; https://doi.org/10.3390/ph19010125 (registering DOI) - 10 Jan 2026

Abstract

Background: Tumor necrosis factor-α (TNFα) inhibitors have significantly improved outcomes in children with non-systemic juvenile idiopathic arthritis (JIA), achieving long-term clinical remission for many patients. However, the optimal strategy for TNF-α inhibitor withdrawal remains unknown, whether through abrupt discontinuation, gradual dose reduction, or [...] Read more.

Background: Tumor necrosis factor-α (TNFα) inhibitors have significantly improved outcomes in children with non-systemic juvenile idiopathic arthritis (JIA), achieving long-term clinical remission for many patients. However, the optimal strategy for TNF-α inhibitor withdrawal remains unknown, whether through abrupt discontinuation, gradual dose reduction, or interval extension. Objective: We aim to identify patient-, disease-, and treatment-related predictors of successful TNF-α inhibitor withdrawal in children with non-systemic JIA. Methods: In this prospective, randomized, open-label, single-center study, 76 children with non-systemic JIA in stable remission for ≥24 months on etanercept or adalimumab were enrolled. At the time of TNF-α inhibitor discontinuation, all patients underwent a comprehensive evaluation, including a clinical examination, laboratory tests (serum calprotectin [S100 proteins] and high-sensitivity C-reactive protein [hsCRP]), and advanced joint imaging (musculoskeletal ultrasound and magnetic resonance imaging [MRI]) to assess subclinical disease activity. Patients were randomized (1:1:1, sealed-envelope allocation) to one of three predefined tapering strategies: (I) abrupt discontinuation; (II) extension of dosing intervals (etanercept 0.8 mg/kg every 2 weeks; adalimumab 24 mg/m² every 4 weeks); or (III) gradual dose reduction (etanercept 0.4 mg/kg weekly; adalimumab 12 mg/m² every 2 weeks). Follow-up visits were scheduled at 3, 6, 9, 12, and 18 months to monitor for disease relapse. Results: Higher baseline Childhood Health Assessment Questionnaire (CHAQ) scores (≥2), elevated serum calprotectin [S100 proteins] and hsCRP levels at withdrawal, imaging evidence of subclinical synovitis, and a history of uveitis were all significantly associated with increased risk of flare. No significant associations were found for other clinical or demographic characteristics. Conclusions: Early significant clinical response, absence of subclinical disease activity, and concomitant low-dose methotrexate therapy were key predictors of sustained drug-free remission. These findings may inform personalized strategies for biologic tapering in pediatric JIA. Full article

(This article belongs to the Special Issue Emerging Biomarkers in Autoimmune Diseases: From Pharmacodynamic Insights to Therapeutic Translation)

17 pages, 3858 KB

Open AccessArticle

The Allosteric Regulation of the DNA-Binding Domain of p53 by the Intrinsically Disordered C-Terminal Domain

by Shangbo Ning, Chengwei Zeng, Huiwen Wang, Junfeng Zhang, Yun Xue and Yunjie Zhao

Pharmaceuticals 2026, 19(1), 124; https://doi.org/10.3390/ph19010124 (registering DOI) - 10 Jan 2026

Abstract

Background: Intrinsically disordered regions (IDRs) within proteins often act as pivotal linkage units for the interaction of functional domains. The p53 tumor suppressor protein contains intrinsically disordered N-terminal and C-terminal domains (NTD and CTD), playing crucial regulatory roles in cellular processes. Furthermore, [...] Read more.

Background: Intrinsically disordered regions (IDRs) within proteins often act as pivotal linkage units for the interaction of functional domains. The p53 tumor suppressor protein contains intrinsically disordered N-terminal and C-terminal domains (NTD and CTD), playing crucial regulatory roles in cellular processes. Furthermore, experimental approaches have encountered challenges in elucidating the structural regulation by the IDRs. Methods: In this work, we employed microsecond-scale molecular dynamics simulations to explore the allosteric regulation mechanism of the p53 DNA binding domain (DBD) induced by the CTD and the DNA binding. Subsequently, we integrated dynamic cross-correlation analysis with binding free energy calculations to evaluate the interaction between the CTD and DNA. Results: The free energy landscapes (FELs) were utilized to identify the conformational ensemble of the p53 DBD. The FELs revealed that the CTD enhances the allosteric regulatory mechanisms. Conclusions: Firstly, the conformation of DBD changes on the S6-S7 loop and L1 upon DNA binding. Then the CTD directly interacts with DNA and further regulates the allosteric network (involving the S6-S7 loop, L1 loop, S4, S10, H1, and H3) to promote the binding of DBD to DNA. The allosteric mechanisms presented in this work will provide new insights into the functional mechanisms of the p53 CTD and inform the rational design of p53-targeted drugs. Full article

(This article belongs to the Special Issue Computational Methods in Drug Development)

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23 pages, 10024 KB

Open AccessArticle

Investigating the Protective Mechanisms of Ginseng-Natto Composite Fermentation Products in Alzheimer’s Disease: A Gut Microbiota and Metabolomic Approach

by Zhimeng Li, He Wang, Huiyang Yuan, Yue Zhang, Bo Yang, Guoxin Ji, Zhuangzhuang Yao, Mingfang Kuang, Xian Wu, Shumin Wang and Huan Wang

Pharmaceuticals 2026, 19(1), 123; https://doi.org/10.3390/ph19010123 (registering DOI) - 10 Jan 2026

Abstract

Background: Alzheimer’s disease (AD), a progressive brain disorder, is the most common form of dementia and necessitates the development of effective intervention strategies. Ginseng-Natto composite fermentation products (GN) have demonstrated beneficial bioactivities in mouse models of AD; however, the underlying mechanism of action [...] Read more.

Background: Alzheimer’s disease (AD), a progressive brain disorder, is the most common form of dementia and necessitates the development of effective intervention strategies. Ginseng-Natto composite fermentation products (GN) have demonstrated beneficial bioactivities in mouse models of AD; however, the underlying mechanism of action through which GN ameliorates AD requires further elucidation. Methods: Mice received daily intragastric administration of low- or high-dose GN for 4 weeks, followed by intraperitoneal injection of scopolamine to induce the AD model. The pharmacological effects of GN were systematically evaluated using the Morris water maze test, ELISA, and H&E staining. To further investigate the underlying mechanisms, 16S rRNA gene sequencing and metabolomics were employed to analyze the regulatory effects of GN on the gut–brain axis. Additionally, Western blotting was performed to assess the impact of GN on blood–brain barrier (BBB) integrity. Results: GN intervention significantly ameliorated cognitive deficits and attenuated neuropathological injury in AD mice, restoring the brain levels of acetylcholine (ACh), acetylcholinesterase (AChE), superoxide dismutase (SOD), malondialdehyde (MDA), glutathione peroxidase (GSH-Px), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) to normal ranges. GN reshaped the gut microbiota by promoting beneficial bacteria and inhibiting pro-inflammatory strains. It also regulated key metabolic pathways related to amino acid and unsaturated fatty acid metabolism. This metabolic remodeling restored the compromised BBB integrity by upregulating tight junction proteins (ZO-1, Occludin and Claudin-1). Conclusions: Our findings demonstrate that GN ameliorates AD through a gut-to-brain pathway, mediated by reshaping the microbiota-metabolite axis and repairing the BBB. Thus, GN may represent a promising intervention candidate for AD. Full article

(This article belongs to the Section Natural Products)

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14 pages, 2967 KB

Open AccessArticle

Kinetics of MM1.S Multiple Myeloma Cells in a 3D Polymer Particle Culture System with Bone Marrow Stromal Cells and Bortezomib

by Shin Aizawa, Miyuki Yuda, Shuichi Hirai, Isao Tsuboi, Takashi Koike, Yoshihiro Hatta, Katsuhiro Miura and Masahiro Yasuda

Pharmaceuticals 2026, 19(1), 122; https://doi.org/10.3390/ph19010122 (registering DOI) - 10 Jan 2026

Abstract

Background: Three-dimensional (3D) culture systems use polymer particles with a bone marrow stroma cell feeder layer to reproduce a biostructural hematopoiesis state more effectively than in conventional two-dimensional (2D) culture methods. The 3D culture maintains normal hematopoiesis, resulting in prolongation of hematopoietic stem [...] Read more.

Background: Three-dimensional (3D) culture systems use polymer particles with a bone marrow stroma cell feeder layer to reproduce a biostructural hematopoiesis state more effectively than in conventional two-dimensional (2D) culture methods. The 3D culture maintains normal hematopoiesis, resulting in prolongation of hematopoietic stem cell proliferation and differentiation, while the bone marrow stromal cells in the culture alter the growth of leukemic cells and protect them from anticancer agents. However, the effect of stromal cells on hematopoietic stem cell proliferation and differentiation and neoplastic cells, including leukemia, in 3D culture is still a point of contention. Methods: We assessed the mechanism of two different bone-marrow-derived stromal cells (i.e., MS-5 and Tst-4) with different characteristics by using a feeder layer in the 3D culture to compare their supportive action on leukemic cells, focusing on the role of 3D cultures constructed with bone marrow stromal cells in leukemic cell growth. Multiple myeloma cells are strongly related to stromal cells in their proliferation; hence, cloned MM1.S cells derived from multiple myeloma were cocultured in 3D, and their cell growth was examined. We also examined the effect of the antineoplastic agent bortezomib, a proteasome inhibitor, in the 3D culture system with a different stromal cell feeder. Results and Conclusions: When MM1.S myeloma cells were cultured with MS-5 stroma in 3D conditions, cell growth was found to be slow compared with that in 2D culture, as well as with those in both the 2D and 3D cocultures with Tst-4 stroma. Additionally, the MS-5 cells in the 3D culture protected the MM1.S cells from the cytocidal effect of the bortezomib treatment. Different MM1.S cell kinetics were observed depending on the stromal cells used, suggesting their inherent and complicated characteristics. Full article

(This article belongs to the Special Issue 2D and 3D Culture Systems: Current Trends and Biomedical Applications)

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17 pages, 2387 KB

Open AccessArticle

Exploring the Anti-Inflammatory Effects of Aloe vera Flower (AVF) and Its Active Ingredients in a Skin Inflammation Model Induced by Glyoxal-Derived Advanced Glycation End Products (GO-AGEs)

by Eun Yoo Lee, Seong-Min Hong, Sun Yeou Kim and Razia Sultana

Pharmaceuticals 2026, 19(1), 121; https://doi.org/10.3390/ph19010121 (registering DOI) - 9 Jan 2026

Abstract

Objective: Advanced glycation end-products (AGEs) contribute to oxidative stress and inflammation, leading to various disorders, including skin inflammation. Here, we investigated the anti-inflammatory effects of Aloe vera flower (AVF) extract and its active constituents, vitexin (V) and isovitexin (IV), in a glyoxal-derived [...] Read more.

Objective: Advanced glycation end-products (AGEs) contribute to oxidative stress and inflammation, leading to various disorders, including skin inflammation. Here, we investigated the anti-inflammatory effects of Aloe vera flower (AVF) extract and its active constituents, vitexin (V) and isovitexin (IV), in a glyoxal-derived AGE (GO-AGE)-induced skin inflammaging model. Methods: We evaluated the effects of AVF, V, and IV in epidermal keratinocytes (HaCaT cells) using enzyme-linked immunosorbent assay, Western blotting, quantitative real-time polymerase chain reaction, and in silico molecular docking. Results: Treatment of HaCaT cells with AVF, V, or IV significantly suppressed the secretion and expression of interleukins (IL-6 and IL-8) at both the mRNA and protein level, and reduced the expression of key inflammatory proteins, including kappa-light-chain-enhancer of activated B cells (NF-κB) and cyclooxygenase-2 (COX-2), and phosphorylation of mitogen-activated protein kinase (MAPK) pathway proteins. Notably, the inhibitory effects of V and IV on COX-2 expression were more comparable to or exceeded those of the positive control (Epigallocatechin gallate), even at a lower concentration. Conversely, the expression of sirtuin 1 (SIRT1) was upregulated by AVF, V, and IV, with IV showing 1.5-fold upregulation. Molecular docking analyses supported these findings, with IV displaying a particularly high binding affinity for COX-2 (−11.0 kcal/mol). Conclusions: These findings highlight the potential of AVF, V, and IV as novel therapeutic agents for managing skin inflammaging by modulating inflammatory pathways. Full article

(This article belongs to the Special Issue Advances in Natural Products: Basic, Therapeutic, and Computational Approaches in Chronic and Infectious Diseases)

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18 pages, 1585 KB

Open AccessArticle

Affinity- and Format-Dependent Pharmacokinetics of ⁸⁹Zr-Labeled Albumin-Binding VHH Constructs

by Simon Leekens, Peter Casteels, Tom Van Bogaert, Pieter Deschaght, Veronique De Brabandere, Christopher Cawthorne, Guy Bormans and Frederik Cleeren

Pharmaceuticals 2026, 19(1), 120; https://doi.org/10.3390/ph19010120 - 9 Jan 2026

Abstract

Background/Objectives: NANOBODY^® molecules (VHHs) are attractive vectors for radiopharmaceuticals due to their small size and high target affinity, but rapid clearance and pronounced kidney retention limit their therapeutic applicability. Binding to serum albumin is a widely used strategy to prolong circulation, yet [...] Read more.

Background/Objectives: NANOBODY^® molecules (VHHs) are attractive vectors for radiopharmaceuticals due to their small size and high target affinity, but rapid clearance and pronounced kidney retention limit their therapeutic applicability. Binding to serum albumin is a widely used strategy to prolong circulation, yet the respective contributions of albumin-binding affinity and molecular format remain insufficiently defined. This study aimed to systematically evaluate how affinity and valency modulate VHH pharmacokinetics. Methods: Four monovalent albumin-binding VHHs spanning nanomolar to micromolar affinities and two bivalent constructs were engineered, generated by fusing an albumin-binding VHH to an irrelevant non-binding VHH. All constructs incorporated a site-specific cysteine for DFO* conjugation, enabling uniform zirconium-89 labeling with high radiochemical purity. Pharmacokinetics were assessed in healthy mice using serial blood sampling and positron emission tomography. Blood and kidney exposure were quantified by non-compartmental analysis. Results: All albumin-binding constructs showed increased systemic exposure and reduced kidney uptake relative to a non-binding control. Nanomolar-affinity binders reached maximal exposure, and further affinity increases (K_D < ~100 nM) did not improve pharmacokinetics, suggesting a threshold. The micromolar binder showed intermediate exposure but still reduced renal retention compared with control. Valency effects were affinity-dependent. They were negligible at high affinity but pronounced at low affinity, where bivalency reduced systemic exposure and increased kidney uptake toward control levels. Conclusions: Albumin binding enables tuning of VHH pharmacokinetics in an affinity-dependent manner. Above an apparent affinity threshold, pharmacokinetics become format independent, whereas below this threshold, molecular format substantially influences systemic and renal disposition. Full article

(This article belongs to the Special Issue Advances in Theranostic Radiopharmaceuticals)

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18 pages, 1911 KB

Open AccessArticle

Mechanistic Exploration of N,N′-Disubstituted Diamines as Promising Chagas Disease Treatments

by Alejandro I. Recio-Balsells, Chantal Reigada, María Gabriela Mediavilla, Esteban Panozzo-Zénere, Miguel Villarreal Parra, Patricia S. Doyle, Juan C. Engel, Claudio A. Pereira, Julia A. Cricco and Guillermo R. Labadie

Pharmaceuticals 2026, 19(1), 119; https://doi.org/10.3390/ph19010119 - 9 Jan 2026

Abstract

Introduction: Chagas disease, caused by the protozoan Trypanosoma cruzi, remains a major public health concern due to the limited effectiveness of current treatments, especially in the chronic stage. Objective: Here, we wanted to advance a library of 30 N,N′-disubstituted [...] Read more.

Introduction: Chagas disease, caused by the protozoan Trypanosoma cruzi, remains a major public health concern due to the limited effectiveness of current treatments, especially in the chronic stage. Objective: Here, we wanted to advance a library of 30 N,N′-disubstituted diamines as promising antichagasic agents and gain insight into the mechanism of action. Methods: The library was evaluated for activity against the T. cruzi amastigote stage and trypanocidal efficacy. In addition, selected compounds were tested as potential polyamine transport inhibitors, and a fluorescent analog was employed to investigate compound internalization. Results: Five compounds exhibited potent activity (pIC₅₀ > 6.0), particularly those with short aliphatic linkers (3–6 carbon atoms), suggesting a structure–activity relationship favouring shorter chains. Mechanistic studies showed that compound 3c strongly inhibited polyamine transport, a vital pathway in T. cruzi, though this was not a universal mechanism among active hits, indicating the potential for multiple targets. A fluorescent analog confirmed intracellular uptake in amastigotes but lacked antiparasitic activity, likely due to disrupted pharmacophoric features. Importantly, none of the compounds demonstrated trypanocidal activity in long-term assays, and some showed cytotoxicity, particularly in the benzyloxy-substituted series. Conclusions: These findings position N,N′-disubstituted diamines as a viable scaffold for Chagas disease drug discovery. However, further optimization is required to enhance selectivity, achieve trypanocidal effects, and better understand the underlying mechanisms of action. Full article

(This article belongs to the Special Issue Novel Developments in Antileishmanial and Antitrypanosomal Agents)

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23 pages, 609 KB

Open AccessReview

Microbiota-Driven Strategies for Managing IBD-Associated Risks: From Infections to Mental Health

by Patrycja Krynicka, Pablo Cortegoso Valdivia, Maciej Morawski, Wojciech Marlicz, Karolina Skonieczna-Żydecka and Anastasios Koulaouzidis

Pharmaceuticals 2026, 19(1), 118; https://doi.org/10.3390/ph19010118 - 9 Jan 2026

Abstract

Inflammatory bowel diseases (IBD) are increasingly acknowledged not merely as confined gastrointestinal disorders but as systemic immunometabolic syndromes. Central to this paradigm is the gut microbiota including non-bacterial components such as the virome, whose functional disruption marked by reduced short-chain fatty acids (SCFAs), [...] Read more.

Inflammatory bowel diseases (IBD) are increasingly acknowledged not merely as confined gastrointestinal disorders but as systemic immunometabolic syndromes. Central to this paradigm is the gut microbiota including non-bacterial components such as the virome, whose functional disruption marked by reduced short-chain fatty acids (SCFAs), increasingly implicated in pathogenic processes extending beyond intestinal mucosa. This review outlines how these alternations compromise the epithelial barrier and immune regulation, increasing the risk of recurrent Clostridioides difficile infections to anemia, neuropsychiatric comorbidities, and extraintestinal manifestations. We critically evaluate emerging microbiota-targeted strategies, including fecal microbiota transplantation (FMT), live biotherapeutic products (LBPs), and precision postbiotics, positioning them as potential adjuncts to conventional immunosuppression. Finally, we discuss the current barriers to clinical translation, such as safety and heterogeneity, and propose a future framework for personalized, functionally integrated IBD care aimed at restoring long-term microbiota homeostasis. Full article

(This article belongs to the Section Biopharmaceuticals)

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22 pages, 2746 KB

Open AccessArticle

Characterization of Novel Sigma Receptor Ligands Derived from Multicomponent Reactions as Efficacious Treatments for Neuropathic Pain

by Ryosuke Shinouchi, Bengisu Turgutalp, Rohini S. Ople, Shainnel O. Eans, Ashai K. Williams, Haylee R. Hammond, Andras Varadi, Rebecca Notis Dardashti, Susruta Majumdar and Jay P. McLaughlin

Pharmaceuticals 2026, 19(1), 117; https://doi.org/10.3390/ph19010117 - 8 Jan 2026

Abstract

Background/Objectives: Neuropathic pain remains a significant clinical challenge, with current treatments often providing inadequate relief and adverse effects. Sigma receptors (SRs) modulate nociception and have emerged as potential therapeutic targets for neuropathic pain. Although putative sigma-1 receptor (S1R) ligands have demonstrated analgesic [...] Read more.

Background/Objectives: Neuropathic pain remains a significant clinical challenge, with current treatments often providing inadequate relief and adverse effects. Sigma receptors (SRs) modulate nociception and have emerged as potential therapeutic targets for neuropathic pain. Although putative sigma-1 receptor (S1R) ligands have demonstrated analgesic efficacy in preclinical models, their in vivo efficacy and safety profiles require further clarification. Methods: Analogs of well-known selective S1R ligand UVM147 were synthesized using 3-component Ugi reactions and examined in vitro for receptor affinity in radioligand competition binding assays and in vivo with mouse models of neuropathic and inflammatory pain and adverse effects. Results: Three novel heterocyclic compounds (RO-4-3, RO-5-3, and RO-7-3) displayed in vitro nanomolar affinity with varying selectivity for both SR subtypes (S1R and S2R). When screened in vivo at a dose of 30 mg/kg s.c. in mice first subjected to chronic constriction injury (CCI), RO-5-3 and RO-7-3 possessed anti-allodynic potential, while UVM147 was inactive. Upon full characterization, RO-5-3 significantly attenuated mechanical allodynia in a dose-dependent manner, while RO-7-3 was ineffective at higher doses. Both compounds dose-dependently attenuated nociceptive behaviors in the mouse formalin assay. RO-5-3 induced mild respiratory depression without impairing locomotor activity, whereas RO-7-3 caused transient respiratory depression and locomotor impairment. Additionally, RO-5-3, but not RO-7-3, induced conditioned place aversion consistent with potential S2R involvement. Conclusions: RO-5-3 exerts antinociceptive and anti-allodynic effects with minimal adverse behavioral effects, supporting the role of SRs in pain modulation. These results add to growing evidence supporting the development of SR ligands as efficacious therapeutics for neuropathic pain with fewer clinical liabilities. Full article

(This article belongs to the Special Issue Current Advances in Therapeutic Potential of Sigma Receptor Ligands)

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15 pages, 4122 KB

Open AccessArticle

Purpurin Rescues Contrast-Induced Acute Rat Kidney Injury via Inducing Autophagy and Inhibiting Apoptosis

by Kangxu He, Xiaoying Sun, Xinhui Pan, Xiaoda Yang, Qi Wang and Kai Liao

Pharmaceuticals 2026, 19(1), 116; https://doi.org/10.3390/ph19010116 - 8 Jan 2026

Abstract

Objectives: Contrast-induced acute kidney injury (CIAKI) is a major cause of hospital-acquired renal injury, and strategies for its treatment are currently lacking. This study aimed to investigate the amelioration effect and mechanism of purpurin, a natural antioxidant, against CIAKI via an integrated [...] Read more.

Objectives: Contrast-induced acute kidney injury (CIAKI) is a major cause of hospital-acquired renal injury, and strategies for its treatment are currently lacking. This study aimed to investigate the amelioration effect and mechanism of purpurin, a natural antioxidant, against CIAKI via an integrated analysis of network pharmacology, bioinformatics, molecular docking, and animal experiments. Methods: Network pharmacology approaches were used to predict key targets of purpurin against CIAKI. The differential expression of these key targets was further investigated using bioinformatics analysis and molecular binding with purpurin by molecular docking. A CIAKI model was established in SD rats via iohexol administration, and they were treated with 2.5 mg/kg or 5 mg/kg purpurin. Related physiological and pathological indexes were detected to explore the intervention mechanism. Results: Key gene targets were screened from protein–protein interaction networks, of which Pik3c2a, Esr1, Aktip, HSP90AA1, Bcl2, Caspase3, and SRC in the CIAKI group of GSE189881 were significantly differentially expressed compared to the control group. Molecular docking results show that PI3K, ESR1, HSP90, CASP3, AKTI, and SRC had the highest level of connectivity with purpurin. In vivo experiments demonstrated that the Scr and BUN increased in CIAKI rats, the pathological morphology of renal tissue deteriorated, the levels of TNF-α, IL-1β, and IL-6 increased, the contents of MOD and NO in oxidative stress increased, and the activity of SOD and GSH-PX decreased. After administration of purpurin, the above indexes improved in a dose-dependent manner (<0.05). Western blotting showed that purpurin inhibited the Beclin1/Bcl-2/caspase-3 apoptotic cascade and induced the P62/LC3 autophagy pathway. Conclusions: This study provides experimental evidence supporting purpurin as a potential therapeutic agent for CIAKI and further explores its antioxidant mechanisms. Full article

(This article belongs to the Section Pharmacology)

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29 pages, 20642 KB

Open AccessArticle

Chrysin and Luteolin from Moroccan Propolis to Prevent Aggressive Periodontitis Caused by Aggregatibacter actinomycetemcomitans Leukotoxin: A Computer-Aided Drug Design Approach

by Doha EL Meskini, Fettouma Chraa, Jihane Touhtouh, Mouna Ouadghiri, Monica Gallo, Abdelhakim Bouyahya and Tarik Aanniz

Pharmaceuticals 2026, 19(1), 115; https://doi.org/10.3390/ph19010115 - 8 Jan 2026

Abstract

Background: Aggregatibacter actinomycetemcomitans is a Gram-negative, facultative anaerobic, immobile oral bacterium responsible for the secretion of virulence factors, namely leukotoxin (LtxA), a large exotoxin of the RTX family that enables the bacterium to evade the immune system by destroying leukocytes, resulting in [...] Read more.

Background: Aggregatibacter actinomycetemcomitans is a Gram-negative, facultative anaerobic, immobile oral bacterium responsible for the secretion of virulence factors, namely leukotoxin (LtxA), a large exotoxin of the RTX family that enables the bacterium to evade the immune system by destroying leukocytes, resulting in aggressive periodontitis (AP) leading to tooth loss. Methods: This study aimed to screen 106 molecules derived from Moroccan propolis in order to identify potential inhibitors of the active sites of LtxA based on molecular docking, ADMET property evaluation, and molecular dynamics (MD) simulation. Results: Epigallocatechin gallate (EGCg), used as a reference compound, showed binding energies of −6.9 kcal/mol, −6.1 kcal/mol, −6.5 kcal/mol, and −5.9 kcal/mol with the four active sites P1, P2, P3, and P4, respectively. By establishing conventional hydrogen bonds, pi-alkyl bonds, and non-covalent pi–pi bonds. Chrysin and luteolin showed favorable binding affinities with the four active sites, named as follows: P1–P4 (P1–chrysin = −7.5 kcal/mol; P2–chrysin = −7.9 kcal/mol; P3–chrysin = −8.1 kcal/mol; P4–chrysin = −6.9 kcal/mol; P1–luteolin = −7.3 kcal/mol; P2–luteolin = −7.6 kcal/mol; P3–luteolin = −8.1 kcal/mol; P4–luteolin = −7.3 kcal/mol). The binding affinity of these two propolis derivatives was stabilized by pi−sigma bonds, pi−alkyl bonds, conventional hydrogen bonds, pi-cation interactions, non-covalent pi–pi bonds, and carbon–hydrogen bonds. According to free energy calculations performed with Prime MM-GBSA, the complexes formed by chrysin demonstrated the most stable interactions due to Van der Waals and lipophilic forces. Luteolin formed significant interactions, but slightly weaker than those of chrysin. These results reveal the inhibitory potential of chrysin and luteolin with protein active sites. MD simulations corroborated the excellent stability of complexes formed by chrysin, as indicated by low RMSD values, suggesting favorable dynamic behavior. Conclusions: These results highlight the potential of chrysin as a versatile inhibitor capable of interacting with the four active sites. These findings are a strong foundation for further experimental confirmations. Full article

(This article belongs to the Section Medicinal Chemistry)

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26 pages, 5063 KB

Open AccessArticle

Blocking ASIP to Protect MC1R Signaling and Mitigate Melanoma Risk: An In Silico Study

by Farah Maarfi, Mohammed Cherkaoui, Sana Afreen and Mohd Yasir Khan

Pharmaceuticals 2026, 19(1), 114; https://doi.org/10.3390/ph19010114 - 8 Jan 2026

Abstract

Background: Melanin protects skin and hair from the effects of ultraviolet (UV) radiation damage, which contributes to all forms of skin cancer, including melanoma. Human melanocytes produce two main types of melanin: eumelanin provides effective photoprotection, and pheomelanin offers less protection against UV-induced [...] Read more.

Background: Melanin protects skin and hair from the effects of ultraviolet (UV) radiation damage, which contributes to all forms of skin cancer, including melanoma. Human melanocytes produce two main types of melanin: eumelanin provides effective photoprotection, and pheomelanin offers less protection against UV-induced skin damage. The agouti signaling protein (ASIP) antagonizes the melanocortin-1 receptor (MC1R), hinders melanocyte signaling, and shifts pigmentation toward pheomelanin, promoting UV vulnerability. In this study, we aim to discover compounds that inhibit ASIP–MC1R interaction and effectively preserve eumelanogenic signaling. Methods: The ASIP–MC1R interface-based pharmacophore model from ASIP is implicated in MC1R receptor protein engagement. We performed virtual screening with a validated pharmacophore model for ~4000 compounds curated from ZINCPharmer and applied drug-likeness filters, viz. ADMET and toxicity profiling tests. Further, the screened candidates were targeted for docking to the ASIP C-terminal domain corresponding to the MC1R-binding moiety. Top compounds underwent a 100-nanosecond (ns) run of molecular dynamics (MD) simulations to assess complex stability and persistence of key contacted residues. Results: Sequential triage, including pharmacophore, ADME–toxicity (ADMET), and docking/ΔG, yielded a focused group of candidates against ASIP antagonists with a favorable fit value. The MD run for 100 ns supported pose stability at the targeted pocket. Based on these predictions and analyses, compound ZINC14539068 was screened as a new potent inhibitor of ASIP to preserve α-MSH-mediated signaling of MC1R. Conclusions: Our in silico pipeline identifies ZINC14539068 as a potent inhibitor of ASIP at its C-terminal interface. This compound is predicted to disrupt ASIP–MC1R binding, thereby maintaining eumelanin-biased signaling. These findings motivate experimental validation in melanocytic models and in vivo studies to confirm pathway modulation and anti-melanoma potential. Full article

(This article belongs to the Section AI in Drug Development)

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21 pages, 8145 KB

Open AccessArticle

Scutellarein from Erigeron breviscapus Inhibits Apoptosis-Mediated Epithelial Barrier Disruption and Alleviates Cigarette Smoke-Induced Lung Injury

by Chuchu Xi, Hongrong Fu, Xu Qin, Yujing Wang, Kerui Ren, Mengmeng Song, Huaduan Liang, Fang Zhao and Zhengyu Cao

Pharmaceuticals 2026, 19(1), 113; https://doi.org/10.3390/ph19010113 - 8 Jan 2026

Abstract

Background/Objectives: Cigarette smoke (CS) drives pathogenesis across the spectrum of chronic respiratory disorders, exerting its detrimental effects primarily through oxidative stress and programmed cell death. Scutellarein (Scu), a botanical-origin flavonoid enriched in respiratory therapeutics-oriented Chinese medicinal herbs, demonstrates established anti-inflammatory applications. This [...] Read more.

Background/Objectives: Cigarette smoke (CS) drives pathogenesis across the spectrum of chronic respiratory disorders, exerting its detrimental effects primarily through oxidative stress and programmed cell death. Scutellarein (Scu), a botanical-origin flavonoid enriched in respiratory therapeutics-oriented Chinese medicinal herbs, demonstrates established anti-inflammatory applications. This study systematically evaluated the protective roles of Scu against CS-induced lung injury and explored the underlying mechanisms. Methods: Subacute CS-exposed mice were used to evaluate the therapeutic effects of Scu on lung injury. Immunofluorescence and quantitative PCR were used to examine the expression levels of junctional proteins and proinflammatory mediators. Apoptotic cell death was quantified using Annexin V-FITC/7-AAD staining. Transepithelial electrical resistance and dextran permeability assay were used to access the barrier integrity in alveolar epithelial MLE-12 cells. Western blotting was used to detect the changes in the signal pathway. Results: In CS-exposed mice, Scu administration dose-dependently reduced histopathological scores, pulmonary edema, changes in the alveolar structure, and inflammatory cell infiltration. In MLE-12 cells, Scu significantly suppressed cigarette smoke condensate (CSC)-induced inflammatory mediators, oxidative stress, caspase-3 activation, and apoptosis and preserved CSC-suppressed tight junction protein expression and barrier disruption. Scu also rescued CSC-altered expression levels of Hrk, Ecscr, and Myo5b and mitigated the CSC-suppressed PI3K/AKT/mTOR pathway. Conclusions: Scu alleviates CS-induced subacute lung injury through its antioxidant, anti-apoptotic effects to maintain epithelial barrier integrity likely via the mitigation of the CSC-suppressed PI3K/AKT/mTOR pathway. Full article

(This article belongs to the Section Pharmacology)

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2 pages, 150 KB

Open AccessCorrection

Correction: Iacovitti et al. The Prevalence and Malignancy Risk of Breast Incidental Uptake Detected by PET/CT with Different Radiopharmaceuticals: An Updated Systematic Review and Meta-Analysis. Pharmaceuticals 2025, 18, 1831

by Cesare Michele Iacovitti, Andreea Marin, Slavko Tasevski, Chiara Martinello, Marco Cuzzocrea, Gaetano Paone, Alessio Rizzo, Domenico Albano and Giorgio Treglia

Pharmaceuticals 2026, 19(1), 112; https://doi.org/10.3390/ph19010112 - 8 Jan 2026

Abstract

There was an error in the original publication [...] Full article

22 pages, 5268 KB

Open AccessArticle

Herba Patriniae Component Linarin Induces Cell Cycle Arrest and Senescence in Non-Small-Cell Lung Cancer Associated with Cyclin A2 Downregulation

by Wen Xie, Xia Li, Dongmei Huang, Jiana Xu, Minghan Yu, Yanping Li and Qing K. Wang

Pharmaceuticals 2026, 19(1), 111; https://doi.org/10.3390/ph19010111 - 8 Jan 2026

Abstract

Background: Non-small-cell lung cancer (NSCLC) remains a major therapeutic challenge due to its high incidence and mortality. Herba Patriniae (HP), a traditional Chinese medicine, has long been used for respiratory disorders and exhibits anti-cancer potential. However, the therapeutic effects of HP on [...] Read more.

Background: Non-small-cell lung cancer (NSCLC) remains a major therapeutic challenge due to its high incidence and mortality. Herba Patriniae (HP), a traditional Chinese medicine, has long been used for respiratory disorders and exhibits anti-cancer potential. However, the therapeutic effects of HP on NSCLC and the underlying mechanisms have not been fully elucidated. Methods: Network pharmacology was applied to identify the core active components of HP and their potential targets in NSCLC. The anti-cancer effects of the core HP component Linarin on the malignant phenotypes of NSCLC cells were characterized using Tumor Protein P53 (p53) wild-type A549 and p53-null H1299 cell lines with Cell Counting Kit-8 (CCK-8), EdU fluorescence staining, colony formation, apoptosis analysis, cell cycle analysis, and senescence-associated β-galactosidase (SA-β-gal) staining, together with molecular docking and Western blotting analyses. Results: Network pharmacology analysis identified Linarin as the core active component of HP and screened out six hub targets, including Cyclin Dependent Kinase 1/4 (CDK1/4), Cyclin A2/B1 (CCNA2/B1), and Checkpoint Kinase 1/2 (CHEK1/2), which were found to be mainly enriched in cell cycle and senescence pathways. In vitro assays showed that Linarin dose-dependently (0–200 μM) inhibited NSCLC cell proliferation, induced G0/G1 phase arrest, and promoted cellular senescence and apoptosis in both cell lines, irrespective of p53 status. Molecular docking confirmed strong binding affinities between Linarin and the hub targets, and Western blotting confirmed that Linarin downregulated CCNA2/B1 and CHEK1. Conclusions: This study demonstrates that Linarin, the core active component of HP, exerts potent anti-NSCLC effects by inducing G0/G1 arrest, senescence, and apoptosis. These effects are associated with the downregulation of key cell cycle regulators, including CCNA2/B1 and CHEK1. Together, these findings highlight the potential of Linarin as a promising therapeutic option for NSCLC. Full article

(This article belongs to the Special Issue Adjuvant Therapies for Cancer Treatment: 2nd Edition)

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16 pages, 622 KB

Open AccessArticle

Effect of Celery Seed (Apium graveolens L.) Administration on the Components of Metabolic Syndrome, Insulin Sensitivity, and Insulin Secretion: A Clinical Trial

by Miriam de J. Escobedo-Gutiérrez, Marisol Cortez-Navarrete, Esperanza Martínez-Abundis and Karina G. Pérez-Rubio

Pharmaceuticals 2026, 19(1), 110; https://doi.org/10.3390/ph19010110 - 7 Jan 2026

Abstract

Background/Objectives: Metabolic syndrome (MetS) is a group of cardiometabolic risk factors whose current management relies on lifestyle changes and pharmacological interventions, frequently involving multiple medications. Therefore, the demand for therapies capable of delivering comprehensive management of MetS is increasing. In this context, [...] Read more.

Background/Objectives: Metabolic syndrome (MetS) is a group of cardiometabolic risk factors whose current management relies on lifestyle changes and pharmacological interventions, frequently involving multiple medications. Therefore, the demand for therapies capable of delivering comprehensive management of MetS is increasing. In this context, nutraceuticals such as celery seed have attracted increasing scientific interest. This study aimed to evaluate the effect of celery seed (Apium graveolens L.) administration on the components of MetS, insulin sensitivity, and insulin secretion. Methods: A randomized, double-blind, placebo-controlled clinical trial was carried out in 28 patients with MetS. Fourteen patients randomly received celery seed (150 mg/day) for 12 weeks, and 14 subjects received a placebo. Clinical and laboratory determinations were evaluated at baseline and the end of the study. Results: After celery seed administration, patients showed a significant decrease in their systolic blood pressure (SBP) (121.0 ± 9.7 mmHg vs. 115.7 ± 12.8 mmHg, p = 0.005), diastolic blood pressure (DBP) (82.2 ± 5.9 mmHg vs. 78.5 ± 8.6 mmHg, p = 0.013), triglycerides (TG) (2.3 ± 0.9 mmol/L vs. 1.8 ± 0.6 mmol/L, p = 0.016), very low-density lipoprotein (VLDL) (0.4 ± 0.1 mmol/L vs. 0.3 ± 0.1 mmol/L, p = 0.016) and uric acid (297.4 ± 53.5 µmol/L vs. 261.7 ± 53.5 µmol/L, p = 0.009). Insulin sensitivity and insulin secretion showed no statistically significant differences in the celery seed group. Conclusions: Celery seed administration significantly reduced SBP, DBP, TG, VLDL, and uric acid. The protocol was registered at ClinicalTrials.gov with the identifier NCT06061926. Full article

(This article belongs to the Special Issue Medicinal Plants: Exploring Plant-Based Bioactive Compounds for Metabolic Diseases Prevention and Intervention)

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14 pages, 4737 KB

Open AccessArticle

Phytochemical Optimization and Anti-Inflammatory Mechanism of an Aerial-Part Extract from Echinacea purpurea in DSS-Induced Colitis

by Huanhuan Jia, Geng Lu, Sa Huang, Chuangzan Yang, Zhixuan Peng, Junfeng Ban, Huanling Xing and Hong Wu

Pharmaceuticals 2026, 19(1), 109; https://doi.org/10.3390/ph19010109 - 7 Jan 2026

Abstract

Objective: Echinacea purpurea, an herb with diverse pharmacological activities, has its roots widely used for anti-inflammatory and immunomodulatory purposes. Interestingly, its aerial parts, which are also rich in bioactive compounds, remain underutilized. This study aims to optimize the extraction and purification [...] Read more.

Objective: Echinacea purpurea, an herb with diverse pharmacological activities, has its roots widely used for anti-inflammatory and immunomodulatory purposes. Interestingly, its aerial parts, which are also rich in bioactive compounds, remain underutilized. This study aims to optimize the extraction and purification processes to obtain the aerial part extract of Echinacea purpurea (APE-EP) to enhance the content of active constituents and improve its anti-inflammatory and immunomodulatory effects. Methods: We analyzed the chemical composition of APE-EP using HPLC-MS. The intestinal absorption characteristics of APE-EP were evaluated using an ex vivo everted gut sac assay. Furthermore, the anti-inflammatory and immunomodulatory effects of APE-EP were validated using a DSS-induced colitis mouse model. Results: Several phenolic acids were identified, including chicoric acid and caffeic acid, which have significant antioxidant and anti-inflammatory activities. The everted gut sac assay revealed concentration-dependent absorption of chicoric acid in the gut. Results from the mouse model showed that APE-EP promoted macrophage polarization from pro-inflammatory M1 to anti-inflammatory M2 macrophages at the lesion sites, effectively suppressing inflammation and alleviating colitis-related pathological damage. Conclusions: This study enhances the medicinal value of the E. purpurea, provides new insights for the efficient utilization of plant resources, and offers a potential natural drug candidate for inflammatory bowel disease treatment. Full article

(This article belongs to the Section Natural Products)

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42 pages, 9322 KB

Open AccessArticle

Characterization of a New Biocomposite Based on Bioactive Compounds from Ganoderma lucidum and Jellyfish Collagen Destined for In Vitro Evaluation of Antitumor Effects in the Oral Cavity

by Carolina Pascale, Alexandru Burcea, Claudia Florina Bogdan-Andreescu, Emin Cadar, Antoanela Popescu, Ticuta Negreanu-Pirjol, Florica Busuricu, Ana-Maria Pesterau, Adrian Cosmin Rosca and Rodica Sirbu

Pharmaceuticals 2026, 19(1), 108; https://doi.org/10.3390/ph19010108 - 7 Jan 2026

Abstract

Background/Objectives: Oral squamous cell carcinoma (OSCC) remains a major therapeutic challenge due to treatment-related toxicity and impaired oral tissue regeneration. This study aimed to develop and characterize a novel biocomposite based on bioactive compounds from Ganoderma lucidum incorporated into marine collagen derived from [...] Read more.

Background/Objectives: Oral squamous cell carcinoma (OSCC) remains a major therapeutic challenge due to treatment-related toxicity and impaired oral tissue regeneration. This study aimed to develop and characterize a novel biocomposite based on bioactive compounds from Ganoderma lucidum incorporated into marine collagen derived from Rhizostoma pulmo and to evaluate its physicochemical properties, antioxidant and antimicrobial activities, and in vitro antitumor potential in the oral cavity. Methods: Hydroalcoholic extracts of G. lucidum and pepsin-soluble collagen peptides from R. pulmo jellyfish were prepared and combined to obtain two hydrogel biocomposites with different component ratios. Chemical and structural characterization was performed using HPLC-DAD, SDS-PAGE, FT-IR, circular dichroism, and spectrophotometric assays. Antioxidant activity was assessed by DPPH radical scavenging and reducing power assays, while antimicrobial activity was evaluated against oral pathogens using diffusion and MIC methods. In vitro biological activity was investigated using MTT viability and scratch migration assays on human OSCC cell lines (SCC-9 and HSC-3). Results: The biocomposites preserved the structural integrity of type I collagen and incorporated polysaccharides and polyphenols from G. lucidum. The combined formulations showed enhanced antioxidant and antimicrobial activities compared with collagen alone. In vitro assays demonstrated dose- and time-dependent reductions in OSCC cell viability and delayed cell migration, with effects comparable to those of G. lucidum extract. Conclusions: The G. lucidum–R. pulmo biocomposite exhibits favorable physicochemical properties and demonstrates antioxidant, antimicrobial, and in vitro antitumor activity. These findings support its potential as a multifunctional biomaterial for further investigation as an adjunct approach in oral cancer-related applications. Full article

(This article belongs to the Special Issue Research Progress and Drug Intervention Strategies for Oral Health-Related Diseases)

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