Pharmaceuticals

31 pages, 2036 KB

Open AccessReview

Cardiovascular Effects, Phytochemistry, Drug Interactions, and Safety Profile of Foeniculum vulgare Mill. (Fennel): A Comprehensive Review

by Amal Zahi, Amama Rani, Nahida Aktary, Muntajin Rahman, Hassane Mekhfi, Abderrahim Ziyyat, Moon Nyeo Park, Abdelkhaleq Legssyer and Bonglee Kim

Pharmaceuticals 2025, 18(11), 1761; https://doi.org/10.3390/ph18111761 - 19 Nov 2025

Abstract

Background/Objectives: Cardiovascular diseases remain the leading cause of mortality worldwide. According to the World Heart Federation, more than 500 million people were living with cardiovascular diseases in 2021. In this context, the use of medicinal plants has become increasingly widespread in populations as [...] Read more.

Background/Objectives: Cardiovascular diseases remain the leading cause of mortality worldwide. According to the World Heart Federation, more than 500 million people were living with cardiovascular diseases in 2021. In this context, the use of medicinal plants has become increasingly widespread in populations as a preventive strategy against cardiovascular disorders. Foeniculum vulgare Mill., commonly known as fennel, is an aromatic and medicinal plant recognized for its beneficial properties in the treatment of various ailments, due to its richness in bioactive compounds. This review aims to summarize and analyze the cardiovascular activities of this plant, based on experimental evidence, and to provide an updated overview of its phytochemical composition and safety profile. Methods: A comprehensive literature search was conducted using databases including PubMed, Scopus, Web of Science, and Google Scholar, encompassing all publications available up to 2024. This search included research articles, reviews, mini-reviews, and clinical studies published in English. Exclusion criteria comprised publication types such as letters, conference abstracts, unpublished theses, and non-peer-reviewed reports. Studies were also excluded if they did not specifically address Foeniculum vulgare Mill. or its cardiovascular activities. All studies were screened according to predefined inclusion and exclusion criteria, and relevant data were systematically extracted and analyzed to synthesize current knowledge on the cardiovascular activities, mechanisms of action, phytochemical composition, safety, and potential drug interactions of Foeniculum vulgare Mill. Results: Numerous in vitro and in vivo studies have demonstrated that Foeniculum vulgare Mill. exhibits a wide range of activities beneficial for cardiovascular health. These include antihypertensive, cardioprotective, vasorelaxant, anti-inflammatory, antioxidant, diuretic, hypotensive, hypolipidemic, antiplatelet, and anticoagulant effects. Such pharmacological actions are largely attributed to its rich phytochemical composition, particularly its volatile oils (e.g., trans-anethole, fenchone), flavonoids (e.g., quercetin, kaempferol), and phenolic acids (e.g., p-coumaric acid, ferulic acid). Most studies report no significant signs of toxicity. Conclusions: Foeniculum vulgare Mill. emerges as a promising medicinal plant for the prevention and management of cardiovascular diseases, owing to its multifaceted beneficial effects and its favorable safety profile. However, potential interactions with cardiovascular drugs and the current limitations of existing studies highlight the need for further clinical research to fully establish its therapeutic potential. Full article

(This article belongs to the Special Issue Bioactive Compounds from Plants and Foods: From Traditional Medicine to Modern Applications in Nutrition and Health)

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15 pages, 2282 KB

Open AccessArticle

Modelling the Full-Length Inactive PKC-δ Structure to Explore Regulatory Accessibility and Selective Targeting Opportunities

by Rasha Khader and Lodewijk V. Dekker

Pharmaceuticals 2025, 18(11), 1760; https://doi.org/10.3390/ph18111760 - 18 Nov 2025

Abstract

Background/Objectives: Protein kinase C-δ (PKC-δ) is a pivotal regulator of cellular signalling, and its dysregulation contributes to oncogenesis. While certain isolated PKC-δ domains have been crystallised, the full-length architecture and interdomain interactions remain largely unresolved, limiting mechanistic insight and the design of selective [...] Read more.

Background/Objectives: Protein kinase C-δ (PKC-δ) is a pivotal regulator of cellular signalling, and its dysregulation contributes to oncogenesis. While certain isolated PKC-δ domains have been crystallised, the full-length architecture and interdomain interactions remain largely unresolved, limiting mechanistic insight and the design of selective modulators. We aimed to define the full-length, inactive conformation of PKC-δ and identify accessible, functionally relevant binding sites for ligand discovery. Methods: We generated a consensus structural model of full-length inactive PKC-δ using multi-template comparative modelling guided by established inactivity markers. Molecular docking was used to predict ligands targeting the C2 domain, which were subsequently validated in breast cancer cell models, including wild-type and C2 domain-overexpressing lines. Results: Analysis of the model revealed the architecture of the C2/V5 interdomain space, providing a structural rationale for regulation of the nuclear localisation signal (NLS). Docking identified two ligand classes: ligand 1 engaged a C2 domain surface oriented toward the C2/V5 pocket, while ligand 2 targeted the C2 domain phosphotyrosine-binding domain (PTD). Experimental validation in breast cancer cell models demonstrated that both ligands reduced cell viability; ligand 1 showed enhanced effects in C2-overexpressing cells, consistent with predicted accessibility, whereas ligand 2 partially counteracted the C2 domain-induced viability phenotype, likely via interference with PTD-mediated interactions. Conclusions: Full-length structural context is essential for identifying accessible, functionally relevant binding sites and understanding context-dependent kinase regulation. Integrating computational modelling with phenotypic validation establishes a framework for selective PKC-δ modulation, offering insights to guide ligand discovery, improve isoform selectivity, and inform strategies to mitigate kinase inhibitor resistance in precision oncology. Full article

(This article belongs to the Special Issue Structural Insights into Protein Kinases-Targeted Therapies: Overcoming Resistance and Advancing Precision Oncology)

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27 pages, 9854 KB

Open AccessArticle

DHDK, a Plant-Derived Natural Small Molecule, Protects Against Doxorubicin-Induced Cardiotoxicity via the PPARG-CPT1B-FAO Axis

by Jing Hong, Fangyu Zhang, Ruizhen Zhang, Hongyang Fu, Dongang Shen, Xinyue Wang, Yuting Yang, Jiamei Wu, Lin Meng, Hongyang Lü, Xiwei Jiang and Yunli Zhao

Pharmaceuticals 2025, 18(11), 1759; https://doi.org/10.3390/ph18111759 - 18 Nov 2025

Abstract

Background: Doxorubicin (DOX) is a highly effective chemotherapy drug, but its use is limited by dose-dependent cardiotoxicity, driving the search for protective natural products. Although the herb Viscum coloratum (Kom.) Nakai is known for its cardiovascular benefits, the cardioprotective effects and mechanisms of [...] Read more.

Background: Doxorubicin (DOX) is a highly effective chemotherapy drug, but its use is limited by dose-dependent cardiotoxicity, driving the search for protective natural products. Although the herb Viscum coloratum (Kom.) Nakai is known for its cardiovascular benefits, the cardioprotective effects and mechanisms of its isolated compound, DHDK, remain unexplored. Methods: The protective effect of DHDK was first evaluated in DOX-injured H9c2 cardiomyocytes. Subsequently, an integrated network toxicology (incorporating DOX-induced toxicity targets and relevant chronic disease pathways such as aging and lipid metabolism) and pharmacology (DHDK) approach identified core targets, which were then refined through Protein–Protein Interaction (PPI) analysis and molecular docking. The underlying mechanism was investigated using lipidomics and validated through a series of in vitro assays, including CCK-8, q-PCR, biochemical tests, and flow cytometry, as well as in an in vivo rat model. Results: DHDK significantly alleviated DOX-induced cardiomyocyte toxicity. Integrated analysis identified 56 intersecting targets, with PPARG confirmed as the primary target via PPI and molecular docking. Lipidomics revealed that DHDK potently attenuated DOX-induced accumulation of pathogenic lipids (e.g., fatty acids, ceramides). Mechanistically, DHDK activated PPARG, which in turn upregulated CPT1B, a key regulator of fatty acid β-oxidation (FAO). This enhanced cell viability, ATP production, and mitochondrial membrane potential while reducing oxidative stress. These protective effects, which were abolished by the inhibition of PPARG or CPT1B, were further validated in vivo. Conclusion: This study demonstrates that DHDK exerts its cardioprotective effect by activating the PPARG-CPT1B-FAO axis, effectively correcting lipid metabolic disorders. Given that lipid dysregulation is a hallmark of various internal metabolic diseases, DHDK may also hold therapeutic potential for other heart conditions driven by metabolic disturbances, such as diabetic cardiomyopathy, highlighting its broad relevance to the field of internal diseases. Full article

(This article belongs to the Special Issue Plant-Derived Products in the Treatment of Internal Diseases: 2nd Edition)

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21 pages, 3428 KB

Open AccessArticle

Thymoquinone Overcomes Hypoxia-Induced Carboplatin Resistance Through ROS-Independent Apoptosis but Promotes Cancer Stem Cell Enrichment: Implications on Oral Cancer Adaptation and Recurrence

by Ishrat Rahman, Hanan Henidi, Manal M. Alkahtani, Zaha Al Makhlafi, Sahar ElRefai, Manal A. AlSheddi, Rizwan Ali, Sara K. Albassam, Hazar S. Alharbi, Maha G. Omar, Hend M. Salem, Alia Alturki, Hourya Alnofaie, Arwa Alharbi, Nuha Aloraini, Reema Alswied, Samaa Almutairi, Joud Alshahrani, Reem Fahad Alsuwaidan, Shrooq Alqahtani, Aalia Alharthi, Hadeel Alzahrani, Raghad Alkhattabi and Shams A. Altwaim Show full author list Hide full author list

Pharmaceuticals 2025, 18(11), 1758; https://doi.org/10.3390/ph18111758 - 18 Nov 2025

Abstract

Background: Carboplatin is a first-line chemotherapy agent for patients with oral squamous cell carcinoma (OSCC), but chemoresistance significantly impacts treatment outcomes. This study evaluated the ability of thymoquinone, a natural metabolite found in food products, to modulate cytotoxicity, ROS, apoptosis, autophagy, and cancer [...] Read more.

Background: Carboplatin is a first-line chemotherapy agent for patients with oral squamous cell carcinoma (OSCC), but chemoresistance significantly impacts treatment outcomes. This study evaluated the ability of thymoquinone, a natural metabolite found in food products, to modulate cytotoxicity, ROS, apoptosis, autophagy, and cancer stem cell markers in early- and late-stage OSCC cell models to identify mechanisms of chemoresistance and determine the influence of dietary metabolites on treatment outcomes. Methods: OECM-1 cells were treated with concentrations (1 mM to 1 pM) of thymoquinone, carboplatin, or their combination under normoxic and hypoxic conditions. HIF-1α levels were measured using ELISA, and cytotoxicity was assessed by the MTT assay. ROS, apoptosis, autophagy, and cell surface markers (CD44+, CD133+, CD147+) were evaluated. All experiments were repeated three times, and the data were analyzed using GraphPad Prism. Under hypoxia, HIF-1α increased 12-fold. Results: Carboplatin demonstrated reduced potency (110 μM) and efficacy (40%) compared to normoxia (82 μM, 88%), accompanied by increased apoptosis (75%) and decreased ROS (25%). Thymoquinone was more potent than carboplatin, further reducing ROS (50%), increasing apoptosis (95%), and downregulating autophagy, while the proportion of CD133+ expressing cells increased significantly (75%) in the hypoxic model. For the combined treatment across both models, thymoquinones’ efficacy remained high (>90%). Between models, no further change in any parameter was observed, except for apoptosis induction, which increased to 65% (normoxia) and 50% (hypoxia). Conclusions: Thymoquinones’ superior efficacy under hypoxic conditions demonstrates ROS-independent cytotoxic mechanisms; however, the enrichment of CD133+ cells raises essential questions about long-term therapeutic outcomes and the risks of tumor recurrence. Natural pharmaceutical metabolites can influence the tumor microenvironment, which is highly implicated in cancer therapeutics and cancer adaptation. Full article

(This article belongs to the Special Issue Natural Pharmacons: Biologically Active Plant-Based Pharmaceuticals—4th Edition)

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25 pages, 1466 KB

Open AccessReview

Golexanolone Attenuates Neuroinflammation, Fatigue, and Cognitive and Motor Impairment in Diverse Neuroinflammatory Disorders

by Marta Llansola, Gergana Mincheva, Yaiza M. Arenas, Paula Izquierdo-Altarejos, Maria A. Pedrosa, Thomas P. Blackburn, Torbjörn Bäckström, Bruce F. Scharschmidt, Magnus Doverskog and Vicente Felipo

Pharmaceuticals 2025, 18(11), 1757; https://doi.org/10.3390/ph18111757 - 18 Nov 2025

Abstract

Background and Objectives: Neuroinflammation plays a significant role in liver and neurological disorders via its disruption of neurotransmission, which alters cerebral function, resulting in cognitive and motor impairment, fatigue, anxiety, and depression. A key interaction exists between GABAergic neurotransmission and neuroinflammation, whereby [...] Read more.

Background and Objectives: Neuroinflammation plays a significant role in liver and neurological disorders via its disruption of neurotransmission, which alters cerebral function, resulting in cognitive and motor impairment, fatigue, anxiety, and depression. A key interaction exists between GABAergic neurotransmission and neuroinflammation, whereby excessive GABA_A receptor activation exacerbates cognitive and behavioural impairment. Golexanolone, a novel GABA_A-receptor-modulating steroid antagonist (GAMSA), primarily attenuates GABAergic potentiation via GABA_A-positive steroid allosteric receptor modulators such as allopregnanolone. This review aims to summarize new evidence showing that golexanolone improves peripheral inflammation, neuroinflammation, and neurological alterations in animal models of different neurological pathologies. We provide an overview of the first clinical trial using this novel compound. Results: In rat models of hyperammonemia and minimal hepatic encephalopathy (MHE), peripheral inflammation induces microglia and astrocyte activation and neuroinflammation, altering GABAergic neurotransmission and resulting in cognitive and motor impairment. Golexanolone’s unique dual action reduces peripheral inflammation and glial activation, thus normalizing neurotransmission and cognitive and motor function. Furthermore, a phase II study in cirrhotic patients with MHE shows that golexanolone is well tolerated and improves cognition. Similarly, in a model of primary biliary cholangitis (PBC) involving bile-duct ligation, peripheral inflammation, neuroinflammation, and altered neurotransmission—associated with fatigue, impaired memory, and locomotor gait and motor incoordination—were reversed by the dual action of golexanolone. In the Parkinson’s disease (PD) rat model induced by neurotoxin 6-OHDA, rats exhibited fatigue, anhedonia, impaired memory, and locomotor gait and motor incoordination, which were associated with microglia and astrocyte activation in the substantia nigra and striatum, in addition to tyrosine hydroxylase (TH) loss. Golexanolone reduces microglia and astrocyte activation, partially reduces TH loss, and improves fatigue, anhedonia, memory, locomotor gait, and motor incoordination. Golexanolone also normalizes elevated levels of α-synuclein. Conclusions: These findings suggest that golexanolone has beneficial therapeutic effects for treating fatigue, depression, motor, and cognitive impairment across diverse neuroinflammatory conditions, including synucleinopathies. Full article

(This article belongs to the Special Issue Innovative Approaches to GABAergic Drug Discovery: From Molecular Mechanisms to Advanced Therapeutics)

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20 pages, 1717 KB

Open AccessArticle

Coleus aromaticus Benth.—A Plant with Strong Anticancer and Antioxidant Potential In Vitro

by Justyna Stefanowicz-Hajduk, Anna Hering, Rafał Hałasa, Szymon Masiak, Karolina Turczyn, J. Renata Ochocka and Monika Asztemborska

Pharmaceuticals 2025, 18(11), 1756; https://doi.org/10.3390/ph18111756 - 18 Nov 2025

Abstract

Background/Objectives: Gastrointestinal cancers, including gastric and colon cancers, constitute a serious threat to global health due to their high incidence and limited treatment outcomes. Thus, natural products are becoming increasingly popular as potential chemopreventive agents. Coleus aromaticus Benth. is mainly used as [...] Read more.

Background/Objectives: Gastrointestinal cancers, including gastric and colon cancers, constitute a serious threat to global health due to their high incidence and limited treatment outcomes. Thus, natural products are becoming increasingly popular as potential chemopreventive agents. Coleus aromaticus Benth. is mainly used as a tasty addition to dishes and juices due to its aromatic and nutritional properties. The plant has many biological and pharmacological effects that require deeper evaluation. In this study, anticancer, antioxidant, and antimicrobial activities of ethanol, ethanol/water extracts, and juice from C. aromaticus leaves were evaluated. Methods: (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) MTT assay, DPPH (2,2-diphenyl-1-picrylhydrazyl), ABTS (2,2-azinobis-(3-ethylbenzothiazoline-6-sulfonate)), molybdenum reducing power assay, and broth microdilution technique were used, respectively. Additionally, total phenolic (TPC) and total flavonoid content (TFC) with basic phytochemical composition of volatile compounds by GC-MS and GC-FID were assessed. Results: The results indicate that the strongest anticancer activity was provided by the ethanol extract with IC₅₀ values of 4.94 ± 0.48 and 24.99 ± 1.80 µg/mL on human gastric AGS cells and human colorectal HCT 116 cells, respectively. The antioxidant potential was also the highest for the ethanol extract with IC₅₀ values of 13.34 ± 0.11 (ABTS), 22.90 ± 1.30 (DPPH), and 290.17 ± 4.23 µg/mL (molybdenum reducing power). Antimicrobial experiments revealed that ethanol and ethanol/water extracts were the most potent on Clostridium perfringens (MIC value was <0.02 mg/mL). Phytochemical analysis showed a significant content of phenolic and flavonoid compounds in the ethanol extract (75.87 ± 0.96 mg gallic acid equivalent/g dry extract and 176.01 ± 3.58 mg quercetin equivalent/g dry extract, respectively). Furthermore, all the extracts contained carvacrol (49.09, 28.15, and 25.68% of volatile fraction in ethanol, ethanol/water extracts and juice, respectively). Camphor and oleamide were also detected in large quantity. Conclusions: C. aromaticus can be considered as a potential agent in the prevention and treatment of gastrointestinal cancers, especially the ethanol extract from the plant leaves due to its strong anticancer and antioxidant properties. Full article

(This article belongs to the Special Issue Natural Compounds as Potential Anticancer, Anti-inflammatory and Antioxidant Agents in Medicine)

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21 pages, 2981 KB

Open AccessArticle

Impact of Ethanol on Electrostatic Behaviour of Fluorocarbon Pharmaceutical Propellants

by Lochana Ranatunge, Manoochehr Rasekh, Hussein Ahmad and Wamadeva Balachandran

Pharmaceuticals 2025, 18(11), 1755; https://doi.org/10.3390/ph18111755 - 18 Nov 2025

Abstract

Background/Objectives: Triboelectrification in fluid systems, and specifically in hydrofluorocarbon (HFC)-based propellants, used in pressurised metered-dose inhalers (pMDIs) remains understudied despite its impact on aerosol behaviour and does delivery. This study investigates how ethanol concentration affects charge generation and dissipation in HFC-152a (1,1-difluoroethane; R152a) [...] Read more.

Background/Objectives: Triboelectrification in fluid systems, and specifically in hydrofluorocarbon (HFC)-based propellants, used in pressurised metered-dose inhalers (pMDIs) remains understudied despite its impact on aerosol behaviour and does delivery. This study investigates how ethanol concentration affects charge generation and dissipation in HFC-152a (1,1-difluoroethane; R152a) flowing through low-density polyethylene (LDPE) tubing, a common valve-stem material in pMDIs. Methods: Controlled experiments measured electrical current, charge accumulation, and flow stability for HFC-152a with varying ethanol concentrations in LDPE tubing. Statistical analysis (two-way ANOVA, p < 0.05) assessed the effects of the propellant and material. Comparative tests include R134a (1,1,1,2-tetrafluoroethane) and R227ea (1,1,1,2,3,3,3-heptafluoropropane), and the tubing materials are polybutylene terephthalate (PBT), polyvinyl chloride (VINYL), polyoxymethylene (POM), and LDPE. Results: Increasing ethanol concentration produced larger measured currents, reduced net charge accumulation, and improved flow stability; these effects are attributed to ethanol’s higher dielectric constant and conductivity enhancing charge mobility and dissipation. Significant propellant x material interactions were found (p < 0.05): R152a generated the largest responses with PBT and VINYL (~16 nA and ~5.6 nA, respectively), R227ea showed higher responses with POM and LDPE (~8 nA), and R134a delivered the highest flow rates across materials but exhibited limited electrical responsiveness. Conclusions: Ethanol addition mitigates undesirable electrostatic effects in HFC-based propellants by promoting charge dissipation. The results demonstrate the strong material dependence of triboelectric behaviour and underline the importance of optimising propellant–polymer pairings to minimise the electrostatic adhesion of aerosolised particles and improve pMDI drug delivery performance. Full article

(This article belongs to the Special Issue Advances in Drug Analysis and Drug Development, 2nd Edition)

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27 pages, 3452 KB

Open AccessArticle

Aqueous Extracts and Flavonoids Obtained from Annona cherimola Miller as Antidiabetic Treatments Alone and in Combination with Antidiabetic Drugs: In Vivo and In Silico Studies

by Jesica Ramírez-Santos, Fernando Calzada, Julita Martínez-Rodríguez, Miguel Valdes, Elizabeth Barbosa and Claudia Velázquez

Pharmaceuticals 2025, 18(11), 1754; https://doi.org/10.3390/ph18111754 - 18 Nov 2025

Abstract

Background: Annona cherimola Miller (A. cherimola) is traditionally used in Mexico to treat diabetes. Objectives: this study aimed to evaluate the antihyperglycemic activity of the aqueous leaf extracts (AEAcL) and stem (AEAcS) of A. cherimola alone and combined with [...] Read more.

Background: Annona cherimola Miller (A. cherimola) is traditionally used in Mexico to treat diabetes. Objectives: this study aimed to evaluate the antihyperglycemic activity of the aqueous leaf extracts (AEAcL) and stem (AEAcS) of A. cherimola alone and combined with oral antidiabetic drugs (OADs), as well as to determine their effect on % HbA1c, lipid parameters and toxicity. As well, the study aimed to isolate and identify some of its compounds to propose findings about its mode of action. Methods: Antihyperglycemic activity was evaluated using in vivo models with streptozotocin-induced experimental diabetes in Balb/c mice. Computer tools were used to obtain the pharmacokinetic and toxicological properties of the identified flavonoids; to obtain findings on their potential as α-glucosidase and SGLT1 inhibitors, in vivo and in silico studies were carried out using oral sucrose tolerance (OSTT) and glucose (OGTT) tests and molecular coupling studies. Results: ÇAEs and aSAAcS administered alone at 200 mg/kg showed a significant reduction in hyperglycemia. The best combination was AEAcL + Met (100/500 mg/kg), which significantly reduced hyperglycemic values and the % of HbA1c, TG, and LDL. The flavonoids isolated from AEAcL were identified as rutin, nicotiflorin, and narcissin. The molecular coupling assay and OSTT and OGTT tests showed that the flavonoids could inhibit α-glucosidase and SGLT1. Conclusions: AEAcL shows significant antihyperglycemic and antihyperlipidemic activity in murine models of diabetes, both alone (100 mg/kg) and in combination with metformin (100/500 mg/kg). Isolated flavonoids (rutin, nicotiflorin, and narcissine) appear to be partly responsible for these effects, although they have pharmacokinetic limitations. In silico and in vivo studies suggest a possible mechanism of action by inhibition of α-glucosidase and SGLT1. Full article

(This article belongs to the Section Natural Products)

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11 pages, 833 KB

Open AccessArticle

Structure-Activity Relationships of closo- and nido-Carborane Erlotinib Analogs: Lipophilicity as a Key Modulator of Anti-Glioma Activity

by Belén Dávila, Pablo Vignolo, Martina Silvarrey, Andrés Benítez, Juliana González Schmidt, Carmela de Arteaga Guidotti, María Fernanda García, Hugo Cerecetto and Marcos Couto

Pharmaceuticals 2025, 18(11), 1753; https://doi.org/10.3390/ph18111753 - 18 Nov 2025

Abstract

Background/Objectives: To enhance the anti-glioma activity of erlotinib, we previously developed a series of carborane-based analogs exploiting the concept of three-dimensional bioisosterism. These carboranes generally exhibited improved cytotoxicity against glioma cell lines compared with the parent compound erlotinib and additionally showed varying [...] Read more.

Background/Objectives: To enhance the anti-glioma activity of erlotinib, we previously developed a series of carborane-based analogs exploiting the concept of three-dimensional bioisosterism. These carboranes generally exhibited improved cytotoxicity against glioma cell lines compared with the parent compound erlotinib and additionally showed varying degrees of EGFR inhibition. Given the well-described influence of lipophilicity on pharmacological properties, we aimed to determine this parameter for the new analogs and explore its correlations with biological behaviors. Methods: Lipophilicity was assessed experimentally, through chromatographic procedure, in terms of R_M⁰ and theoretically via fragment-based logP calculations (flogP) using Hansch–Fujita hydrophobic parameters π of some substituents and the experimentally determined logD_n_{-octanol/buffer(7.4)} of 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline. Additionally, the electronic properties of the carborane clusters were considered using the NMR chemical shifts of cluster carbon-bound protons. Results: For the series of carboranes, the R_M⁰ discretely correlated to the flogP. Neither R_M⁰ nor flogP correlated with the electronic characteristics of the carboranes. From the correlation between R_M⁰ and flogP, it was possible to estimate the π value for a nido-carboranyl substituent. Cytotoxicities, against glioma cells, exhibited a parabolic dependence on lipophilicity, finding optimal flogP for each cellular system. Some tendencies were observed between EGFR inhibition and flogP, requiring more hydrophilic compounds for optimal wild-type EGFR inhibition or a specific flogP for mutant EGFR inhibition. It was observed that the electronic features of the boron cluster also influenced both biological activities studied. Conclusions: Unlike our previous reports, which focused on the synthesis and biological evaluation of carborane-erlotinib analogs, this study establishes for the first time the correlation of lipophilicity and electronic features with cytotoxic and EGFR-inhibitory activities, providing new insights into their structure–activity relationships. Full article

(This article belongs to the Special Issue Boron-Containing Compounds: Identification, Synthesis, Biological Actions and Pharmacology)

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16 pages, 2574 KB

Open AccessArticle

YM155 Inhibition of Survivin Enhances Carboplatin Efficacy in Metastatic Castration-Resistant Prostate Cancer

by Vicenç Ruiz de Porras, Martin K. Bakht, Maria Fernandez-Saorín, Clara Alcon, Luis Palomero, Júlia Francisco-Rodon, Mariona Figols, Joan Montero, Vincenza Conteduca, Himisha Beltran and Albert Font

Pharmaceuticals 2025, 18(11), 1752; https://doi.org/10.3390/ph18111752 - 18 Nov 2025

Abstract

Background/Objectives: Metastatic castration-resistant prostate cancer (mCRPC) remains a major clinical challenge due to its aggressive behavior and resistance to therapy. Survivin, a member of the inhibitor of apoptosis protein family, is overexpressed in various cancers and associated with poor prognosis. YM155 (Sepantronium [...] Read more.

Background/Objectives: Metastatic castration-resistant prostate cancer (mCRPC) remains a major clinical challenge due to its aggressive behavior and resistance to therapy. Survivin, a member of the inhibitor of apoptosis protein family, is overexpressed in various cancers and associated with poor prognosis. YM155 (Sepantronium bromide) suppresses survivin expression and has demonstrated antitumor activity in preclinical models. We investigated the association between survivin expression and clinical outcomes in mCRPC patients and evaluated the antitumor activity of YM155, alone and in combination with carboplatin, in mCRPC cell lines. Methods: Analysis of publicly available RNA-seq datasets from mCRPC patients was performed to assess correlations between survivin expression and clinical outcomes. Radiographic progression-free survival (rPFS) and overall survival (OS) were estimated using the Kaplan–Meier method and compared via log-rank or Fisher’s exact tests. In vitro assays were conducted on mCRPC cell lines treated with YM155, carboplatin, or both, to evaluate cell viability, clonogenicity, and apoptosis. Results: Survivin was significantly overexpressed in mCRPC compared with localized prostate cancer and was even higher in castration-resistant neuroendocrine disease. High survivin levels were associated with shorter OS (p = 0.006). In patients treated with platinum-based therapies, high survivin was also linked to shorter rPFS (p = 0.01), reduced OS (p = 0.006), and a smaller PSA decline (p = 0.006). In vitro, YM155 reduced survivin expression, impaired cell viability and colony formation, induced apoptosis, and synergistically enhanced the cytotoxicity of carboplatin. Conclusions: Our findings suggest that survivin may serve as a prognostic biomarker and potential therapeutic target in platinum-treated, AR-independent mCRPC. The integration of clinical and functional data provides translational support for combining the survivin inhibitor YM155 with platinum-based therapy. These results warrant further validation in larger patient cohorts and in vivo models. Full article

(This article belongs to the Special Issue Advances in Prostate Cancer Therapeutics)

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13 pages, 3414 KB

Open AccessArticle

9-Methylfascaplysin, a Marine-Derived Bioactive Compound, Promotes Neurite Outgrowth via the Inhibition of ROCK2

by Meilin Zheng, Kangyang Gao, Yirui Hong, Jingyang Le, Jingjing Cai, Hongze Liang and Wei Cui

Pharmaceuticals 2025, 18(11), 1751; https://doi.org/10.3390/ph18111751 - 17 Nov 2025

Abstract

Background: The impairment of neurite outgrowth is an early pathological hallmark underlying various neurodegenerative disorders. The promotion of neurite outgrowth was considered as a feasible strategy to treat neurodegenerative disorders. 9-Methylfascaplysin (9-MF), a marine-derived, bioactive compound, has exhibited multiple neuroprotective activities. Methods and [...] Read more.

Background: The impairment of neurite outgrowth is an early pathological hallmark underlying various neurodegenerative disorders. The promotion of neurite outgrowth was considered as a feasible strategy to treat neurodegenerative disorders. 9-Methylfascaplysin (9-MF), a marine-derived, bioactive compound, has exhibited multiple neuroprotective activities. Methods and Result: In this study, 9-MF at nanomolar concentrations promoted neurite outgrowth, upregulated the expression of growth-associated protein-43 (GAP-43), and increased the mitochondrial positive area with similar efficacy as retinoic acid in PC12 cells. 9-MF-associated differentiated expressed genes were enriched in mitochondria and synapse, forming a Rho-associated coiled-coil containing a protein kinase 2 (ROCK2)-centralized network. CMap analysis further identified positive connections between 9-MF-induced perturbation and perturbations caused by the inhibition of the ROCK2 pathway. Molecular docking analysis demonstrated a high binding affinity between 9-MF and ROCK2, indicating that 9-MF could inhibit ROCK2. Furthermore, 9-MF significantly reduced the phosphorylation of ROCK2 with a similar efficacy as fasudil, a ROCK2 inhibitor. Narciclasine, a known ROCK2 activator, almost completely abolished the effects of 9-MF on the induction of neurite outgrowth in PC12 cells. Conclusions: 9-MF effectively promoted neurite outgrowth possibly via the inhibition of ROCK2, providing supporting evidence that 9-MF might be developed as a novel neurological drug. Full article

(This article belongs to the Section Medicinal Chemistry)

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14 pages, 1862 KB

Open AccessArticle

Genistein Inhibits Fine-Dust-Induced Matrix Metalloproteinase-1 in Human Keratinocytes

by Dong Keun Song, Yun Young Jeong, Eunmiri Roh, Hyun Young Shin and Jong-Eun Kim

Pharmaceuticals 2025, 18(11), 1750; https://doi.org/10.3390/ph18111750 - 17 Nov 2025

Abstract

Background/Objectives: Particulate matter (PM), which comprises airborne pollutants characterized by small sizes (typically from 5 to 8 μm in Korea), adversely affect skin health and accelerate aging by inducing oxidative stress and upregulating the expression of matrix metalloproteinase-1 (MMP-1), an enzyme responsible for [...] Read more.

Background/Objectives: Particulate matter (PM), which comprises airborne pollutants characterized by small sizes (typically from 5 to 8 μm in Korea), adversely affect skin health and accelerate aging by inducing oxidative stress and upregulating the expression of matrix metalloproteinase-1 (MMP-1), an enzyme responsible for collagen degradation. The skin, which is the largest organ and the primary barrier against harmful external stimuli such as air pollution, is particularly vulnerable to continuous PM exposure, which can cause skin aging and carcinogenesis. Given the effects of PM on skin aging, identifying compounds that can mitigate these adverse effects is crucial. Genistein is a naturally occurring isoflavone that has not been extensively studied in the context of PM-induced skin aging. Methods: In this study, we investigated the protective effects of genistein against PM-induced skin aging in HaCaT human keratinocytes. Results: Our results demonstrated that genistein treatment significantly reduced PM-induced MMP-1 expression, indicating a protective effect against collagen degradation. Additionally, genistein decreased the expression of the transcription factors activator protein-1 (AP-1) and nuclear factor kappa B (NF-κB), both of which are involved in the regulation of MMP-1. Furthermore, genistein markedly reduced the production of reactive oxygen species (ROS), a key marker of oxidative stress induced by PM exposure. Conclusions: These findings suggest that genistein exerts protective effects against PM-induced skin aging by attenuating collagen degradation and oxidative stress, indicating its potential as a therapeutic agent for improving skin aging associated with PM exposure. Full article

(This article belongs to the Special Issue Bioactive Compounds Derived from Plants and Their Medicinal Potential, 2nd Edition)

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24 pages, 5161 KB

Open AccessReview

Organoselenium Compounds Derived from Natural Metabolites

by Agata J. Pacuła-Miszewska, Magdalena Obieziurska-Fabisiak and Jacek Ścianowski

Pharmaceuticals 2025, 18(11), 1749; https://doi.org/10.3390/ph18111749 - 17 Nov 2025

Abstract

Background/Objectives: Natural metabolites, due to their abundance, structural diversity, and availability in enantiomerically pure form, are broadly utilized in the synthesis of reagents, catalysts, building blocks, and potential therapeutics. To date, various organoselenium compounds, including selenides, diselenides, selenols, selenonium salts, and ylides, [...] Read more.

Background/Objectives: Natural metabolites, due to their abundance, structural diversity, and availability in enantiomerically pure form, are broadly utilized in the synthesis of reagents, catalysts, building blocks, and potential therapeutics. To date, various organoselenium compounds, including selenides, diselenides, selenols, selenonium salts, and ylides, have been created based on the scaffold of primary and secondary metabolites like amino acids, sugars, nucleic bases, terpenes, and steroids. Their synthesis and application routes as reagents and catalysts in organic synthesis and biological systems are summarized in the presented review. Methods: The gathered material has been divided into two sections—naturally derived organoselenium compounds, such as antioxidants and GPx-mimetics, and reagents utilized in modern organic transformations. Results: The review summarizes the utility of natural scaffolds in the construction of organoselenium compounds with promising applications as antioxidant-type catalysts in biological systems (GPx-mimetics) and potent reagents for organic transformations, including asymmetric reactions. Conclusions: This review provides a comprehensive overview of known organoselenium reagents derived from natural compounds, discusses the advantages of their use in medicinal chemistry and modern organic synthesis, and outlines prospective directions for future development in this area. Full article

(This article belongs to the Special Issue Organochalcogen Derivatives in Medicinal Chemistry)

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16 pages, 1661 KB

Open AccessArticle

Generating and Modeling Virtual Patient Data from Published Population Pharmacokinetic Analyses: A Vancomycin Case Study

by Moeko Suzuki, Hidefumi Kasai, Takahiko Aoyama and Yasuhiro Tsuji

Pharmaceuticals 2025, 18(11), 1748; https://doi.org/10.3390/ph18111748 - 17 Nov 2025

Abstract

Background/Objectives: In recent years, clinical pharmacometrics has become vital for drug development and clinical practice, particularly for predicting drug efficacy and safety. Population pharmacokinetic models are used for drugs for which therapeutic drug monitoring is recommended in clinical practice. Numerous population pharmacokinetic [...] Read more.

Background/Objectives: In recent years, clinical pharmacometrics has become vital for drug development and clinical practice, particularly for predicting drug efficacy and safety. Population pharmacokinetic models are used for drugs for which therapeutic drug monitoring is recommended in clinical practice. Numerous population pharmacokinetic models have been developed for patients with similar clinical and demographic characteristics, resulting in reduced inter-individual variability. Despite the existence of diverse-population pharmacokinetic models, selecting an appropriate model for bedside use remains challenging. This study proposes a model-simulated model-based meta-analysis (M-cubed) to construct a unified model capable of accommodating a wide range of patient backgrounds. Methods: Vancomycin (VCM), a drug used for therapeutic drug monitoring, was used as an example. Using information from published VCM models, the M-cubed method was employed to generate virtual patient data for each publication through simulation, followed by modeling the integrated dataset. Results: Population pharmacokinetic analysis was performed on data from 19 virtual patient models, resulting in a total of 2303 cases. Covariates in the final model included creatinine clearance and body weight. The predictive ability of the model was robust. Conclusions: A model that integrates several population studies using the M-cubed method is required to address the need in clinical practice. Full article

(This article belongs to the Special Issue Mathematical Modeling in Drug Metabolism and Pharmacokinetics)

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28 pages, 5988 KB

Open AccessArticle

Effect of Nano-Gefitinib on Solid Ehrlich Carcinoma via Targeting EGFR, RIPK2 Pathways, and Macrophage Reprogramming

by Neveen R. Ashoura, Hebatallah M. Saad, Enas I. El Zahaby, Alyaa R. Salama, Nihal E. Amer, Omnya Elhussieny, Hanan A. Edres, Hisham A. Nematalla and Salman A. A. Mohammed

Pharmaceuticals 2025, 18(11), 1747; https://doi.org/10.3390/ph18111747 - 17 Nov 2025

Abstract

Background/Objectives: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are a promising therapeutic avenue against mammary cancer. Thus, we investigated whether the EGFR inhibitor Nano-Gefitinib bilosome decreases Ehrlich tumor cells in a murine model, given that EGFR has been linked to carcinoma–macrophage crosstalk. [...] Read more.

Background/Objectives: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are a promising therapeutic avenue against mammary cancer. Thus, we investigated whether the EGFR inhibitor Nano-Gefitinib bilosome decreases Ehrlich tumor cells in a murine model, given that EGFR has been linked to carcinoma–macrophage crosstalk. Methods: Forty female mice were divided into control, Nano-Gefitinib, Ehrlich tumor and combination groups; the latter received Nano-Gefitinib treatment after tumor induction and lasted for 18 days. Results: Our results showed that Nano-Gefitinib ameliorated Ehrlich-induced hepatic injury, oxidative stress, and apoptosis in mice, as indicated by a significant reduction in serum level of hepatic enzymes, oxidative biomarkers (malondialdehyde and oxidized glutathione), total cholesterol, triglycerides, LDL, and BAX, along with an increase in antioxidant biomarkers, serum total protein, albumin, HDL, and hepatic antiapoptotic Bcl-2. A substantial reduction in tumor volume and size was noted in the combination group and was evidenced histopathologically by a reduction in tumor cell progression, mitotic activity, and giant cell formation. In addition, Nano-Gefitinib significantly inhibited EGFR/p-AKT/ERK1/2/RIPK2/NF-κB with subsequent suppression of TGF-triggered M2 macrophage reprogramming, evidenced by the lowered protein expression of the M2 surface markers CD163 and decreased M2 protein expression (Fizz1, MMPs, and VEGF). Additionally, Nano-Gefitinib significantly increased M1 macrophage phenotype, evidenced by the upregulation in the immunoexpression of the CD68, in addition to increasing CD8 and caspase-3 and decreasing CD4, with VEGF immunoreactivity in the combination group. Conclusions: Gefitinib biosomes encouraged macrophage polarization, apoptosis, and reduced inflammation, with a subsequent decrease in tumor volume. Full article

(This article belongs to the Section Pharmacology)

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14 pages, 3857 KB

Open AccessArticle

Coating Doyle Nasal Silicone Splints with a Sustained Release Varnish Containing Antibiotics Provides Long-Term Protection from Staphylococcus aureus: An In Vitro Study

by Ahmad Siag, Ronit Vogt Sionov, Irith Gati, Michael Friedman, Doron Steinberg and Menachem Gross

Pharmaceuticals 2025, 18(11), 1746; https://doi.org/10.3390/ph18111746 - 17 Nov 2025

Abstract

Background/Objectives: Doyle nasal silicone splints are commonly used in nasal surgeries to maintain the shape of the nasal passage and prevent scar tissue formation. However, these implants are prone to bacterial colonization, particularly by Staphylococcus aureus, which is associated with severely [...] Read more.

Background/Objectives: Doyle nasal silicone splints are commonly used in nasal surgeries to maintain the shape of the nasal passage and prevent scar tissue formation. However, these implants are prone to bacterial colonization, particularly by Staphylococcus aureus, which is associated with severely recurrent and recalcitrant cases of infected sinonasal cavities. The aim of this study was to develop a sustained-release varnish (SRV) with antibacterial properties that can be applied to Doyle splints to provide an antibacterial environment for an extended period. Methods: Doyle nasal splints (1 cm × 1 cm segments) were coated with SRV containing one of the three antibiotics: augmentin, ciprofloxacin, or chloramphenicol. A placebo varnish without antibiotics served as a control. The coated splints were exposed daily to a fresh culture of S. aureus, and antibacterial activity was assessed by monitoring bacterial growth. Antibiofilm activity was determined using an MTT metabolic assay. Antibacterial activity was further studied by the kinetic disk diffusion assay, where the stents were transferred daily to new, freshly coated S. aureus plates. Biofilm formation on the coated splints was visualized by high-resolution scanning electron microscopy (HR-SEM). Results: Doyle segments coated with augmentin, ciprofloxacin, or chloramphenicol effectively inhibited S. aureus planktonic growth for 9 ± 1, 18 ± 1, and 21 ± 1 days, respectively. Biofilm formation was prevented for 10 ± 1, 18 ± 1, and 21 ± 1 days, and bacterial clearance occurred for 14 ± 1, 52 ± 1, and >65 days, respectively. HR-SEM images showed the prevention of biofilm formation on the coated segments. Conclusions: Our findings demonstrate that coating Doyle nasal silicon splints with SRV containing augmentin, ciprofloxacin, or chloramphenicol provides long-term antibacterial and antibiofilm activity, with SRV–chloramphenicol being superior. Further studies are needed to confirm the in vivo efficacy of this approach. Full article

(This article belongs to the Special Issue Challenges in Discovering Innovations Related to Biofilms: Virulence, Spread, Control Strategies and Treatment)

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43 pages, 6125 KB

Open AccessArticle

Design, Synthesis, and Biological Evaluation of 5′,7-Disubstituted 7-Deaza-adenosine Analogues as Irreversible Pan-FGFR Inhibitors

by Jung Hoon Park, Phuong Thao Tran, Hye Lin Ko, Seonghee Mun, Sung Chul Jang, Dong Hyun Moon, Jaeho Han, Jieun Kim, Gibae Kim, Hongseok Choi, Seung Woo Kim, Minjae Kim, Sang Kook Lee, Byung Woo Han, Keon Wook Kang and Lak Shin Jeong

Pharmaceuticals 2025, 18(11), 1745; https://doi.org/10.3390/ph18111745 - 17 Nov 2025

Abstract

Background/Objectives: Fibroblast growth factor receptors (FGFRs) are frequently dysregulated in diverse cancers and represent important therapeutic targets. Here, we report the design and synthesis of a novel nucleoside-based scaffold which enables irreversible pan-FGFR inhibition as a potential anticancer strategy. Methods: A [...] Read more.

Background/Objectives: Fibroblast growth factor receptors (FGFRs) are frequently dysregulated in diverse cancers and represent important therapeutic targets. Here, we report the design and synthesis of a novel nucleoside-based scaffold which enables irreversible pan-FGFR inhibition as a potential anticancer strategy. Methods: A series of nucleoside analogues was synthesized and assessed through structure–activity relationship studies. Structural analyses, including X-ray co-crystallography and molecular dynamics simulations, were performed to define key determinants of potency and selectivity. Biochemical assays against FGFR1–4 proteins, cellular antiproliferative assays in HCT116 (FGFR1 amplification) and RT4 (FGFR3-TACC3) models, metabolic stability evaluations and covalent bonding confirmation were conducted to characterize representative compounds. Results: SAR studies revealed that fused aromatic substituents and 4′-thio ribose enhanced FGFR potency, whereas enantiomeric inversion of ribose reduced activity. X-ray co-crystallography further demonstrated that two hydroxyl groups form a key water-mediated hydrogen bond network, uniquely stabilizing the ligand and enhancing potency of inhibitors compared to reference compounds. The 7-methoxy-5-methylbenzo[b]thiophene scaffold and ribose moiety emerged as critical features. Compounds 13f, 19e, and 22f demonstrated potent inhibition of FGFR1-4 and dose-dependent suppression of FGFR1-mediated signaling, with strong antiproliferative activity in both FGFR-driven and wild-type cancer models. Compound 22f showed efficient irreversible covalent engagement of FGFRs, confirmed at the protein and cellular levels, and exhibited improved metabolic stability. Conclusions: Nucleoside analogues represent a privileged scaffold for covalent pan-FGFR inhibition. The findings highlight their potential as promising therapeutic candidates for targeting FGFR-driven malignancies. Future efforts will focus on further improving stability and optimizing physicochemical properties to advance these compounds toward translational development. Full article

(This article belongs to the Special Issue Advances in Enzyme Inhibitors and Protein Degraders as Anticancer Agents)

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21 pages, 1797 KB

Open AccessArticle

Volumetric Absorptive Microsampling of Saliva for Pharmacokinetic Evaluation of Mycophenolic Acid and Its Glucuronide Metabolite in Pediatric Renal Transplant Recipients: Bioanalytical Method Validation and Clinical Feasibility Evaluation

by Arkadiusz Kocur, Joanna Sobiak, Agnieszka Czajkowska, Jacek Rubik and Tomasz Pawiński

Pharmaceuticals 2025, 18(11), 1744; https://doi.org/10.3390/ph18111744 - 17 Nov 2025

Abstract

Background: Mycophenolic acid (MPA) is frequently used in pediatric renal transplantation as part of immunosuppressive therapy, yet therapeutic drug monitoring (TDM) remains challenging. Accurate monitoring is essential due to MPA’s narrow therapeutic window, variable pharmacokinetics, and high protein binding. This study examined whether [...] Read more.

Background: Mycophenolic acid (MPA) is frequently used in pediatric renal transplantation as part of immunosuppressive therapy, yet therapeutic drug monitoring (TDM) remains challenging. Accurate monitoring is essential due to MPA’s narrow therapeutic window, variable pharmacokinetics, and high protein binding. This study examined whether saliva could serve as a non-invasive alternative to plasma for measuring MPA exposure. Methods and Results: Concentrations of MPA and its primary glucuronide metabolite (MPAG) were determined in plasma, capillary blood, plasma ultrafiltrate, wet saliva, and dried saliva collected using volumetric absorptive microsampling (VAMS). A novel LC–MS/MS method for quantifying MPA and MPAG in dried saliva collected with the Mitra™ device was developed and validated within a 1–700 μg/L calibration range, demonstrating robust analytical performance. Dried and wet saliva showed high correlation (r = 0.99 and 0.98 for MPA and MPAG, respectively). However, both salivary matrices—dried saliva collected with Mitra™ (vsMPA, vsMPAG) and wet saliva (sMPA, sMPAG)—exhibited poor correlation with unbound (fMPA, fMPAG) and total plasma concentrations (tMPA, tMPAG). A modest, yet positive, correlation was observed between the measured concentrations for the following pairs: sMPA versus fMPA (r = 0.376, p = 0.1036), sMPA versus tMPA (r = 0.305, p = 0.1904), sMPAG versus fMPAG (r = 0.205, p = 0.3851), and sMPAG versus tMPAG (r = 0.472, p = 0.0012). Pharmacokinetic parameters supported these findings, highlighting discrepancies between saliva and plasma. Conclusions: From a clinical perspective, saliva sampling—although minimally invasive and patient-friendly—does not offer a reliable substitute for plasma in routine TDM of MPA and MPAG. Capillary blood collected through VAMS remains a promising alternative for long-term monitoring of pediatric patients; however, several considerations still need to be addressed. Full article

(This article belongs to the Special Issue Therapeutic Drug Monitoring: Techniques and Applications in Pharmaceutical Analysis)

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28 pages, 5847 KB

Open AccessArticle

Dual-Algorithm Integration Framework Reveals Qing-Wei-Zhi-Tong’s Dual Mechanisms in Chronic Gastritis

by Zhijie Shu, Ying Huang, Yujie Xi, Bo Zhang, Rui Cai, He Xu and Feifei Guo

Pharmaceuticals 2025, 18(11), 1743; https://doi.org/10.3390/ph18111743 - 17 Nov 2025

Abstract

Background: Chronic gastritis (CG) involves gastric mucosal imbalance, with H. pylori (>90% cases), acid-pepsin imbalance, and bile reflux as druggable mechanisms. FDA-approved drugs show limited efficacy against antibiotic-resistant strains and fail to target undruggable pathways (e.g., inflammation, autoimmune atrophy). Traditional Chinese Medicine [...] Read more.

Background: Chronic gastritis (CG) involves gastric mucosal imbalance, with H. pylori (>90% cases), acid-pepsin imbalance, and bile reflux as druggable mechanisms. FDA-approved drugs show limited efficacy against antibiotic-resistant strains and fail to target undruggable pathways (e.g., inflammation, autoimmune atrophy). Traditional Chinese Medicine (TCM), particularly Qing-Wei-Zhi-Tong micro-pills (QWZT), offers multi-target advantages, though its mechanisms remain poorly understood. Methods: The dual-algorithm integration framework predicts QWZT’s pharmacological effects to treat gastritis. For druggable processes (pathways targeted by existing drugs), the structure–target–pathway similarity algorithm quantifies QWZT similar activities to FDA drugs, validated by gastrointestinal smooth muscle experiments. For undruggable processes (novel biological mechanisms not addressed by current therapies), the multi-target perturbation algorithm predicts QWZT’s unique capacity to undruggable processes and is validated via LPS-induced inflammation in RAW264.7 and GES-1 cells. Results: Structure–target–pathway similarity algorithm identified QWZT compounds sharing prokinetic mechanisms with FDA drugs, validated by dopamine-induced relaxations and acetylcholine-induced contractions in gastrointestinal smooth muscle. Multi-target perturbation algorithm quantified QWZT’s superior disruption of undruggable immune/inflammation networks, confirmed by restored cell viability in LPS-injured GES-1 cells and significantly reduced the expression of NO, IL-6, and TNF-α in RAW264.7 cells via key compounds (paeoniflorin and berberine). Conclusions: QWZT may exert its regulatory effects on gastrointestinal smooth muscle by mediating muscarinic and dopamine receptor D2 (DRD2), and reduce the expression of NO, IL-6, and TNF-α to achieve anti-inflammatory effects, thereby effectively treating CG. The integration strategy that integrates algorithms and experiments to reveal the common and distinct mechanisms of QWZT compared to FDA-approved drugs, offering a novel approach for studying Traditional Chinese Medicine mechanisms. Full article

(This article belongs to the Section Pharmacology)

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