Pharmaceuticals

14 pages, 784 KB

Open AccessArticle

Effect of Submaximal Doses of Semaglutide in Patients with Obesity on Metabolic Profile and Serum Levels of Adipocytokines

by Martin Jozef Péč, Jakub Jurica, Monika Péčová, Norbert Nagy, Boris Focko, Zuzana Miertová, Nikola Ferencová, Ivana Ságová, Ingrid Tonhajzerová, Tomáš Bolek, Peter Galajda, Marián Mokáň and Matej Samoš

Pharmaceuticals 2025, 18(9), 1364; https://doi.org/10.3390/ph18091364 (registering DOI) - 12 Sep 2025

Abstract

Background: Obesity is closely linked to metabolic dysfunction and systemic low-grade inflammation. Glucagon-like peptide-1 receptor agonists (GLP-1RA) are increasingly utilized for obesity treatment due to their significant metabolic benefits, including weight loss and improved glycemic control. The aim of the study was to [...] Read more.

Background: Obesity is closely linked to metabolic dysfunction and systemic low-grade inflammation. Glucagon-like peptide-1 receptor agonists (GLP-1RA) are increasingly utilized for obesity treatment due to their significant metabolic benefits, including weight loss and improved glycemic control. The aim of the study was to evaluate the effect of submaximal doses of long-lasting GLP-1RA semaglutide on selected biomarkers of obesity-related inflammation, adipocytokines levels and metabolism in a real-world population of obese patients. Methods: We performed a prospective, observational study involving 32 adult patients (11 men, 21 women; mean age 49 ± 12 years; BMI 40.5 ± 7.3 kg/m²) treated with submaximal doses of semaglutide over 12 weeks, together with hypocaloric diet and increased physical activity based. We analyzed selected biomarkers including insulin, leptin, ferritin, resistin, interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α) and plasminogen activator inhibitor-1 (PAI-1) before and after three months of treatment. Results: We observed significant reductions in weight, BMI, waist circumference, insulin and leptin levels (all p < 0.001). On the other hand, no significant changes were recorded in ferritin (p = 0.806), IL-6 (p = 0.607), TNF-α (p = 0.633), resistin (p = 0.250) or PAI-1 (p = 0.134) levels. Correlation analyses revealed the correlation between IL-6 and adiposity indices (BMI, waist circumference) both before and after treatment. Ferritin and PAI-1 levels positively correlated with waist circumference, while resistin showed a negative correlation with central obesity. Conclusions: Submaximal-dose GLP-1 RA therapy was associated with significant improvements in metabolic parameters and adipokine regulation, but did not affect systemic inflammatory markers within 12 weeks. Future studies with larger cohorts and longer follow-ups are needed to clarify the associations. Full article

(This article belongs to the Special Issue Potential Therapeutic Targets for the Management of Diabetes Mellitus, Obesity and Cancer)

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19 pages, 6106 KB

Open AccessArticle

Therapeutic Potential of Bioactive Compounds in Edible Mushroom-Derived Extracellular Vesicles: Isolation and Characterization of EVs from Pleurotus eryngii

by Gaia Cusumano, Agnese Bertoldi, Eleonora Calzoni, Husam B. R. Alabed, Roberto Maria Pellegrino, Lorena Urbanelli, Gokhan Zengin, Giancarlo Angeles Flores, Roberto Venanzoni, Paola Angelini and Carla Emiliani

Pharmaceuticals 2025, 18(9), 1362; https://doi.org/10.3390/ph18091362 (registering DOI) - 12 Sep 2025

Abstract

Background/Objectives: Over the past twenty years, there has been a rapid increase in studies aimed at comprehending how cells communicate with each other via Extracellular Vesicles (EVs), accompanied by a heightened interest in plant-derived extracellular vesicles due to their potential relevance in [...] Read more.

Background/Objectives: Over the past twenty years, there has been a rapid increase in studies aimed at comprehending how cells communicate with each other via Extracellular Vesicles (EVs), accompanied by a heightened interest in plant-derived extracellular vesicles due to their potential relevance in dietary supplementation and therapeutic applications. However, there is a limited amount of research on extracellular vesicles derived from mushrooms (MDEVs). Among edible mushrooms, Pleurotus eryngii is peculiar due to its flavor and interesting nutritional profiling. It also produces a wide array of secondary metabolites including biologically active compounds with many health-promoting benefits such as anticancer, antioxidant, antitumor, antiviral, antibacterial, antidiabetic, and anti-hypercholesteremic activities. The aim of this work has been to isolate EVs from the fruiting body and mycelium of P. eryngii in order to investigate their potential applications as nutraceuticals. Methods: MDEVs were isolated by differential and density gradient centrifugation, characterized by Nanoparticle Tracking Analysis (NTA), Scanning Electron Microscopy (SEM) and immunoblotting, and subjected to metabolomic and phenolic profiling. Their antioxidant potential was assessed through in vitro radical scavenging (DPPH, ABTS) and metal-reducing (CUPRAC, FRAP) assays. Results: The findings suggest that mycelium-derived EVs may represent a valuable source of high-quality MDEVs, which exhibited promising antioxidant properties in all assays conducted, particularly in radical scavenging assays. Conclusions: These results highlight the potential of P. eryngii mycelium-derived EVs as a novel natural source of bioactive compounds, paving the way for future applications in nutraceutical and therapeutic fields. Full article

(This article belongs to the Special Issue Plant-Based Extracts and the Therapeutic Potential of Bioactive Compounds, 2nd Edition)

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17 pages, 7071 KB

Open AccessArticle

Oligomeric Proanthocyanidins Reverse Lenvatinib Resistance in Hepatocellular Carcinoma Through ITGA3-Mediated Pathway

by Takayuki Noma, Yuan Li, Yuma Wada, Yuji Morine, Tetsuya Ikemoto, Yu Saito, Shinichiro Yamada, Hiroki Teraoku, Mitsuo Shimada and Ajay Goel

Pharmaceuticals 2025, 18(9), 1361; https://doi.org/10.3390/ph18091361 (registering DOI) - 12 Sep 2025

Abstract

Background: Oligomeric proanthocyanidins (OPCs) are natural polyphenolic compounds with strong antitumor properties and have gained attention as potential agents to overcome drug resistance. Hepatocellular carcinoma (HCC) remains a major cause of cancer deaths worldwide, and although Lenvatinib is widely used, its effectiveness [...] Read more.

Background: Oligomeric proanthocyanidins (OPCs) are natural polyphenolic compounds with strong antitumor properties and have gained attention as potential agents to overcome drug resistance. Hepatocellular carcinoma (HCC) remains a major cause of cancer deaths worldwide, and although Lenvatinib is widely used, its effectiveness is limited by acquired resistance. This study explores the potential of OPCs to overcome Lenvatinib resistance in HCC. Methods: To evaluate the potential of OPCs to overcome Lenvatinib resistance in HCC, we established Lenvatinib-resistant Huh-7 and PLC-PRF-5 cell lines and conducted systematic cell culture experiments to assess their antitumor effects. Furthermore, genome-wide transcriptomic profiling, network pharmacology approaches, and pathway enrichment analysis were performed to identify resistance-associated signaling pathways that could serve as therapeutic targets. Results: The combination of OPCs and Lenvatinib demonstrated a significant synergistic anti-proliferative effect in resistant hepatocellular carcinoma cells, with the most synergistic dose combinations showing Bliss synergy scores exceeding 10. Transcriptomic profiling revealed that the adhesion molecule ITGA3 is a key factor in Lenvatinib resistance and contributes to the acquisition of anoikis resistance. The combination treatment suppressed ITGA3–EGFR–AKT signaling, restored anoikis sensitivity, significantly reduced spheroid formation (fold change = 0.10–0.12; p < 0.001), and markedly increased apoptosis (fold change = 2.7–5.0; p < 0.001). Conclusions: This study is the first to demonstrate that OPCs can overcome chemotherapy resistance by targeting the integrin pathway, providing scientific evidence for their potential use as an adjunctive therapy for chemotherapy-resistant HCC. Full article

(This article belongs to the Special Issue Network Pharmacology of Natural Products, 2nd Edition)

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19 pages, 1238 KB

Open AccessReview

Pharmacogenetics and the Response to Antidepressants in Major Depressive Disorder

by Amanda Gollo Bertollo, Ricieri Mocelin and Zuleide Maria Ignácio

Pharmaceuticals 2025, 18(9), 1360; https://doi.org/10.3390/ph18091360 - 11 Sep 2025

Abstract

Purpose: Genetic polymorphisms within specific genes play a role in both the genetic predisposition to Major Depressive Disorder (MDD) and the variation observed in responses to antidepressant treatments. Pharmacogenetics examines how these polymorphisms affect medication response. This review highlights significant disparities in the [...] Read more.

Purpose: Genetic polymorphisms within specific genes play a role in both the genetic predisposition to Major Depressive Disorder (MDD) and the variation observed in responses to antidepressant treatments. Pharmacogenetics examines how these polymorphisms affect medication response. This review highlights significant disparities in the pharmacogenetic influences on antidepressant response, with a focus on ethnic and sex-based differences. Methods: This review synthesizes findings from a comprehensive literature search conducted between 2000 and 2025. It utilized databases such as PubMed, Scopus, and Web of Science, using search terms including “pharmacogenetics”, “antidepressants”, “Major Depressive Disorder”, “CYP450”, “neuroplasticity”, and “genetic variations”. This review integrates pharmacogenetics with neurotransmitters and their transporters, neuroplasticity, growth factors, and the cytochrome P450 family, providing promising insights for personalized MDD treatment strategies. We analyzed and synthesized findings from over 50 relevant studies, focusing on those with a clear emphasis on genetic associations with antidepressant efficacy and adverse effects. Results: Pharmacogenetic analysis facilitates personalized antidepressant prescriptions by identifying key genetic variants that influence treatment outcomes. Specifically, variations in CYP2D6 and CYP2C19 can significantly impact drug metabolism and tolerability. A high percentage of patients with non-normal metabolizer phenotypes are predisposed to adverse drug reactions or ineffective responses. Furthermore, this review identifies significant ethnic and sex-based disparities in treatment response. For example, the L allele of the 5-HTTLPR polymorphism confers a higher likelihood of response and remission following SSRI treatment in white people compared to Asians. Additionally, in women, specific 5-HTTLPR polymorphisms have a more pronounced influence on mood and MDD pathophysiology, with a significant reduction in mood in response to tryptophan depletion. Conclusions: Integrating pharmacogenetic insights, encompassing genetic factors, neurotransmitter pathways, neuroplasticity, and the influence of ethnicity and sex, is crucial for developing personalized antidepressant treatment strategies. This will ultimately optimize patient recovery and minimize adverse effects. Full article

(This article belongs to the Special Issue Treatment and Molecular Mechanisms of Depression)

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19 pages, 852 KB

Open AccessReview

Advances and Challenges in the Development of New and Novel Treatment Strategies for Eosinophilic Esophagitis (EoE)

by Ivna Olic, Piero Marin Zivkovic, Ivan Zaja, Nikola Pavlovic, Marko Kumric and Josko Bozic

Pharmaceuticals 2025, 18(9), 1359; https://doi.org/10.3390/ph18091359 - 11 Sep 2025

Abstract

Eosinophilic esophagitis (EoE) is a long-term, immune-driven condition of the esophagus, which can lead to severe fibrostenosis of the esophagus, and the aim is to control clinical, endoscopic, and histopathologic disorder activity. Currently, treatment options include the use of proton pump inhibitors, topical [...] Read more.

Eosinophilic esophagitis (EoE) is a long-term, immune-driven condition of the esophagus, which can lead to severe fibrostenosis of the esophagus, and the aim is to control clinical, endoscopic, and histopathologic disorder activity. Currently, treatment options include the use of proton pump inhibitors, topical steroids, and dietary elimination as basic treatments; however, the introduction of dupilumab has provided an additional therapeutic approach. Numerous biologic agents target specific immune pathways, which are promising pharmacologic options in managing this progressive disease. The final goal is to treat the target, with complete resolution as the final objective. To accomplish this, however, effective agents capable of modifying the disease process are required. In this review, we aimed to provide an overall review of EoE therapeutics options, as well as the benefits and safety of new treatment strategies for EoE. Full article

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

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18 pages, 1564 KB

Open AccessArticle

Antimicrobial Activity and Potential of Olive Leaf Extract as a Topical Agent to Combat Staphylococcus aureus and MRSA Strains: An In Vitro Evaluation

by Laura Clusa, Miriam Latorre-Millán, Ana María Milagro, Alexander Tristancho-Baró, Ana Isabel López-Calleja, Juan Manuel García-Lechuz, Blanca Fortuño, Nuno del Villar, Mario Asensio, Olga Martín-Belloso, Isabel Odriozola-Serrano, Roberto Martínez-Beamonte, Jesús Osada, Antonio Rezusta and Yolanda Gilaberte

Pharmaceuticals 2025, 18(9), 1358; https://doi.org/10.3390/ph18091358 - 11 Sep 2025

Abstract

Background: Staphylococcus aureus is one of the most prevalent bacteria in skin and soft tissue infections (SSTIs). Multidrug-resistant strain emergence, particularly methicillin-resistant S. aureus (MRSA), highlights the need for alternative treatments. Objectives: This study investigates the antimicrobial properties of olive leaf [...] Read more.

Background: Staphylococcus aureus is one of the most prevalent bacteria in skin and soft tissue infections (SSTIs). Multidrug-resistant strain emergence, particularly methicillin-resistant S. aureus (MRSA), highlights the need for alternative treatments. Objectives: This study investigates the antimicrobial properties of olive leaf extract (OLE) and describes an epidemiological profiling of patients with SSTI who may benefit from it. Methods: OLE was tested in two reference strains, methicillin-susceptible S. aureus (MSSA) ATCC 29213 and MRSA ATCC 700699, and in 126 clinical isolates from patients with SSTIs according to Clinical Laboratory Standards Institute guidelines. Results: The minimum bactericidal concentration (MBC) ranged from 3.12% to 6.25% w/v for MSSA and 1.56% to 3.12% for MRSA. The lethal curve showed a reduction of 6 log₁₀CFU/mL after two hours of incubation. Most of the 126 clinical samples (103 MSSA and 23 MRSA) came from skin lesions, surgical wounds, and ulcers. Over 90% of MSSA strains were resistant to less than five antibiotics, while 82% of MRSA strains were resistant to more than six. Penicillins demonstrated the lowest susceptibility rate (19.8%), whereas linezolid, daptomycin, pristinamycin, trimethoprim–sulfamethoxazole, teicoplanin, vancomycin, and OLE exhibited 100% susceptibility. No growth was observed for all clinical strains with OLE at ≥6.25% w/v. Conclusions: The findings suggest that OLE could become a promising alternative treatment for skin infections, particularly in the context of increasing antibiotic resistance. Full article

(This article belongs to the Special Issue Infectious Disease Epidemiology and Pharmaceutical Development in the Era of Antimicrobial Resistance (AMR))

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17 pages, 1220 KB

Open AccessReview

Advances in Pharmacological Properties, Molecular Mechanisms, and Bioavailability Strategies of Chlorogenic Acid in Cardiovascular Diseases Therapy

by Kai Huang, Duosu Zhang, Ruting Wang, Jiahao Duan, Long Hu, Fan Huang, Wei Liu, Jia Gu, Songlin Li, Chun Yang and Ling Yang

Pharmaceuticals 2025, 18(9), 1357; https://doi.org/10.3390/ph18091357 - 11 Sep 2025

Abstract

Cardiovascular diseases (CVDs), a group of global diseases, are characterized by high morbidity and mortality, imposing a significant burden on clinical practice. Chlorogenic acid (CGA), a natural compound composed of caffeic acid and quinic acid, is widely found in and extracted from plants [...] Read more.

Cardiovascular diseases (CVDs), a group of global diseases, are characterized by high morbidity and mortality, imposing a significant burden on clinical practice. Chlorogenic acid (CGA), a natural compound composed of caffeic acid and quinic acid, is widely found in and extracted from plants such as Lonicera japonica (honeysuckle), Eucommia ulmoides (hardy rubber tree), tea leaves, and coffee beans. In recent years, increasing attention has been directed towards the pharmacological mechanisms of CGA in the treatment of CVDs. This review comprehensively summarizes the current knowledge on the preparation, metabolic pathways, pharmacological effects, and safety profile of CGA. Furthermore, it systematically analyzes the biological effects and molecular targets of CGA in the cardiovascular therapy and highlights strategies to enhance its bioavailability. These insights aim to provide a scientific basis for future basic research and clinical applications. Full article

(This article belongs to the Section Pharmacology)

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19 pages, 2323 KB

Open AccessArticle

Covalently Functionalized Halloysite-Calixarene Nanotubes for Injectable Hydrogels: A Multicavity Platform for Hydrophobic Drug Delivery

by Giuseppe Cinà, Marina Massaro, Andrea Pappalardo, Carmela Bonaccorso, Cosimo G. Fortuna, Placido G. Mineo, Angelo Nicosia, Paola Poma, Rita Sánchez-Espejo, Caterina Testa, César Viseras and Serena Riela

Pharmaceuticals 2025, 18(9), 1356; https://doi.org/10.3390/ph18091356 - 11 Sep 2025

Abstract

Background: Poor water solubility is a major limitation for the therapeutic use of many anticancer drugs. In this study, we report the design and development of two halloysite-based hybrid nanomaterials for the encapsulation and delivery of hydrophobic and positively charged drugs. Methods: [...] Read more.

Background: Poor water solubility is a major limitation for the therapeutic use of many anticancer drugs. In this study, we report the design and development of two halloysite-based hybrid nanomaterials for the encapsulation and delivery of hydrophobic and positively charged drugs. Methods: A novel multicavity platform was obtained by covalently grafting calix[⁵]arene macrocycles onto the external surface of halloysite nanotubes (HNTs), combining lumen encapsulation with supramolecular host–guest recognition. PB4, a planar and hydrophobic pyridinium salt with significant antiproliferative activity, was selected as a model compound. Both PB4-loaded HNTs (HNTs/PB4) and calixarene-functionalized HNTs (HNTs-Calix/PB4) were incorporated into Laponite^®-based thixotropic hydrogels to obtain injectable and biocompatible systems. Results: The nanomaterials were thoroughly characterized, and their loading efficiency, release behavior, and aqueous dispersibility were evaluated. Antiproliferative tests on MCF-7 cells demonstrated that both hydrogels retained PB4 activity, with distinct release profiles: the pristine HNTs allowed faster drug availability, while calix[⁵]arene-functionalized systems promoted sustained release. Conclusions: This work introduces the first example of covalently calixarene-functionalized halloysite and presents a versatile drug delivery platform adaptable to different therapeutic contexts and combination strategies. Full article

(This article belongs to the Special Issue Progress of Hydrogel Applications in Novel Drug Delivery Platforms)

2 pages, 351 KB

Open AccessCorrection

Correction: Hou et al. S-72, a Novel Orally Available Tubulin Inhibitor, Overcomes Paclitaxel Resistance via Inactivation of the STING Pathway in Breast Cancer. Pharmaceuticals 2023, 16, 749

by Zhenyan Hou, Songwen Lin, Tingting Du, Mingjin Wang, Weida Wang, Shen You, Nina Xue, Yichen Liu, Ming Ji, Heng Xu and Xiaoguang Chen

Pharmaceuticals 2025, 18(9), 1355; https://doi.org/10.3390/ph18091355 - 10 Sep 2025

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Abstract

In the original publication [...] Full article

13 pages, 4190 KB

Open AccessArticle

Nasal Administration of Durvillaea antarctica Fucoidan Inhibits Lung Cancer Growth in Mice Through Immune Activation

by Hee Sung Kim, Peter C. W. Lee and Jun-O Jin

Pharmaceuticals 2025, 18(9), 1354; https://doi.org/10.3390/ph18091354 - 9 Sep 2025

Viewed by 145

Abstract

Background: Various studies have demonstrated fucoidan’s immunomodulatory effects. A previous study reported the anticancer effects of Durvillaea antarctica fucoidan (DAF) via immune activation in mice. Methods: In this study, we confirmed the DAF’s pulmonary immune activation ability by nasal administration of the dendritic [...] Read more.

Background: Various studies have demonstrated fucoidan’s immunomodulatory effects. A previous study reported the anticancer effects of Durvillaea antarctica fucoidan (DAF) via immune activation in mice. Methods: In this study, we confirmed the DAF’s pulmonary immune activation ability by nasal administration of the dendritic cells (DCs) and T cells. Furthermore, we examined its ability to enhance the efficacy of lung cancer treatment by combining it with anti-PD-L1 antibodies to activate the lung immune response. Results: Nasal DAF administration increased C-C chemokine receptor type 7 expression in DCs and promoted DC migration to the mediastinal lymph nodes (mLN). Specifically, DAF increased conventional DC type 1 (cDC1) and cDC2 numbers in mLN and potently activated cDC1. Furthermore, the nasal administration of DAF increased the production of inflammatory cytokines in the lungs and peripheral blood. Repeated intranasal administration of DAF induced T-cell activation, resulting in the enhanced production of interferon-gamma and tumor necrosis factor-alpha in CD4 T and CD8 T cells. CD8 T cells also showed increased secretion of cytotoxic mediators after DAF treatment, and the proportion of Tregs expressing FoxP3 decreased in the mLN. DAF inhibited lung cancer growth in Lewis lung carcinoma 2 cells, which was enhanced by combining it with an anti-programmed death-ligand 1 antibody. Finally, the anticancer effects of DAF were not observed in mice with depleted CD4-positive and CD8-positive cells. Conclusions: Nasal administration of DAF may inhibit lung cancer growth by inducing lung immune activation and is expected to be helpful as an immune activator for nasal administration. Full article

(This article belongs to the Special Issue Therapeutic Potential of Natural Extracts in Cancer Prevention and Treatment)

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44 pages, 15813 KB

Open AccessSystematic Review

Echinops as a Source of Bioactive Compounds—A Systematic Review

by Simona Ivanova, Alexandra Ivanova, Mina Todorova, Vera Gledacheva and Stoyanka Nikolova

Pharmaceuticals 2025, 18(9), 1353; https://doi.org/10.3390/ph18091353 - 9 Sep 2025

Viewed by 268

Abstract

Background: Echinops is a genus of spiny, herbaceous perennials in the Asteraceae family, known for its distinct morphology and broad pharmacological potential. Both traditional and modern medicinal systems have identified species in this genus as sources of bioactive compounds with anti-inflammatory, antimalarial, [...] Read more.

Background: Echinops is a genus of spiny, herbaceous perennials in the Asteraceae family, known for its distinct morphology and broad pharmacological potential. Both traditional and modern medicinal systems have identified species in this genus as sources of bioactive compounds with anti-inflammatory, antimalarial, antidiabetic, anticancer, and neuroprotective effects. Aims: This study aimed to conduct a systematic literature review and update previous overviews of the recently reported phytochemicals and pharmacological properties of Echinops, systematically summarizing biological activities and their therapeutic applications. Methods: Major electronic medical databases—PubMed, Scopus, Science Direct, Web of Science, and Google Scholar—were systematically searched for publications from 1990 to 2025. Results: A total of 134 studies met our inclusion criteria. Thiophenes and terpenes emerged as characteristic metabolites of the genus, and along with flavonoids and alkaloids, contributed to a wide range of bioactivities. Experimental evidence supports the potential of these compounds as multifunctional agents, although clinical validation remains limited. Conclusions: Echinops is a promising source of structurally diverse metabolites with therapeutic relevance. Further pharmacological and toxicological studies are needed to establish their efficacy and ensure safe medical application. Full article

(This article belongs to the Special Issue Natural Products as an Alternative for Treatment of Human Diseases)

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25 pages, 2041 KB

Open AccessReview

Genetic Basis of Non-Syndromic Childhood Glaucoma Associated with Anterior Segment Dysgenesis: A Narrative Review

by Nicola Cronbach, Cécile Méjécase and Mariya Moosajee

Pharmaceuticals 2025, 18(9), 1352; https://doi.org/10.3390/ph18091352 - 9 Sep 2025

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Abstract

Twenty causative genes have been reported that cause non-syndromic childhood glaucoma associated with anterior segment dysgenesis. FOXC1, PAX6 and PITX2 are the most well-known, but cases linked to SLC4A11, PITX3 and SOX11 have also been reported. As genetic testing becomes increasingly [...] Read more.

Twenty causative genes have been reported that cause non-syndromic childhood glaucoma associated with anterior segment dysgenesis. FOXC1, PAX6 and PITX2 are the most well-known, but cases linked to SLC4A11, PITX3 and SOX11 have also been reported. As genetic testing becomes increasingly widespread and rates of molecular diagnosis rise, the extent of phenotypic overlap between the different genetic causes of non-syndromic glaucoma associated with anterior segment dysgenesis is becoming more evident. Taking aniridia as an example, whilst PAX6 mutations remain the predominant cause, variants in CYP1B1, FOXC1, PXDN and SOX11 have also been reported in patients with childhood glaucoma and aniridia. Developments in molecular-based therapies for retinal and corneal disease are advancing rapidly, and pre-clinical studies of gene-based treatments for glaucoma and aniridia are showing promising results. Use of adeno-associated viral vectors for gene delivery is most common, with improvements in intraocular pressure and retinal ganglion cell survival in Tg-MYOC^Y437H mouse models of glaucoma, and successful correction of a germline PAX6^G194X nonsense variant in mice using CRISPR-Cas9 gene editing. This review will explore the actions and interactions of the genetic causes of non-syndromic glaucoma associated with anterior segment dysgenesis and discuss the current developments in molecular therapies for these patients. Full article

(This article belongs to the Special Issue 20th Anniversary of Pharmaceuticals—Advances in Pathophysiology, Pharmacology and Neuroprotection in Glaucoma)

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40 pages, 543 KB

Open AccessReview

Dietary Modulation of CYP3A4 and Its Impact on Statins and Antidiabetic Drugs: A Narrative Review

by Manuel Hernández-Lorca, Isabel M. Timón, Pura Ballester, Paula Henarejos-Escudero, Ana María García-Muñoz, Desirée Victoria-Montesinos and Pablo Barcina-Pérez

Pharmaceuticals 2025, 18(9), 1351; https://doi.org/10.3390/ph18091351 - 9 Sep 2025

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Abstract

Cytochrome P450 3A4 (CYP3A4) is a key enzyme involved in the metabolism of nearly half of all clinically used drugs, including widely prescribed statins and antidiabetic agents. Dietary constituents can modulate CYP3A4 expression and activity through various mechanisms, thereby altering drug pharmacokinetics and [...] Read more.

Cytochrome P450 3A4 (CYP3A4) is a key enzyme involved in the metabolism of nearly half of all clinically used drugs, including widely prescribed statins and antidiabetic agents. Dietary constituents can modulate CYP3A4 expression and activity through various mechanisms, thereby altering drug pharmacokinetics and potentially leading to therapeutic failure or toxicity. This narrative review compiles current evidence on dietary modulation of CYP3A4, with a particular focus on pharmacological and clinical implications for lipid-lowering and glucose-lowering drugs. Literature was identified through a comprehensive search in PubMed, Scopus, and Web of Science, including preclinical and clinical studies addressing food–drug interactions involving CYP3A4 substrates. Numerous dietary compounds, such as citrus furanocoumarins, polyphenols, herbal extracts, and vitamins, act as CYP3A4 inhibitors or inducers through competitive, mechanism-based, or nuclear receptor-mediated pathways. Specific examples include simvastatin, atorvastatin, repaglinide, and saxagliptin, whose systemic exposure can be significantly altered by dietary factors. Moreover, interindividual variability in CYP3A4 activity may be shaped by genetic polymorphisms, microbiota-derived metabolites, and epigenetic regulation, further influencing drug response. Understanding these interactions is crucial, especially in polymedicated patients or those receiving drugs with a narrow therapeutic index. Clinicians should remain aware of potential CYP3A4-related food–drug interactions and consider dietary habits and supplement use in therapeutic decision-making. Future research should aim to integrate pharmacogenomics, gut microbiome profiling, and personalized nutrition in order to improve the prediction and prevention of clinically significant interactions. Full article

(This article belongs to the Special Issue The Application of Pharmacogenetics in Toxicity Prevention and Drug Effect Improvement)

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18 pages, 1987 KB

Open AccessArticle

Anticonvulsant Potential of 1-Aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolines: Insights from Strychnine and Nicotine Models in In Vivo and In Silico Studies

by Azizbek A. Azamatov, Nilufar Z. Mamadalieva, Asmaa A. Mandour, Sherzod N. Zhurakulov, Urkhiya K. Aytmuratova, Valentina I. Vinogradova, Fazliddin S. Jalilov and Firuza M. Tursunkhodzhaeva

Pharmaceuticals 2025, 18(9), 1350; https://doi.org/10.3390/ph18091350 - 9 Sep 2025

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Abstract

Background: Epilepsy is a chronic, non-communicable brain disorder characterized by recurrent seizures. Some derivatives of 1,2,3,4-tetrahydroisoquinolines have demonstrated anticonvulsant effects. This study aims to investigate the effects of 33 derivatives of 1-aryl-1,2,3,4-tetrahydroisoquinoline on seizures induced by nicotine and strychnine. Methods: The anticonvulsant [...] Read more.

Background: Epilepsy is a chronic, non-communicable brain disorder characterized by recurrent seizures. Some derivatives of 1,2,3,4-tetrahydroisoquinolines have demonstrated anticonvulsant effects. This study aims to investigate the effects of 33 derivatives of 1-aryl-1,2,3,4-tetrahydroisoquinoline on seizures induced by nicotine and strychnine. Methods: The anticonvulsant effects of 1-aryl-1,2,3,4-tetrahydroisoquinoline derivatives were evaluated in white male mice. Convulsant agents were administered subcutaneously at doses of 10.0 mg/kg for nicotine and 1.5 mg/kg for strychnine, 60 min after the oral administration of the test compounds at doses ranging from 0.1 to 10 mg/kg. The onset time, duration of tremors and seizures, and survival rate of the animals were recorded. The docking studies were conducted for 32 tested compounds targeting the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (PDB ID: 1FTL). Furthermore, a predictive ADMET study was conducted to evaluate the pharmacokinetic and toxicity profiles of the compounds. Results: Compounds 20 and 25 exhibited the highest activity against strychnine-induced seizures. When evaluating the effects of 1-aryl-1,2,3,4-tetrahydroisoquinolines and reference drugs on the tremorogenic and convulsive actions of nicotine at doses of 0.1–5 mg/kg, compounds 3, 6, 8, 14, 16, 25, 27, 29, 30, 31, and 34 demonstrated comparable activity to the reference drugs. The docking results targeting AMPA (PDB ID: 1FTL) revealed comparable binding interactions for most of the compounds, with a (−)C-Docker interaction energy range of 33.82–45.41 Kcal/mol, compared to that of the ligand (41.60 Kcal/mol). The structural requirements of the studied scaffold were analyzed to identify the essential pharmacophoric features for anticonvulsant activity. Furthermore, a predictive ADMET study was conducted to evaluate the pharmacokinetic and toxicity profiles of the compounds. Conclusions: Certain derivatives of 1,2,3,4-tetrahydroisoquinolines may serve as potential anticonvulsant agents for epilepsy. Full article

(This article belongs to the Section Medicinal Chemistry)

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28 pages, 4754 KB

Open AccessArticle

Tribulus terrestris-Mediated ZnO/Ag-Halloysite Nanohybrids for Targeted Cisplatin and Carboplatin Delivery in Cervical Cancer Treatment

by Ammar AlAbdullatif, Sarah Almofty, Gazali Tanimu, Hatim Dafalla, Fatimah Alahmari and B. Rabindran Jermy

Pharmaceuticals 2025, 18(9), 1349; https://doi.org/10.3390/ph18091349 - 8 Sep 2025

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Abstract

Background/Objectives: Cervical cancer remains a major health challenge, especially in low-resource regions with limited diagnostic and advanced treatment options. Nanotechnology-based strategies offer promising alternatives to conventional chemotherapy by reducing systemic toxicity and enabling site-specific delivery. Methods: In this study, halloysite (Hall) was functionalized [...] Read more.

Background/Objectives: Cervical cancer remains a major health challenge, especially in low-resource regions with limited diagnostic and advanced treatment options. Nanotechnology-based strategies offer promising alternatives to conventional chemotherapy by reducing systemic toxicity and enabling site-specific delivery. Methods: In this study, halloysite (Hall) was functionalized with green-synthesized 2 wt% zinc oxide (GZn) and silver (GAg) nanoparticles (NPs) using Tribulus terrestris extract (25 mM) to enhance cisplatin (Cp) and carboplatin (Cbpt) delivery for targeted cervical cancer therapy. Results: Structural and morphological analyses confirmed the successful integration of GZn and GAg NPs into the Hall without compromising its tubular integrity. Cp or Cbpt adsorption studies with varying times (0.15–12 h), as well as drug/Hall ratios (10–50) and pH levels (5; 6.6; 7.4; 9.0; and 10.5), revealed greater Cp adsorption than Cbpt, attributed to its higher reactivity and affinity toward the Hall surface. pH-responsive release studies biphasic drug release for non-PEGYlated formulations, with Cp (14% with 2 h) and Cbpt (10% with 0.5 h), whereas PEGYlated systems exhibited sustained release under acidic tumor-like conditions, achieving 14% in 72 h for Cp and 4.5% in 72 h for Cbpt. Release kinetics followed either Fickian or non-Fickian diffusion depending on pH and drug type, with the Korsmeyer–Peppas model offering a strong fit (R² > 0.85). In vitro assays revealed that Cbpt/GZn-Hall/PEG, Cp/GZn-Hall/PEG, and Cbpt/GAg-Hall/PEG induced dose-dependent cytotoxicity against HeLa while sparing HFF-1 fibroblasts. Conclusions: These findings indicate that green-synthesized nanohybrids are promising carriers for targeted Cp and Cbpt delivery, warranting further in vivo evaluation for cervical cancer therapy. Full article

(This article belongs to the Special Issue Therapeutic Potential of Silver Nanoparticles (AgNPs), 2nd Edition)

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74 pages, 8029 KB

Open AccessReview

Antimicrobial Activity of 1,3,4-Thiadiazole Derivatives

by Sebastian Górecki, Agnieszka Kudelko and Monika Olesiejuk

Pharmaceuticals 2025, 18(9), 1348; https://doi.org/10.3390/ph18091348 - 8 Sep 2025

Viewed by 117

Abstract

The 1,3,4-thiadiazole core has attracted significant attention due to its unique electronic structure, physicochemical properties, and wide-ranging pharmacological potential. This heterocyclic scaffold exhibits a broad spectrum of biological activities, often attributed to its capacity to modulate enzyme function, interact with receptors, and disrupt [...] Read more.

The 1,3,4-thiadiazole core has attracted significant attention due to its unique electronic structure, physicochemical properties, and wide-ranging pharmacological potential. This heterocyclic scaffold exhibits a broad spectrum of biological activities, often attributed to its capacity to modulate enzyme function, interact with receptors, and disrupt key biochemical pathways in both pathogens and host cells. Additionally, 1,3,4-thiadiazoles typically display favorable pharmacokinetic properties, including high metabolic stability and appropriate lipophilicity, which enhance their drug-likeness and bioavailability. This review presents an overview of antibacterial and antifungal compounds bearing the 1,3,4-thiadiazole scaffold that have been reported over the past five years. This publication details the chemical structures of novel 1,3,4-thiadiazole derivatives and reports the results of antibacterial and antifungal activity assays conducted against a range of microbial strains. Furthermore, it provides conclusions regarding the structural features that influence the observed biological activity of the synthesized compounds. Antimicrobial activity assessments conducted against ten Gram-negative and nine Gram-positive bacterial strains revealed that 79 newly synthesized 1,3,4-thiadiazole derivatives exhibited either superior inhibitory efficacy relative to standard reference antibiotics or achieved a high level of bacterial growth suppression, defined as 90–100% inhibition. In antifungal assays, the compounds were evaluated against 25 fungal species representing 15 genera. Among the tested derivatives, 75 compounds demonstrated antifungal potency exceeding that of reference antifungal agents or produced growth inhibition within the 90–100% range. The information provided herein may serve as a valuable resource for medicinal and agricultural chemists engaged in the development of novel drug candidates and plant protection agents. Full article

(This article belongs to the Special Issue Advances in the Synthesis and Application of Heterocyclic Compounds)

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23 pages, 7539 KB

Open AccessArticle

Effect and Mechanism of Qihua Tongtiao Formula (QHTTF) on Improving Glucose and Lipid Metabolism Disorders in ZDF Rats by Integrating Network Pharmacology, Metabolomics, and Biological Validation

by Yuhua Jiang, Hong Yu, Yajing Pan, Binghan Zhang, Yeteng Jing, Jingjing Lei, Ning Li and Jinsheng Yang

Pharmaceuticals 2025, 18(9), 1347; https://doi.org/10.3390/ph18091347 - 8 Sep 2025

Viewed by 260

Abstract

Background: The dysregulation of both glucose and lipid metabolism is the main clinical features of type 2 diabetes. Qihua Tongtiao Formula (QHTTF) is our team’s current clinical empirical formula, and the related patent has been granted. It is composed of Astragalus membranaceus, [...] Read more.

Background: The dysregulation of both glucose and lipid metabolism is the main clinical features of type 2 diabetes. Qihua Tongtiao Formula (QHTTF) is our team’s current clinical empirical formula, and the related patent has been granted. It is composed of Astragalus membranaceus, Atractylodes macrocephala koidz, Aurantii Fructus Immaturus, Radix Bupleuri, Ligusticum chuanxiong hort, Angelicae sinensis radix, Raphanus sativus, and Polyporus umbellatus. It can alleviate tissue pathological damage in type 2 diabetic rats by improving glycolipid metabolism disorders. Nevertheless, the specific mechanisms of QHTTF in the treatment of type 2 diabetes remain unclear. Purpose: This research aims to explore the fundamental effect and underlying mechanism of the QHTTF formula in ZDF rats via network pharmacology, biological validation, and metabolomics technology. Methods: The chemical compounds of QHTTF were initially identified via UHPLC-MS/MS analysis. Meanwhile, drug targets, genes, related diseases, and differential metabolites of QHTTF in the treatment of T2DM were obtained through network pharmacology, molecular docking, and metabolomics. Then, we conducted animal experiments to further explore the therapeutic molecular mechanism of QHTTF in ZDF rats. Results: A total of 39 main chemical components were recognized through LC-MS/MS technology, and 22 remained after the second screening. Network pharmacology and molecular docking results revealed that 59 intersection targets were involved in the treatment of glycolipid metabolic disorders, and the PPARα, PPARγ, and TNF proteins were identified as crucial targets through PPI network analysis. Additionally, serum metabolomics analysis of ZDF rats showed that QHTTF could regulate linoleic acid metabolism, fructose and mannose metabolism, galactose metabolism, fatty acid biosynthesis, and other related signaling pathways. The results of biological experiments proved that QHTTF effectively lowered blood glucose and lipid levels, alleviated hepatic and pancreatic pathological damage, increased the expression of IRS-1 and GLUT4 in the pancreas, and improved insulin resistance, while inhibiting the inflammatory response and oxidative stress, as well as enhancing the expression of liver PPARα, PPARγ, and AMPK proteins in ZDF rats. Conclusions: In summary, QHTTF exerted a significant effect in improving glycolipid metabolism disorders of ZDF rats, which might show therapeutic effects by relieving insulin resistance, mitigating inflammation and oxidative damage, regulating related glucose, fatty acid, and amino acid metabolism, and increasing the expression of PPARα, PPARγ, and AMPK proteins by combining network analysis, metabolomics, and biological research. Full article

(This article belongs to the Special Issue Emerging Therapies for Diabetes and Obesity)

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39 pages, 4081 KB

Open AccessReview

Two Sides of the Same Coin for Health: Adaptogenic Botanicals as Nutraceuticals for Nutrition and Pharmaceuticals in Medicine

by Alexander Panossian and Terrence Lemerond

Pharmaceuticals 2025, 18(9), 1346; https://doi.org/10.3390/ph18091346 - 8 Sep 2025

Viewed by 172

Abstract

Background: Adaptogens, commonly used as traditional herbal medicinal products for the relief of symptoms of stress, such as fatigue and exhaustion, belong to a category of physiologically active compounds related to the physiological process of adaptability to stressors. They are used both as [...] Read more.

Background: Adaptogens, commonly used as traditional herbal medicinal products for the relief of symptoms of stress, such as fatigue and exhaustion, belong to a category of physiologically active compounds related to the physiological process of adaptability to stressors. They are used both as pharmaceuticals in medicine and as dietary supplements or nutraceuticals in nutrition, depending on the doses, indications to treat diseases, or support health functions. However, such a dual-faced nature of adaptogens can lead to inconsistencies and contradictory outcomes from Food and Drug regulatory authorities in various countries. Aims: This narrative literature review aimed to (i) specify five steps of pharmacological testing of adaptogens, (ii) identify the sources of inconsistencies in the assessment of evidence the safety, efficacy, and quality of multitarget adaptogenic botanicals, and (iii) propose potential solutions to address some food and drug regulatory issues, specifically adaptogenic botanicals used for prevention and treatment of complex etiology diseases including stress-induced, and aging-related disorders. Overview: This critically oriented narrative review is focused on (i) five steps of pharmacological testing of adaptogens are required in a sequential order, including appropriate in vivo and in vitro models in animals, in vitro model, and mechanisms of action by a proper biochemical assay and molecular biology technique in combination with network pharmacology analysis, and clinical trials in stress-induced and aging-related disorders; (ii) the differences between the requirements for the quality of pharmaceuticals and dietary supplements of botanical origin; (iii) progress, trends, pitfalls, and challenges in the adaptogens research; (iv) inadequate assignment of some plants to adaptogens, or insufficient scientific data in case of Eurycoma longifolia; (v) inconsistencies in botanical risk assessments in the case of Withania somnifera. Conclusions: This narrative review highlights the importance of harmonized standards, transparent methodologies, and a balanced, evidence-informed approach to ensure consumers receive effective and safe botanicals. Future perspectives and proposed solutions include (i) establish internationally harmonized guidelines for evaluating botanicals based on their intended use (e.g., pharmaceutical vs. dietary supplement), incorporating traditional use data alongside modern scientific methods; (ii) encourage peer review and transparency in national assessments by mandating public disclosure of methodologies, data sources, and expert affiliations; (iii) create a tiered evidence framework that allows differentiated standards of proof for traditional botanical supplements versus pharmaceutical candidates; (iv) promote international scientific dialogs among regulators, researchers, and industry to develop consensus positions and avoid unilateral bans that may lack scientific rigor; (v) formally recognize adaptogens a category of natural products for prevention stress induced brain fatigue, behavioral, and aging related disorders. Full article

(This article belongs to the Special Issue Network Pharmacology of Natural Products, 2nd Edition)

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14 pages, 1031 KB

Open AccessArticle

Plasma Glutathione Concentrations Are Associated with Leukocyte and Neutrophils’ Counts in Clozapine-Treated Patients

by Erick José Martínez-Rodríguez, Verónica Barón-Flores, Jesús Ramirez-Bermudez, Carlos Aviña-Cervantes, Dinora González-Esquivel, Araceli Diaz-Ruiz and Camilo Ríos

Pharmaceuticals 2025, 18(9), 1345; https://doi.org/10.3390/ph18091345 - 8 Sep 2025

Viewed by 200

Abstract

Clozapine’s potential hematological toxicity, particularly its effect on white blood cell counts, is well documented and routinely monitored in clinical practice. In this study, a significant association was identified between reduced glutathione levels and neutrophil counts in patients undergoing clozapine treatment. Among the [...] Read more.

Clozapine’s potential hematological toxicity, particularly its effect on white blood cell counts, is well documented and routinely monitored in clinical practice. In this study, a significant association was identified between reduced glutathione levels and neutrophil counts in patients undergoing clozapine treatment. Among the variables analyzed, glutathione concentration showed the strongest correlation with neutrophil levels, suggesting a potential role for antioxidant status in mediating clozapine’s hematological effects. Objective: The study aimed to evaluate the relationship between plasma concentrations of clozapine, its active metabolite N-desmethylclozapine, reduced glutathione, and treatment duration, in relation to total leukocyte and neutrophil counts in patients attending an outpatient psychiatric clinic. Methods: Plasma levels of clozapine, N-desmethylclozapine, and reduced glutathione were quantified using validated analytical techniques. Complete blood counts were obtained, and a multiple regression analysis was conducted to identify factors most strongly associated with variations in neutrophil count. Results: Reduced glutathione levels were significantly associated with neutrophil counts (p = 0.009), representing the most robust association among the variables examined. Clozapine concentration and duration of treatment were also found to be relevant contributors to changes in hematological parameters. Conclusions: These findings suggest that individual antioxidant capacity, particularly involving glutathione metabolism, may influence susceptibility to clozapine-related neutropenia. This insight could inform future strategies for monitoring and managing clozapine-treated patients, potentially aiding in the identification of those at increased risk for hematological side effects. Full article

(This article belongs to the Section Pharmacology)

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26 pages, 7888 KB

Open AccessArticle

Identification of Methylstat as a Potential Therapeutic Agent for Human Glioma Cells by Targeting Cell Cycle Arrest

by Haoge Yao, Tingyi Meng, Yingying Yang, Huaping Tao, Wenwen Lu, Mingqi Liu, Xiaofeng Zhao, Mengsheng Qiu and Aifen Yang

Pharmaceuticals 2025, 18(9), 1344; https://doi.org/10.3390/ph18091344 - 8 Sep 2025

Viewed by 268

Abstract

Background/Objectives: Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults, with a poor prognosis and limited therapeutic options. This study aimed to repurpose methylstat, a selective histone demethylase inhibitor, as a novel anti-glioma agent. We characterized its anti-proliferative [...] Read more.

Background/Objectives: Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults, with a poor prognosis and limited therapeutic options. This study aimed to repurpose methylstat, a selective histone demethylase inhibitor, as a novel anti-glioma agent. We characterized its anti-proliferative efficacy, elucidated mechanisms of cell cycle regulation, and evaluated its blood–brain barrier (BBB) permeability potential. Methods: Compounds with transcriptional profiles enriched for cell cycle arrest and tumor-suppressive pathways were identified via Connectivity Map (CMAP) analysis. Methylstat was selected based on its high connectivity score and favorable physicochemical properties. In vitro assays were performed to evaluate its effects on cell viability, proliferation, cell cycle progression, and expression of related molecular markers in U251 and HOG glioma cell lines. Molecular docking and 200 ns molecular dynamics (MD) simulations were performed to evaluate the binding mode and stability of the Methylstat–JMJD2A complex. An in vitro BBB model was established to assess the ability of Methylstat to cross the BBB. Results: Methylstat significantly inhibited glioma cell proliferation in a dose-dependent manner without inducing apoptosis. It caused G1-phase arrest in U251 cells and G2-phase arrest in HOG cells. Mechanistically, methylstat downregulated cyclins and cyclin-dependent kinases via the p53/p21 pathway. Additionally, methylstat reduced the expression of JMJD2A and its downstream targets, including PDK1, AKT, and mTOR. Molecular docking studies and 200 ns MD simulations confirmed the stable binding of methylstat to the catalytic pocket of JMJD2A, effectively inhibiting its enzymatic activity. HPLC analysis confirmed that methylstat could penetrate the in vitro BBB model to varying extents. Conclusions: Methylstat is a promising small-molecule agent that effectively suppresses glioma cell growth by modulating key cell cycle regulators. Its ability to cross the BBB highlights its potential as a novel therapeutic strategy for GBM and other brain tumors. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Treatment of Brain Cancer: Recent Advances and Future Trends)

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2 pages, 1258 KB

Open AccessCorrection

Correction: Hora et al. Isoorientin Improves Excisional Skin Wound Healing in Mice. Pharmaceuticals 2024, 17, 1368

by Aline B. Hora, Laiza S. Biano, Ana Carla S. Nascimento, Zaine T. Camargo, Greice I. Heiden, Ricardo L. C. Albulquerque-Júnior, Renata Grespan, Jessica M. D. A. Aragão and Enilton A. Camargo

Pharmaceuticals 2025, 18(9), 1343; https://doi.org/10.3390/ph18091343 - 8 Sep 2025

Viewed by 125

Abstract

In the original publication [...] Full article

(This article belongs to the Special Issue Pharmacological Activities of Flavonoids and Their Analogues 2024)

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20 pages, 1780 KB

Open AccessArticle

Exploring the Impact of Ultrasound-Assisted Extraction on the Phytochemical Composition and Bioactivity of Tamus communis L. Fruits

by Irene Gouvinhas, Maria José Saavedra, Maria José Alves and Juliana Garcia

Pharmaceuticals 2025, 18(9), 1342; https://doi.org/10.3390/ph18091342 - 6 Sep 2025

Viewed by 346

Abstract

Background/Objectives: The health benefits of Tamus communis fruits have been associated with their high phenolic content, which comprises several flavonoids. However, the extraction methods might significantly impact these valuable compounds’ bioactivity. Therefore, the current study assesses how different extraction techniques affect T. [...] Read more.

Background/Objectives: The health benefits of Tamus communis fruits have been associated with their high phenolic content, which comprises several flavonoids. However, the extraction methods might significantly impact these valuable compounds’ bioactivity. Therefore, the current study assesses how different extraction techniques affect T. communis extracts’ antioxidant, anti-aging, antimicrobial, cytotoxic, anti-inflammatory, and phenolic contents. Methods: Conventional method (TCE-CM) and ultrasound-assisted extraction (TCE-UM) were the methods employed. Results: The increased phenolic content of TCE-UM, particularly flavonoids and phenolic acids, was demonstrated to be a contributing factor to its higher biological activity. Key enzymes linked to dermatological conditions, such as elastase, collagenase, hyaluronidase, and tyrosinase, were significantly inhibited by both extracts at 1 mg/mL; TCE-UM showed the highest tyrosinase inhibition (65.61 ± 5.21%) compared to TCE-CM (21.78 ± 2.19%). TCE-UM also demonstrated exceptional antibacterial performance, showing notable antibiofilm and metabolic inactivation effects and potent activity against pathogens such as Staphylococcus aureus, Escherichia coli, and Candida albicans. Both extracts showed concentration-dependent anti-inflammatory properties; TCE-UM had a lower IC50 value (26.46 ± 2.30%) in nitric oxide inhibition tests, suggesting stronger anti-inflammatory capabilities. Conclusions: These findings underscore the superior bioactivity of TCE-UM and suggest that ultrasonic extraction is a more efficient method for isolating bioactive phenolic compounds from T. communis fruits, presenting promising applications in anti-aging and antimicrobial formulations. Full article

(This article belongs to the Special Issue Plant-Based Extracts and the Therapeutic Potential of Bioactive Compounds, 2nd Edition)

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51 pages, 5968 KB

Open AccessArticle

Structure–Activity Relationship Study of 3-Alkynyl-6-aryl-isothiazolo[4,3-b]pyridines as Dual Inhibitors of the Lipid Kinases PIKfyve and PIP4K2C

by Demian Kalebic, Ling-Jie Gao, Belén Martinez-Gualda, Marwah Karim, Sirle Saul, Do Hoang Nhu Tran, Jef Rozenski, Leentje Persoons, Dominique Schols, Wim Dehaen, Shirit Einav and Steven De Jonghe

Pharmaceuticals 2025, 18(9), 1341; https://doi.org/10.3390/ph18091341 - 6 Sep 2025

Viewed by 289

Abstract

Background/Objectives: RMC-113, a 3-alkynyl-6-aryl-disubstituted isothiazolo[4,3-b]pyridine, is a dual inhibitor of the lipid kinases PIKfyve and PIP4K2C with broad-spectrum antiviral activity. The aim was to study the structure–activity relationship (SAR) of isothiazolo[4,3-b]pyridines as dual PIKfyve/PIP4K2C inhibitors. Methods: A [...] Read more.

Background/Objectives: RMC-113, a 3-alkynyl-6-aryl-disubstituted isothiazolo[4,3-b]pyridine, is a dual inhibitor of the lipid kinases PIKfyve and PIP4K2C with broad-spectrum antiviral activity. The aim was to study the structure–activity relationship (SAR) of isothiazolo[4,3-b]pyridines as dual PIKfyve/PIP4K2C inhibitors. Methods: A series of isothiazolo[4,3-b]pyridines was synthesized by introducing structural variety at positions 3 and 6 of the central scaffold. The primary assay to guide the synthetic chemistry was a biochemical PIKfyve assay, with a number of analogues also tested for PIP4K2C binding affinity. Finally, isothiazolo[4,3-b]pyridines were also evaluated for antiviral and antitumoral activity in cell-based assays. Results: PIKfyve inhibition tolerated a wide variety of substituents on the aryl ring at position 6 of the isothiazolo[4,3-b]pyridine scaffold, with the 4-carboxamide analogue emerging as the most potent (IC₅₀ = 1 nM). The SAR at position 3 was more restricted, although the introduction of electron-donating groups (such as a methyl and methoxy) on the pyridinyl ring yielded potent PIKfyve inhibitors, with IC₅₀ values in the low nM range. The acetylenic moiety was essential for PIKfyve inhibition, and only the saturated ethyl linker displayed potent PIKfyve inhibition, albeit less active than the acetylene counterpart. The compounds were 2- to 5-fold less potent on PIP4K2C relative to PIKfyve. These dual PIKfyve/PIP4K2C inhibitors displayed antiviral activity against both the venezuelan equine encephalitis virus (VEEV) and the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A screening against a panel of cancer cell lines revealed antitumoral activity, although some of the potent PIKfyve/PIP5K2C inhibitors lacked antitumoral activity. Conclusions: Isothiazolo[4,3-b]pyridines are dual PIKfyve/PIP4K2C inhibitors displaying broad-spectrum antiviral, as well as antitumoral, activity. Full article

(This article belongs to the Special Issue Advances in the Synthesis and Application of Heterocyclic Compounds)

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20 pages, 3655 KB

Open AccessArticle

Pan-Amyloid Reactive Peptides p5+14 and p5R Exhibit Specific Charge-Dependent Binding to Glycosaminoglycans

by Trevor J. Hancock, Angela D. Williams, James S. Foster, Jonathan S. Wall and Emily B. Martin

Pharmaceuticals 2025, 18(9), 1340; https://doi.org/10.3390/ph18091340 - 6 Sep 2025

Viewed by 398

Abstract

Background: Polybasic peptides are being developed as components of reagents for diagnosing and treating patients with systemic amyloidosis. In addition to fibrils, amyloid deposits ubiquitously contain heparan sulfate proteoglycans. We have hypothesized that pan amyloid-targeting peptides can specifically engage, in addition to [...] Read more.

Background: Polybasic peptides are being developed as components of reagents for diagnosing and treating patients with systemic amyloidosis. In addition to fibrils, amyloid deposits ubiquitously contain heparan sulfate proteoglycans. We have hypothesized that pan amyloid-targeting peptides can specifically engage, in addition to fibrils, a subset of glycosaminoglycans (GAGs) with high negative charge density. In this study, we characterized the binding of peptides p5+14 (a PET imaging agent for amyloid [¹²⁴I-evuzamitide]) and p5R (a fusion protein used in the therapeutic AT-02) to GAGs. Methods: The peptide structure was evaluated in the presence of low molecular weight heparin using circular dichroism, and their interaction with synthetic GAGs of varying length and charge was interrogated. The binding patterns of p5+14 and p5R were compared using correlation analyses. Results: The peptides exist as mixed structural-fractions in solution but adopt an α-helical structure in the presence of heparin. Both peptides preferentially recognize heparin and heparan sulfate GAGs with a linear positive correlation between binding and the total charge and charge density. Conclusions: These peptides have previously been shown to specifically target amyloid deposits in vivo. A component of this specificity is their preferential interaction with a subset of heparan sulfate GAGs that have high charge density, potentially related to the degree of 6-O-sulfation. These data support the hypotheses that amyloid-associated GAGs have unique sulfation patterns, thereby explaining why these peptides do not bind GAGs found on the plasma membrane and extracellular matrix of healthy tissues. Full article

(This article belongs to the Special Issue Amyloid Composition and Structure-Based Development of Therapeutic and Diagnostic Agents)

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17 pages, 4752 KB

Open AccessArticle

Characterizing Population Pharmacokinetics of Vatiquinone in Healthy Volunteers and Patients with Friedreich’s Ataxia

by Yongjun Hu, Lan Gao, Lucy Lee, Jonathan J. Cherry and Ronald Kong

Pharmaceuticals 2025, 18(9), 1339; https://doi.org/10.3390/ph18091339 - 6 Sep 2025

Viewed by 303

Abstract

Introduction: Vatiquinone is a first-in-class, small molecule designed to maintain mitochondrial function in the disorders like Friedreich’s ataxia (FA). Vatiquinone inhibits 15-lipoxygenase, consequently decreasing oxidative stress and neuroinflammatory response pathways. Methods: Population pharmacokinetic modeling analysis was conducted to characterize vatiquinone pharmacokinetic profiles [...] Read more.

Introduction: Vatiquinone is a first-in-class, small molecule designed to maintain mitochondrial function in the disorders like Friedreich’s ataxia (FA). Vatiquinone inhibits 15-lipoxygenase, consequently decreasing oxidative stress and neuroinflammatory response pathways. Methods: Population pharmacokinetic modeling analysis was conducted to characterize vatiquinone pharmacokinetic profiles in healthy volunteers and patients and explore the effects of covariates on vatiquinone exposures. Results: A two-compartment model with parallel zero- and first-order absorption was developed and verified. The values of essential parameters were: absorption fraction through the first-order process, 74.4%; absorption rate constant, 0.20 h⁻¹; delay time, 2.79 h; zero-order absorption duration, 6.03 h; apparent volume of distribution, 180.75 L for the central and 4852.69 L for the peripheral compartment; and apparent clearance, 162.72 L/h. Strong CYP3A4 inducers could reduce exposure by 50%; strong CYP3A4 inhibitors could increase it by 252%. Vatiquinone exposure was 19% lower in patients with Friedreich’s ataxia versus healthy volunteers. A medium-fat meal increased exposure up to 25-fold versus a fasted status. Body weight and body mass index had significant clinical relevance to exposures. Conclusions: A two-compartment model effectively described the pharmacokinetic profiles of vatiquinone after oral administration. Covariates significantly impacted exposures, including body weight, meals, disease status, comedications and body mass index. Full article

(This article belongs to the Section Pharmacology)

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32 pages, 1423 KB

Open AccessReview

Pharmacological Effects and Mechanisms of Tanshinone IIA in Bone Injury Repair

by Weijian Hu, Yameng Si, Xinru Wen, Duan Lin, Zihao Yu, Xin Xie and Jiabin Xu

Pharmaceuticals 2025, 18(9), 1338; https://doi.org/10.3390/ph18091338 - 5 Sep 2025

Viewed by 451

Abstract

Tanshinone IIA (T-IIA), a fat-soluble diterpene quinone extracted from Salvia miltiorrhiza, is widely recognized for its multiple pharmacological properties, including anti-inflammatory, antioxidant, anti-fibrotic, and anti-tumor effects. Recent studies have highlighted its great potential in treating bone metabolic disorders, especially osteoporosis and bone [...] Read more.

Tanshinone IIA (T-IIA), a fat-soluble diterpene quinone extracted from Salvia miltiorrhiza, is widely recognized for its multiple pharmacological properties, including anti-inflammatory, antioxidant, anti-fibrotic, and anti-tumor effects. Recent studies have highlighted its great potential in treating bone metabolic disorders, especially osteoporosis and bone damage repair. Bone health depends on the dynamic balance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption. Disruption of this balance can lead to diseases such as osteoporosis, which is often diagnosed after a fracture, seriously affecting the quality of life and increasing the medical burden. Early identification of high-risk groups and appropriate treatment are essential for preventing fracture recurrence. Studies have shown that T-IIA can promote osteoblast differentiation and inhibit osteoclast activity, targeting key signaling pathways such as NF-κB, PI3K/Akt, and Wnt/β-catenin, all of which are closely related to bone metabolism. T-IIA has a dual role in regulating bone formation and bone resorption, making it a potential drug for the treatment of osteoporosis. In addition, T-IIA has neuroprotective, hepatic, renal, cardiac, and cerebral effects, which enhance its therapeutic effect. Despite the remarkable efficacy of T-IIA, its clinical application is limited due to poor solubility and low bioavailability. Recent advances in drug delivery systems, such as liposome formulations and nanocarriers, have improved their pharmacokinetics, increased absorption rate, and bioavailability. Combination therapy with growth factors or stem cells can further enhance its efficacy. Future studies should focus on optimizing the delivery system of T-IIA and exploring its combined application with other therapeutic strategies to expand its clinical application range. Full article

(This article belongs to the Section Pharmacology)

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16 pages, 1217 KB

Open AccessSystematic Review

Efficacy of SGLT2 Inhibitors, GLP-1 Receptor Agonists, DPP-4 Inhibitors, and Sulfonylureas on Moderate-to-Severe COPD Exacerbations Among Patients with Type 2 Diabetes: A Systematic Review and Network Meta-Analysis

by Edoardo Pirera, Domenico Di Raimondo, Lucio D’Anna and Antonino Tuttolomondo

Pharmaceuticals 2025, 18(9), 1337; https://doi.org/10.3390/ph18091337 - 5 Sep 2025

Viewed by 293

Abstract

Background/Objectives: Chronic obstructive pulmonary disease (COPD) and type 2 diabetes mellitus (T2DM) frequently coexist, contributing to worse clinical outcomes and increased risk of exacerbations. While newer glucose-lowering agents have demonstrated cardiovascular and renal benefits, their comparative efficacy on COPD exacerbations remain uncertain. [...] Read more.

Background/Objectives: Chronic obstructive pulmonary disease (COPD) and type 2 diabetes mellitus (T2DM) frequently coexist, contributing to worse clinical outcomes and increased risk of exacerbations. While newer glucose-lowering agents have demonstrated cardiovascular and renal benefits, their comparative efficacy on COPD exacerbations remain uncertain. Methods: We systematically searched PubMed, Embase, Web of Science, Cochrane Library, and ClinicalTrials.gov from inception to June 2025. We included randomised controlled trials (RCTs) and observational studies enrolling adults with COPD and T2DM that reported the risk of COPD exacerbations following initiation of SGLT2is, GLP-1RAs, DPP-4is, or sulfonylureas, with an active comparator group. The primary outcome was a composite of moderate-to-severe COPD exacerbations. Secondary outcomes included the individual components separately. A Bayesian random-effects network meta-analysis was performed to estimate risk ratio (RR) with 95% credible intervals (95% CIs). Results: Nine observational studies were ultimately included. No RCTs were retrieved. Compared to sulfonylureas, initiation of SGLT2is (RR 0.64, 0.59–0.69), GLP-1RAs (0.66, 0.60–0.71), and DPP-4is (0.79, 0.74–0.86) was associated with reduced risk of moderate-to-severe exacerbations. Moreover, SGLT2is (0.80, 0.75–0.86) and GLP-1RAs (0.83, 0.77–0.88) were more favourable compared to DPP4is. Consistent results were found for secondary outcomes. Sensitivity analyses confirmed the robustness of the findings for the primary outcome. Robustness was not consistently observed across all treatment comparisons for secondary outcomes. Conclusions: Among patients with COPD and T2DM, newer glucose-lowering agents, particularly SGLT2is and GLP-1RAs, were associated with significantly lower risk of moderate-to-severe exacerbations. These findings support the potential respiratory benefits of these agents and warrant confirmation through RCTs. Full article

(This article belongs to the Special Issue Advancements in Cardiovascular and Antidiabetic Drug Therapy, 2nd Edition)

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25 pages, 9489 KB

Open AccessArticle

Moringa (Moringa oleifera) Leaf Attenuates the High-Cholesterol Diet-Induced Adverse Events in Zebrafish: A 12-Week Dietary Intervention Resulted in an Anti-Obese Effect and Blood Lipid-Lowering Properties

by Kyung-Hyun Cho, Ashutosh Bahuguna, Yunki Lee, Ji-Eun Kim, Sang Hyuk Lee and Krismala Djayanti

Pharmaceuticals 2025, 18(9), 1336; https://doi.org/10.3390/ph18091336 - 5 Sep 2025

Viewed by 501

Abstract

Objective: The study investigates the dietary effects of Moringa oleifera leaf powder on obesity, blood biochemical parameters, and organ health in hyperlipidemic zebrafish (Danio rerio). Methodology: Adult hyperlipidemic zebrafish (n = 56/group) were fed for 12 weeks either with a [...] Read more.

Objective: The study investigates the dietary effects of Moringa oleifera leaf powder on obesity, blood biochemical parameters, and organ health in hyperlipidemic zebrafish (Danio rerio). Methodology: Adult hyperlipidemic zebrafish (n = 56/group) were fed for 12 weeks either with a high-cholesterol diet (HCD, 4% w/w) or HCD supplemented with 0.5% (w/w) M. oleifera leaf powder (0.5% MO) or HCD with 1.0% (w/w) M. oleifera leaf powder (1.0% MO). At different time points (0 to 12 weeks), the survivability and body weight (BW) of zebrafish were measured, while various biochemical and histological evaluations were performed after 12 weeks of feeding the respective diets. Additionally, an in silico approach was used to assess the binding interactions of MO phytoconstituents with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Results: Following 12-week supplementation, higher zebrafish survivability was observed in the MO-supplemented groups compared to the survivability of the HCD group. Relative to the initial BW, only 4% BW enhancement was observed post 12 weeks of dietary intake of 1.0% MO, in contrast to 27% BW gain in the HCD group. MO supplementation at both (0.5% and 1.0%) effectively mitigates the HCD-induced dyslipidemia and significantly minimizes the atherogenic coefficient and atherogenic index. Similarly, MO reduces elevated blood glucose levels, the ALT/AST ratio, and augments ferric ion reduction (FRA) and paraoxonase (PON) activity in a dose-dependent manner. Likewise, MO (particularly at 1.0%) effectively restrained HCD-induced steatosis, hepatic interleukin (IL)-6 production, and protected the kidneys, testes, and ovaries from oxidative stress and cellular senescence. The in silico findings underscore that the six phytoconstituents (chlorogenic acid, isoquercetin, kaempferol 3-O-rutinoside, astragalin, apigetrin, and myricetin) of MO exhibited a strong interaction with HMG-CoA reductase active and binding site residues via hydrogen and hydrophobic interactions. Conclusions: The findings demonstrated an antioxidant, anti-inflammatory, and hypoglycemic effect of MO, guiding the events to prevent HCD-induced metabolic stress and safeguard vital organs. Full article

(This article belongs to the Special Issue Drug Candidates for the Treatment of Obesity, 2nd Edition)

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25 pages, 2178 KB

Open AccessArticle

Pharmacogenetics and Molecular Ancestry of SLC22A1, SLC22A2, SLC22A3, ABCB1, CYP2C8, CYP2C9, and CYP2C19 in Ecuadorian Subjects with Type 2 Diabetes Mellitus

by Adiel Ortega-Ayala, Carla González de la Cruz, Lorena Mora, Mauro Bonilla, Leandro Tana, Fernanda Rodrigues-Soares, Pedro Dorado, Adrián LLerena and Enrique Terán

Pharmaceuticals 2025, 18(9), 1335; https://doi.org/10.3390/ph18091335 - 5 Sep 2025

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Abstract

Background/Objectives: In Ecuador, the prevalence of type 2 diabetes mellitus (T2DM) is the second leading cause of death after ischemic heart disease. Genetic variability in protein-coding genes, single nucleotide variants (SNVs), influences the response to antidiabetic drugs. The frequency of SNVs varies among [...] Read more.

Background/Objectives: In Ecuador, the prevalence of type 2 diabetes mellitus (T2DM) is the second leading cause of death after ischemic heart disease. Genetic variability in protein-coding genes, single nucleotide variants (SNVs), influences the response to antidiabetic drugs. The frequency of SNVs varies among different populations, so studying the ancestral proportions among SNVs is important for personalized medicine in the treatment of T2DM. This study aimed to evaluate the distribution of Native American, European, and African (NATAM, EUR, and AFR) ancestry in 23 allelic variants of the seven genes that encode the relevant enzymes that metabolize antidiabetic drugs in an Ecuadorian population. Methods: Twenty-three allelic variants of seven genes were analyzed in 297 patients with T2DM from Ecuador, and the molecular ancestry of the samples was analyzed considering three ancestral groups, NATAM, EUR, and AFR using 90 ancestry informative markers (AIMs). Allele and ancestry distributions were analyzed using Spearman’s correlation. Results: The Ecuadorian population presents NATAM (61.33%), EUR (34.48%), and AFR (2.60%) ancestry components. CYP2C8*1 and CYP2C9*1 were positively related to NATAM ancestry, while CYP2C8*4 and CYP2C9*2 were positively related to EUR ancestry. CYP2C19*17 was positively correlated to AFR ancestry. The correlation of SLC22A1 variants such as A in rs594709 was positively correlated with NATAM, while GAT in rs72552763 was positive for EUR. The G variant of rs628031 of the SLC22A1 gene was positively correlated with NATAM and negatively correlated with EUR. The C variant of rs2076828 of the SLC22A3 gene was positively correlated with NATAM ancestry. Conclusions: In the Ecuadorian population, a predominance of Native American ancestry has been observed. Among the allelic variants related to enzymes that metabolize antidiabetic drugs, a relationship has been observed between this ancestral component and variants of the CYP2C8*1, CYP2C9*1, SLC22A1 (rs594709 and rs628031), and SLC22A3 (rs2076828) genes. This information is fundamental for the development of strategies for the implementation of personalized medicine programs for Latin American patients. Full article

(This article belongs to the Special Issue Advancements in Cardiovascular and Antidiabetic Drug Therapy, 2nd Edition)

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17 pages, 1022 KB

Open AccessArticle

Bee Venom Proteins Enhance Proton Absorption by Membranes Composed of Phospholipids of the Myelin Sheath and Endoplasmic Reticulum: Pharmacological Relevance

by Zhuoyan Zeng, Mingsi Wei, Shuhao Zhang, Hanchen Cui, Ruben K. Dagda and Edward S. Gasanoff

Pharmaceuticals 2025, 18(9), 1334; https://doi.org/10.3390/ph18091334 - 5 Sep 2025

Viewed by 302

Abstract

Background/Objectives: Recent evidence challenges the classical chemiosmotic theory, suggesting that proton movement along membrane surfaces—not bulk-phase gradients—drives bioenergetic processes. Proton accumulation on membranes like the myelin sheath and endoplasmic reticulum (ER) may represent a universal mechanism for cellular energy storage. This study [...] Read more.

Background/Objectives: Recent evidence challenges the classical chemiosmotic theory, suggesting that proton movement along membrane surfaces—not bulk-phase gradients—drives bioenergetic processes. Proton accumulation on membranes like the myelin sheath and endoplasmic reticulum (ER) may represent a universal mechanism for cellular energy storage. This study investigates whether phospholipids from these membranes, combined with anionic bee venom proteins, enhance proton absorption, potentially elucidating a novel bioenergetic pathway. Methods: Five phospholipids (phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, sphingomyelin, phosphatidylcholine) from rat liver were isolated to model myelin/ER membranes. Anionic proteins (pI 5.65–5.80) were purified from bee venom via cation exchange chromatography. Liposomes (with/without proteins) were prepared, and proton absorption was quantified by pH changes in suspensions versus pure water. Statistical significance was assessed via ANOVA and t-tests. Results: All phospholipid liposomes examined in this study absorbed protons under the tested conditions, with phosphatidylethanolamine showing the highest capacity (pH increase: 7.00 → 7.18). Liposomes enriched with anionic proteins exhibited significantly greater proton absorption (e.g., phosphatidylserine + proteins: pH 8.15 vs. 7.15 alone; p < 2.43 × 10⁻⁶). Sphingomyelin-protein liposomes absorbed the most protons, suggesting that protein–phospholipid interactions modulate surface proton affinity. Conclusions: Anionic bee venom proteins amplify proton absorption by phospholipid membranes, supporting the hypothesis that lipid–protein complexes act as “proton capacitors”. This mechanism may underpin extramitochondrial energy storage in myelin and ER. Pharmacologically, targeting these interactions could mitigate bioenergetic deficits in aging or disease. Further research should define the structural basis of proton capture by membrane-anchored proteins. Full article

(This article belongs to the Special Issue Recent Research in Therapeutic Potentials of Venoms)

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Pharmaceuticals, Volume 18, Issue 9 (September 2025) – 122 articles

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