Towards Dual-Tracer SPECT for Prostate Cancer Imaging Using [^99mTc]Tc-PSMA-I&S and [¹¹¹In]In-RM2
Stem Cells and Organoids: A Paradigm Shift in Preclinical Models Toward Personalized Medicine
Dopamine Partial Agonists in Pregnancy and Lactation: A Systematic Review
The Antidiabetic Activity of Wild-Growing and Cultivated Medicinal Plants Used in Romania for Diabetes Mellitus Management: A Phytochemical and Pharmacological Review

Journal Description

Pharmaceuticals

Pharmaceuticals is a peer-reviewed, open access journal of medicinal chemistry and related drug sciences, published monthly online by MDPI. The Academy of Pharmaceutical Sciences (APS) is affiliated with Pharmaceuticals and its members receive discounts on the article processing charges.

Open Access free for readers, with article processing charges (APC) paid by authors or their institutions.
High Visibility: indexed within Scopus, SCIE (Web of Science), PubMed, PMC, Embase, CAPlus / SciFinder, and other databases.
Journal Rank: JCR - Q1 (Pharmacology and Pharmacy) / CiteScore - Q1 (Pharmaceutical Science)
Rapid Publication: manuscripts are peer-reviewed and a first decision is provided to authors approximately 14 days after submission; acceptance to publication is undertaken in 2.9 days (median values for papers published in this journal in the first half of 2025).
Recognition of Reviewers: reviewers who provide timely, thorough peer-review reports receive vouchers entitling them to a discount on the APC of their next publication in any MDPI journal, in appreciation of the work done.
Testimonials: See what our editors and authors say about Pharmaceuticals.
International Electronic Conference on Medicinal Chemistry (https://sciforum.net/series/ecmc/latest)
Companion journals for Pharmaceuticals include: Pharmacoepidemiology, Psychoactives and Drugs and Drug Candidates.
Journal Clusters-Pharmaceutical Science: Scientia Pharmaceutica, Pharmaceuticals, Pharmaceutics, Pharmacy, Future Pharmacology, Pharmacoepidemiology, Drugs and Drug Candidates and Journal of Pharmaceutical and BioTech Industry.

Impact Factor: 4.8 (2024); 5-Year Impact Factor: 4.9 (2024)

Imprint Information Journal Flyer Open Access ISSN: 1424-8247

Latest Articles

31 pages, 6901 KB

Open AccessArticle

Therapeutic Potential of Food-Derived Rutin Phytosome Nanoparticles: Anti-Tumor, Antioxidant, and Anti-Inflammatory Activity in Ehrlich Ascites Carcinoma

by M. Alfawaz, Ekramy M. Elmorsy, Alaa Samy, Ahmed S. Shams, Mai A. Salem, Aly A. M. Shaalan, Manal S. Fawzy and Nora Hosny

Pharmaceuticals 2025, 18(9), 1410; https://doi.org/10.3390/ph18091410 (registering DOI) - 19 Sep 2025

Abstract

Background/Objectives: Rutin (RT), a promising bioflavonoid, faces clinical limitations due to its poor solubility and bioavailability. In this study, we formulated RT-loaded phytosome nanoparticles (RT-PNPs) via thin-layer hydration and characterized their morphology, size distribution, and zeta potential. Methods: We established a mouse model of Ehrlich ascites carcinoma (EAC), randomly allocating ninety female Swiss albino mice into six groups: untreated controls, RT-treated, RT-PNP-treated, EAC, EAC + RT, and EAC + RT-PNPs. Tumor induction and treatment protocols were controlled, with the oral administration of 25 mg/kg/day of RT or RT-PNPs for 20 days. We comprehensively assessed survival, body weight, ascitic fluid/tumor volume, and cell viability and performed detailed hematological, serum biochemical, and tumor marker analyses. Multiorgan (liver and kidney) function and redox homeostasis were evaluated through enzymatic assays for SOD, CAT, GSH-Px, and GSH, as well as lipid peroxidation assessment. Proinflammatory cytokines and tumor markers (AFP, CEA, CA19-9, CA125, and CA15-3) were quantified via ELISA. Results: Gene expression profiling (TP53, Bax, and Bcl-2) and flow cytometry (p53 and Ki-67) elucidated the modulation of apoptosis. Histopathological scoring documented organ protection, while advanced multivariate (heatmap and principal component) analyses revealed distinct treatment clusterings. The RT-PNPs demonstrated potent anti-tumor, antioxidant, anti-inflammatory, and apoptosis-inducing effects, outperforming free RT in restoring physiological markers and tissue integrity. Conclusions: The current results underscore the potential of RT-PNPs as a multifaceted therapeutic approach to EAC, leveraging nanoparticle technology to optimize efficacy and systemic protection. Full article

(This article belongs to the Special Issue The Discovery and Development of Drug Ingredients from Food Sources)

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18 pages, 3244 KB

Open AccessArticle

Effect of Combination Therapy with Probiotic Bulgarian Goat Yoghurt Enriched with Aronia melanocarpa Fruit Juice in Patients with Type 2 Diabetes Mellitus and Complication of Diabetic Nephropathy: A Pilot Study

by Petya Goycheva, Kamelia Petkova-Parlapanska, Ekaterina Georgieva, Nikolina Zheleva, Mariya Lazarova, Yanka Karamalakova and Galina Nikolova

Pharmaceuticals 2025, 18(9), 1409; https://doi.org/10.3390/ph18091409 (registering DOI) - 19 Sep 2025

Abstract

Background: Goat milk and its fermented products exhibit unique nutritional and therapeutic characteristics corresponding to the management of metabolic disorders, such as type 2 diabetes mellitus (T2DM) and its associated complications, including diabetic nephropathy (DN). Due to its rich content of bioactive compounds and superior digestibility compared to cow’s milk, goat milk enhances nutrient assimilation and exhibits notable anti-inflammatory and antioxidant effects. The primary aim of this investigation was to systematically evaluate the efficacy of goat milk-based nutritional interventions as an integral component of a multifaceted therapeutic approach aimed at attenuating oxidative stress (OS), restoring metabolic homeostasis, and mitigating the progression of long-term complications in patients with diabetes mellitus and concurrent renal dysfunction. Methods: Participants diagnosed with T2DM were stratified into three subgroups based on the severity of renal dysfunction. The results were analyzed in comparison with those of healthy control subjects. Results: Following a dietary regimen that included goat milk enriched with Aronia (Aronia melanocarpa) fruit juice patients—particularly those with DN—exhibited marked reductions in free radical concentrations, decreased cytokine production, and diminished levels of lipid and protein oxidation byproducts. Moreover, a significant improvement was observed in nitric oxide (NO) levels, along with partial restoration of the nitric oxide synthase (NOS) system and an upregulation of endogenous antioxidant enzyme activity (p < 0.05) relative to pre-intervention measurements. Conclusions: These outcomes suggest that the dietary intervention not only attenuated OS but also contributed to improved renal function in affected individuals. The results support the therapeutic potential of functional dairy-based diets—specifically those incorporating bioactive ingredients such as Aronia melanocarpa fruit juice and goat milk—in mitigating oxidative damage and enhancing metabolic and renal health in patients with T2DM and DN. Full article

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

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14 pages, 1030 KB

Open AccessReview

Immunoregulation by ESAT-6: From Pathogenesis of Tuberculosis to Potential Anti-Inflammatory and Anti-Rejection Application

by Weihui Lu, Jingru Lin, Yuming He, Bin Yang, Feifei Qiu and Zhenhua Dai

Pharmaceuticals 2025, 18(9), 1408; https://doi.org/10.3390/ph18091408 - 18 Sep 2025

Abstract

The early secreted antigenic target of 6 kDa (ESAT-6), a main effector molecule of the ESX-1 secretion system, is identified as a virulence determinant and immunoregulatory protein of Mycobacterium tuberculosis (Mtb), affecting the interaction between host immune cells and pathogens. ESAT-6 facilitates the survival of mycobacteria and their cell-to-cell spreading through membrane-permeabilizing activity and the regulation of host immune cell functions. In this review, we first summarize the recent knowledge of the roles of ESAT-6 in the survival of bacteria, phagosomal escape, and pathogenicity during Mtb infection. Then, we focused on its complex immunomodulatory effects on different immune cells, such as macrophages, dendritic cells, neutrophils, and T cells, accentuating its capability to either facilitate or inhibit immune responses through different signaling pathways. While our review has summarized its main roles in immunopathology in the context of tuberculosis, we additionally search for emerging evidence indicating that ESAT-6 has anti-inflammatory and immunosuppressive properties. Particularly, we discuss recent preclinical studies showing its capability to suppress transplant rejection and alloimmunity, probably via the induction of regulatory T cells. Nevertheless, the potential clinical use of ESAT-6 remains uncertain and needs further verification by comprehensive preclinical and clinical studies. Thus, we propose that ESAT-6 may be exploited to ameliorate immunopathology in TB infection and to suppress immune-mediated inflammation or transplant rejection as well. Full article

(This article belongs to the Section Biopharmaceuticals)

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38 pages, 1843 KB

Open AccessReview

Skeletal Muscle Aging: Enhancing Skeletal Muscle Integrity and Function as a Potential Pharmacological Approach

by Sibhghatulla Shaikh, Khurshid Ahmad, Jeong Ho Lim, Syed Sayeed Ahmad, Eun Ju Lee and Inho Choi

Pharmaceuticals 2025, 18(9), 1407; https://doi.org/10.3390/ph18091407 - 18 Sep 2025

Abstract

With the increase in global life expectancy, preserving skeletal muscle (SM) health is essential for the overall well-being of older adults. Gradual decline in muscle mass, strength, and physical performance significantly contributes to frailty, reduced mobility, and heightened vulnerability to chronic diseases. These challenges underscore the need to formulate innovative strategies for safeguarding muscle health in aging demographics. This review analyzes the major biological and lifestyle factors influencing age-related changes, establishing a framework for understanding SM deterioration. The review focuses on structural and functional alterations of SM extracellular matrix components to identify potential intervention points for muscle waste mitigation. Additionally, we discuss novel interventions designed to preserve muscle mass and functionality. In older individuals, emerging pharmacological strategies, including innovative peptides and natural compounds, may mitigate catabolic processes, enhance muscle regeneration, and increase resilience. Concurrent lifestyle interventions, including specialized exercise regimens, nutritional enhancement, and stress reduction, augment these pharmacological approaches. This review provides a thorough resource for researchers, clinicians, and healthcare professionals focused on functional capacity enhancement in older adults. Full article

(This article belongs to the Special Issue The Role of Phytochemicals in Aging and Aging-Related Diseases)

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29 pages, 2368 KB

Open AccessReview

Inflammation-Driven Genomic Instability: A Pathway to Cancer Development and Therapy Resistance

by Nina Rembiałkowska, Zofia Kocik, Amelia Kłosińska, Maja Kübler, Agata Pałkiewicz, Weronika Rozmus, Mikołaj Sędzik, Helena Wojciechowska and Agnieszka Gajewska-Naryniecka

Pharmaceuticals 2025, 18(9), 1406; https://doi.org/10.3390/ph18091406 - 18 Sep 2025

Abstract

Chronic inflammation, while originally a protective physiological response, is increasingly recognized as a key contributor to carcinogenesis. Prolonged inflammatory signaling leads to the sustained production of reactive oxygen and nitrogen species (ROS/RNS), resulting in direct and indirect DNA damage, including base modifications, strand breaks, and DNA cross-linking. Simultaneously, pro-inflammatory mediators such as NF-κB, IL-6, and TNF-α can interfere with DNA repair mechanisms, altering the efficiency of key pathways such as base excision and mismatch repair. Immune cells infiltrating chronically inflamed tissues, including macrophages and neutrophils, further exacerbate genomic instability through ROS/RNS release and cytokine production, creating a tumor-promoting microenvironment. Additionally, chronic inflammation has been implicated in the development of resistance to chemotherapy and radiotherapy by modulating DNA damage response pathways. Understanding the interplay between inflammation, genomic instability, and therapy resistance provides a framework for novel treatment strategies. Targeting chronic inflammation with non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, or biological agents such as monoclonal antibodies offers promising avenues for cancer prevention and treatment. Targeting inflammation with NSAIDs, corticosteroids, and monoclonal antibodies shows promise in cancer prevention and therapy, particularly in lung and pancreatic cancer. These agents act by blocking key inflammatory pathways like COX-2, NF-κB, and cytokine signaling. However, potential adverse effects require further clinical evaluation. Full article

(This article belongs to the Special Issue Novel Anticancer Drug Development and Toxicity Reduction Strategies)

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17 pages, 648 KB

Open AccessArticle

Somatic Mutations in DNA Mismatch Repair Genes, Mutation Rate and Neoantigen Load in Acute Lymphoblastic Leukemia

by Diana Karen Mendiola-Soto, Laura Gómez-Romero, Juan Carlos Núñez-Enríquez, Janet Flores-Lujano, Elva Jiménez-Hernández, Aurora Medina-Sansón, Vilma Carolina Bekker-Méndez, Minerva Mata-Rocha, María Luisa Pérez-Saldívar, David Aldebarán Duarte-Rodríguez, José Refugio Torres-Nava, José Gabriel Peñaloza-González, Luz Victoria Flores-Villegas, Raquel Amador-Sánchez, Martha Margarita Velázquez-Aviña, Jorge Alfonso Martín-Trejo, Laura Elizabeth Merino-Pasaye, Karina Anastacia Solís-Labastida, Rosa Martha Espinosa-Elizondo, Carlos Jhovani Pérez-Amado, Didier Ismael May-Hau, Omar Alejandro Sepúlveda-Robles, Haydee Rosas-Vargas, Juan Manuel Mejía-Aranguré and Silvia Jiménez-Morales Show full author list Hide full author list

Pharmaceuticals 2025, 18(9), 1405; https://doi.org/10.3390/ph18091405 - 18 Sep 2025

Abstract

Background/Objectives: During cancer development, tumor cells accumulate somatic mutations, which could generate tumor-specific neoantigens. The aberrant protein can be recognized by the immune system as no-self, triggering an immune response against cells expressing this aberrant protein which could mediate tumor control or rejection. Since the expression of this mutated protein is exclusive to tumor cells, great efforts are being made to identify neoantigens of relevance in the development of new cancer treatment strategies. In comparison to adulthood tumors, pediatric malignancies present fewer mutations and thus fewer potential neoantigens. Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy worldwide that can be benefited by the identification of neoantigens for immunotherapy approaches, the landscape of neoantigens in ALL is not well known, therefore the aim of our study was to identify potential neoantigens in ALL pediatric patients. Methods: To identify neoantigens in ALL, whole-exome sequencing of matched tumor-normal cells from pediatric cases was performed, with these data HLA-I alleles predicted and somatic mutations identified to propose potential neoantigens based on binding affinity of mutated peptide-HLA-I. Results: We found a strong correlation between tumor mutational burden (TMB) and neoantigen load (p < 0.001) but no correlation with prognosis. Furthermore, TMB and neoantigens were greater in ALL patients with at least one mutated DNA mismatch repair gene (p < 0.001). Also, differences between B- and T-cell ALL were found but statistical significance did not remain after permutation. Conclusions: The presence of neoantigens in pediatric cases with ALL makes the neoantigen-based immunotherapy a promising new strategy for the treatment of this malignancy, especially for patients with relapse. Full article

(This article belongs to the Special Issue Immunogenomics for Drug Discovery in Leukemia)

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24 pages, 20334 KB

Open AccessArticle

Exploring Potential for Repurposing Antiretroviral Drugs Etravirine and Efavirenz in Prostate and Bladder Cancer

by Mariana Pereira and Nuno Vale

Pharmaceuticals 2025, 18(9), 1404; https://doi.org/10.3390/ph18091404 - 18 Sep 2025

Abstract

Background/Objectives: Prostate and bladder cancers are significant global health challenges with increasing incidence and limited treatment options in advanced stages. Drug repurposing offers a cost-effective strategy to accelerate the development of new anticancer therapies. This study investigated the antitumor activity of the non-nucleoside reverse transcriptase inhibitors efavirenz (EFV) and etravirine (ETV) in prostate and bladder cancer models. Methods: PC-3 prostate cancer and UM-UC-5 bladder cancer cell lines were treated with EFV, ETV, or their combination. Cell viability was assessed at 24, 48, and 72 h to evaluate time and concentration-dependent effects. Wound-healing assays were used to measure cell migration, and clonogenic assays assessed long-term proliferative capacity. Results: Both EFV and ETV decreased cell viability in a time and dose-dependent manner. ETV showed greater potency in PC-3 cells, while EFV demonstrated more consistent effects in UM-UC-5 cells. Combination treatment enhanced cytotoxicity, particularly at 48 and 72 h, suggesting potential synergy. Wound-healing assays indicated impaired migration in UM-UC-5 cells treated with ETV or the EFV + ETV combination. Clonogenic assays confirmed reduced long-term proliferation in both cell lines following treatment. Conclusions: EFV and ETV exhibit selective anticancer activity in prostate and bladder cancer cells, with enhanced effects when combined. These findings support their potential as repurposed therapeutic agents and warrant further preclinical evaluation for prostate and bladder cancer therapy. Full article

(This article belongs to the Section Medicinal Chemistry)

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12 pages, 722 KB

Open AccessArticle

Evaluation of Proliferative Activity of Hawaiian Plants on PC-12 and Neuro-2a Cells and Their Effect on the TPH and TH Genes

by Pornphimon Meesakul, Tyler Shea, Xiaohua Wu, Yutaka Kuroki, Aya Wada and Shugeng Cao

Pharmaceuticals 2025, 18(9), 1403; https://doi.org/10.3390/ph18091403 - 18 Sep 2025

Abstract

Background/Objectives: Neurotransmitters such as dopamine and serotonin are critical regulators of mood, cognition, and neuronal homeostasis. This study aimed to evaluate the neuropharmacological potential of Hawaiian plants by investigating their ability to modulate the expression of tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH), key enzymes in neurotransmitter biosynthesis. Methods: A total of 108 aqueous and methanolic extracts of Hawaiian plants were screened for cytotoxicity against PC-12 and Neuro-2A cells using the MTT assay. Fifty-six non-toxic extracts were selected and further analyzed for TH and TPH expression via quantitative real-time PCR (qPCR). Results: Several extracts significantly upregulated TH and TPH expression without inducing cytotoxicity. Extracts derived from Morinda citrifolia, Pipturus albidus, and Hedychium coronarium showed the most notable activity, suggesting their potential to enhance dopaminergic and serotonergic pathways. Conclusions: The findings highlight the promise of native Hawaiian flora as sources of neuroactive compounds that may support neuroprotection and regeneration. These results provide a foundation for in vivo studies and further exploration of novel neurotherapeutic agents. Full article

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

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6 pages, 206 KB

Open AccessReply

Reply to Douxfils, J.; Foidart, J.-M. Critical Considerations in the Interpretation of Bone Turnover Marker Data in Hormonal Contraceptive Users. Comment on “Tassi et al. Hormonal Contraception and Bone Metabolism: Emerging Evidence from a Systematic Review and Meta-Analysis of Studies on Post-Pubertal and Reproductive-Age Women. Pharmaceuticals 2025, 18, 61”

by Alice Tassi, Ambrogio P. Londero, Anjeza Xholli, Giulia Lanzolla, Serena Bertozzi, Luca Savelli, Federico Prefumo and Angelo Cagnacci

Pharmaceuticals 2025, 18(9), 1402; https://doi.org/10.3390/ph18091402 - 18 Sep 2025

Abstract

Dear Editor, [...] Full article

5 pages, 212 KB

Open AccessComment

Critical Considerations in the Interpretation of Bone Turnover Marker Data in Hormonal Contraceptive Users. Comment on Tassi et al. Hormonal Contraception and Bone Metabolism: Emerging Evidence from a Systematic Review and Meta-Analysis of Studies on Post-Pubertal and Reproductive-Age Women. Pharmaceuticals 2025, 18, 61

by Jonathan Douxfils and Jean-Michel Foidart

Pharmaceuticals 2025, 18(9), 1401; https://doi.org/10.3390/ph18091401 - 18 Sep 2025

Abstract

In response to the recent meta-analysis by Tassi et al. on hormonal contraception and bone metabolism, we raise critical concerns regarding the interpretation of bone turnover markers as surrogates for bone mineral density (BMD). While bone turnover markers can offer early insights into bone remodeling, they do not directly predict long-term BMD changes, which require 12–24 months to detect. The assumption that equivalent percentage changes in bone formation and resorption markers reflect stable BMD is not supported by current evidence. Bone metabolism varies significantly across life stages, particularly during adolescence and early adulthood, when peak bone mass is still accruing—underscoring the need for age-specific analyses. Additionally, biomarker interpretation is limited by assay variability, inconsistent sampling protocols, and uncertain clinical implications, especially for formation markers. Mechanistically, estrogen supports bone integrity by inhibiting resorption and promoting formation; thus, combined hormonal contraceptives (CHCs) containing estrogen may help preserve bone health. In contrast, progestin-only methods can suppress endogenous estrogen production, potentially compromising skeletal development. We advocate for longitudinal studies incorporating both BMD and turnover markers, stratified by age and contraceptive formulation, to guide safer and more informed contraceptive choices that protect long-term bone health. Full article

2 pages, 150 KB

Open AccessRetraction

RETRACTED: Naamneh et al. Structure–Activity Relationship of Synthetic Linear KTS-Peptides Containing Meta-Aminobenzoic Acid as Antagonists of α1β1 Integrin with Anti-Angiogenic and Melanoma Anti-Tumor Activities. Pharmaceuticals 2024, 17, 549

by Majdi Saleem Naamneh, Tatjana Momic, Michal Klazas, Julius Grosche, Johannes A. Eble, Cezary Marcinkiewicz, Netaly Khazanov, Hanoch Senderowitz, Amnon Hoffman, Chaim Gilon, Jehoshua Katzhendler and Philip Lazarovici

Pharmaceuticals 2025, 18(9), 1400; https://doi.org/10.3390/ph18091400 - 18 Sep 2025

Abstract

The journal retracts the article titled “Structure–Activity Relationship of Synthetic Linear KTS-Peptides Containing Meta-Aminobenzoic Acid as Antagonists of α1β1 Integrin with Anti-Angiogenic and Melanoma Anti-Tumor Activities” [...] Full article

41 pages, 3167 KB

Open AccessOpinion

Cardiotoxicity Induced by Anticancer Therapies: A Call for Integrated Cardio-Oncology Practice

by Giuliana Ciappina, Luigi Colarusso, Enrica Maiorana, Alessandro Ottaiano, Tindara Franchina, Antonio Picone, Gaetano Facchini, Chiara Barraco, Antonio Ieni, Maurizio Cusmà Piccione, Concetta Zito and Massimiliano Berretta

Pharmaceuticals 2025, 18(9), 1399; https://doi.org/10.3390/ph18091399 - 17 Sep 2025

Abstract

The introduction of novel oncologic therapies, including targeted agents, immunotherapies, and antibody–drug conjugates, has transformed the therapeutic landscape of cancer care. This evolution has resulted in a dual clinical scenario; while survival outcomes have markedly improved, leading to a growing population of long-term cancer survivors, an increasing incidence of previously unrecognized treatment-related toxicities has emerged. Among these, cardiovascular adverse events represent some of the most prevalent and clinically significant complications observed in both conventional chemotherapy and modern therapeutic regimens. Cardiotoxicity has become a major concern, with the potential to adversely affect not only cardiovascular health but also the continuity and efficacy of oncologic treatments, thereby impacting overall survival. This opinion paper synthesizes current evidence, identifies critical gaps in knowledge, and advocates for a multidisciplinary, evidence-based framework to guide the prevention, early detection, and optimal management of cardiotoxicity associated with anticancer therapies. Full article

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

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26 pages, 4042 KB

Open AccessArticle

Design, Synthesis, and Biological Evaluation of Novel Multitarget 7-Alcoxyamino-3-(1,2,3-triazole)-coumarins as Potent Acetylcholinesterase Inhibitors

by Nathalia F. Nadur, Larissa de A. P. Ferreira, Daiana P. Franco, Luciana L. de Azevedo, Lucas Caruso, Thiago da S. Honório, Priscila de S. Furtado, Alice Simon, Lucio M. Cabral, Tobias Werner, Holger Stark and Arthur E. Kümmerle

Pharmaceuticals 2025, 18(9), 1398; https://doi.org/10.3390/ph18091398 - 17 Sep 2025

Abstract

Background: Multitarget-directed ligands (MTDLs), particularly those combining cholinesterase inhibition with additional mechanisms, are promising candidates for Alzheimer’s disease (AD) therapy. Based on our previous identification of a dual-active coumarin derivative, we designed a new series of 7-alkoxyamino-3-(1,2,3-triazole)-coumarins. Methods: These compounds were synthesized by a new Sonogashira protocol and evaluated for AChE and BChE inhibition, enzymatic kinetics, molecular docking, neurotoxicity in SH-SY5Y cells, neuroprotection against H₂O₂-induced oxidative stress, and additional interactions with H₃R and MAOs. Results: All derivatives inhibited AChE with IC₅₀ values of 4–104 nM, displaying high selectivity over BChE (up to 686-fold). Kinetic and docking studies indicated mixed-type inhibition involving both CAS and PAS. The most potent compounds (1h, 1j, 1k, 1q) were non-neurotoxic up to 50 µM, while 1h and 1k also showed neuroprotective effects at 12.5 µM. Selected derivatives (1b, 1h, 1q) demonstrated multitarget potential, including H₃R affinity (K_i as low as 32 nM for 1b) and MAO inhibition (IC₅₀ of 1688 nM for 1q). Conclusions: This series of coumarin–triazole derivatives combines potent and selective AChE inhibition with neuroprotective and multitarget activities, highlighting their promise as candidates for AD therapy. Full article

(This article belongs to the Special Issue A Commemorative Special Issue in Honor of Professor Carlos Alberto Manssour Fraga: Medicinal Chemistry’s Efforts to Discover Novel Bioactive Molecules for Complex Diseases)

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9 pages, 476 KB

Open AccessViewpoint

PROTACs and Glues: Striking Perspectives for Engineering Cancer Therapy À La Carte

by Jean-Marc Ferrero, Jocelyn Gal, Baharia Mograbi and Gérard Milano

Pharmaceuticals 2025, 18(9), 1397; https://doi.org/10.3390/ph18091397 - 17 Sep 2025

Abstract

PROTACs are bifunctional small molecules that simultaneously bind a target protein and a component of the ubiquitin–proteasome system, thereby inducing selective degradation of the target. They represent a class of compounds capable of achieving the complete elimination of disease-relevant proteins. Molecular glues, by contrast, enhance existing surface complementarity between an E3 ligase and a target protein, promoting its ubiquitination and subsequent degradation. Both approaches are at the forefront of current efforts to overcome the long-standing challenge of undruggable tumor targets. In this context, AI-based strategies offer a powerful means to accelerate the discovery, optimization, and production of highly selective protein binders, streamlining access to potent degraders and maximizing therapeutic potential. These capabilities open new horizons for targeting a wide spectrum of previously inaccessible molecular pathways involved in cancer progression. Altogether, these advances position PROTACs and molecular glues as transformative agents for personalized oncology, particularly within the emerging paradigm of molecular tumor boards, where tailored therapeutic decisions and tumor-adapted drugs could be made rapidly accessible for a given patient. Full article

(This article belongs to the Special Issue Application of Computer Simulation in Drug Design)

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18 pages, 793 KB

Open AccessArticle

Herbal Medicine and Lifestyle Modifications for People with Obesity: A Single-Center, Retrospective, Observational Study

by Minwoo Bang, Suyong Shin, Jungsang Kim, Minwhee Kang, Donghun Lee, Junho Kim, Chunghee Kim, Jiyoung Son, Seungyeon Choi, Seonghyeon Jeon, Dasol Park, Byungsoo Kang and Jungtae Leem

Pharmaceuticals 2025, 18(9), 1396; https://doi.org/10.3390/ph18091396 - 17 Sep 2025

Abstract

Objectives: Conventional Western treatments for obesity are associated with various adverse events (AEs). This study aimed to determine the treatment response and safety assessment of an integrative Korean medicine treatment (IKMT), consisting of herbal medicine (HM) and lifestyle modification (LM), for weight loss (WL) in people with obesity. Methods: The electronic medical records of outpatients from July 2021 to May 2023 at a Daeat Korean medicine clinic in Seoul were retrospectively reviewed. A total of 3161 patients were evaluated using bioelectrical impedance analysis (BIA) and blood pressure (BP) index. Moreover, the treatment response to IKMT in the 24 best cases (WL within BMI < 23 kg/m²) was evaluated using BIA and BP index, and the safety profile was determined by analyzing AEs. Results: The mean age was 38.2 ± 11.39 years, and the mean duration of treatment was 142.62 ± 104.92 days (approximately 20 weeks). The mean WL was 8.02 ± 6.67 kg (change from the baseline, 8.71%). Of the 3161 participants, 2146 had a WL of ≥5%. The best-case subgroup (n = 24; age 36.54 ± 11.64 years) achieved 23.02 ± 4.07 kg WL and reached BMIs < 23 kg/m² in 7.83 ± 2.54 months; among those with BP indices available (n = 21), reductions were statistically significant. In this subgroup, the mean treatment duration was 8.71 ± 2.46 months (range, 5–15), exceeding the 6-month safety guideline for Ephedrae Herba-containing HM, and no serious AEs were observed. At the 7-month follow-up, 11 patients maintained a statistically significant WL. Conclusions: This is the first Korean study to apply the professional collaboration of IKMT and dietician-led LM to people with obesity. IKMT combined with LM appears to be a safe and effective approach for obesity management. Prospective studies are needed to confirm these findings and establish standardized treatment protocols. 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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23 pages, 9796 KB

Open AccessArticle

Phlorizin Alleviates Depression-like Behaviors via Gut Microbiota Reprogramming-Induced Methionine to Inhibit Neuroinflammation in Mice Hippocampus

by Lingling Li, Jianxin Chen, Xinyu Zhang, Xuya Zhang, Yan Fu, Hong Jiang, Tianxing Yin, Yali Zhang, Xue Li, Mengyuan Hu and Yi Lu

Pharmaceuticals 2025, 18(9), 1395; https://doi.org/10.3390/ph18091395 - 17 Sep 2025

Abstract

Background: Depression is associated to gut microbiota imbalance. Our research examined the antidepressant potential of phlorizin (PHZ), a natural anti-inflammatory compound that influences gut microbiota, and explored its underlying mechanisms. Methods: A corticosterone (CORT)-induced depression mouse model was used for evaluating the ameliorative influences of PHZ on depressive phenotypes and central neuroinflammation through behavioral tests and biochemical assays. 16S rRNA sequencing and metabolomics were used to evaluate gut microbiota composition and metabolite levels in serum and hippocampal tissue, respectively. Spearman correlation and broad-spectrum antibiotic cocktail (ABx) treatment experiments verified the effect of gut microbes in the PHZ-mediated modulation of key metabolites. A lipopolysaccharide (LPS)-induced BV2 microglial inflammation model was established to evaluate the role of metabolites in PHZ’s antineuroinflammatory effects. Results: PHZ significantly alleviated depressive-like behaviors in CORT mice and suppressed hippocampal neuroinflammation by modulating microglial M1/M2 polarization. Furthermore, PHZ altered gut microbiota composition, influenced serum methionine (Met) metabolism, and significantly increased hippocampal L-methionine (L-Met) and S-adenosylmethionine (SAMe) levels. Cellular experiments confirmed that L-Met plays a critical role in PHZ-mediated antineuroinflammatory effects. Significant correlations were observed between Parabacteroides, Parasutterella, and Alistipes and serum Met levels. ABx treatment suppressed the increase in hippocampal L-Met levels, suggesting that PHZ regulates methionine metabolism via the microbiota. These findings indicate that PHZ alleviates depressive states in CORT mice by modulating the microbiota–gut–brain axis. Conclusions: PHZ modulates the gut microbiota (namely Parabacteroides, Parasutterella, and Alistipes) and increase L-Met and SAMe levels, thereby suppressing neuroinflammation and improving depressive phenotypes in mice. Full article

(This article belongs to the Section Natural Products)

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27 pages, 13654 KB

Open AccessArticle

Influence of PEG Molecular Weight on Washout Resistance and Deposition Efficiency of Magnetoresponsive Nanoclusters Under Pulsatile Flow for Magnetic Drug Targeting

by Sandor I. Bernad and Elena S. Bernad

Pharmaceuticals 2025, 18(9), 1394; https://doi.org/10.3390/ph18091394 - 17 Sep 2025

Abstract

Background/Objectives: Magnetic drug targeting (MDT) using polyethene glycol (PEG)-coated magnetoresponsive nanoclusters (MNCs) can localize therapeutics, but washout from high-shear arterial flow limits efficacy. This study assesses how PEG molecular weight influences MNC deposition and washout resistance under a pulsatile flow. Methods: Magnetite MNCs were synthesized via solvothermal polyol reactions and PEGylated with PEG-2000, PEG-6000, or PEG-10,000. Characterization included TEM, DLS, zeta potential, FTIR, TGA, XPS, magnetic analysis, and rheology. In vitro assays used a 3 mm diameter glass phantom with pulsatile flow (0.10–0.45 m/s, 1 Hz) and a rectangular NdFeB (N35) permanent magnet (30 × 20 × 20 mm, 0.45 T) positioned 11 mm from the vessel wall. Washout performance was quantified by obstruction degree (OD), magnet coverage degree (MCd), washout degree (WD), washout rate constant (k_out), and half-life (τ₁/₂). Results: MNC-6000 balanced magnetic responsiveness (Ms = 72 emu/g), colloidal stability (ζ = +13.1 mV), and hydrodynamic size (535 nm), yielding superior retention (MCd = 72.3%, OD = 19.6%, WD = 17.9%, τ₁/₂ = 6.93 min). MNC-2000 exhibited faster loss (k_out = 0.14 min⁻¹, τ₁/₂ = 4.95 min), while MNC-10,000 produced higher OD (≈53%) with embolic risk. Magnetic mapping indicated vessel wall thresholds of B ≥ 0.18 T and ∇B ≥ 10 T/m for stable capture. Limitations: Limitations of this work include the use of a single-magnet geometry, an in vitro phantom model without endothelial biology, and a maximum targeting depth of ~12–14 mm. Conclusions: The PEG molecular weight modulates MDT performance through its effects on nanocluster stability, deposition morphology, and washout kinetics. The proposed OD, MCd, and WD metrics provide clinically relevant endpoints for optimizing MDT nanoparticle design and magnet configurations. Full article

(This article belongs to the Section Pharmacology)

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15 pages, 1708 KB

Open AccessArticle

Site-Specific Microparticle Inhalation Therapy: A New Approach to Nasopharyngeal Symptoms

by Eride Quarta, Fabio Sonvico, Ignazio La Mantia, Antonio Varricchio, Lucia Gloria, Massimiliano Minale, Niccola Funel, Francesca Buttini and Attilio Varricchio

Pharmaceuticals 2025, 18(9), 1393; https://doi.org/10.3390/ph18091393 - 17 Sep 2025

Abstract

Background/Objectives: Inhalable Microparticles (IMPs) are part of a currently invading field of medicine. In fact, the anatomical district of Rhinopharynx represents a bed for many different pathologies and infections, where the dimension of drug aerosol Microparticles (MPs) represents a discriminating factor to success therapy. The aims of the present work are to demonstrate the efficacy of a new device and its aerosol reproducibility in the nebulization of suspensions to be deposited in the retropharynx. Materials and Methods: The Low-Angle Laser Light Scattering (LALLS) method was used to evaluate both the dimension and distribution of MPs. Six different APIs, used usually in Rhinopharynx pathology, were compared in order to investigate the dimension of MP emissions using four different devices. The results of a retrospective study including 74 subjects treated with standard therapy (ST) and the inhalation of nebulized Sobrerol (NS) were performed. Data regarding the persistence of clinical symptoms (i.e., cough and nasal constipation) were acquired. Results: No significant statistical differences among all the products tested (p > 0.05) were found. One device, Rinubes, demonstrated efficacy and robustness in the fine nebulization of all the pharmaceutical products analyzed. Rinubes delivered an aerosol cloud with significantly lower MMD (66.3 µm) than Mad Nasal and Spray-sol (142.1 and 116.0 µm, respectively), which would allow a higher fraction of drugs to be deposited in the retropharynx. The retrospective clinical study revealed that NS treatment showed higher odds of cough resolution (OR 9.18; p < 0.001) with respect to control ST and showed higher odds of nasal symptom resolution (OR 6.7; p = 0.043). Conclusions: Improved techniques for the administration of inhalable MPs (INPAD) represent significant progress in overcoming the biological and the anatomical barriers in controlling drug release at a specific site. The challenges of nasopharyngeal pathologies offer promising opportunities for the development of non-invasive drug delivery. Full article

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

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27 pages, 907 KB

Open AccessReview

Mesoporous Silica Nanoparticles as Drug Delivery Systems

by Flórián Benkő, Katalin Kristó and Tamás Sovány

Pharmaceuticals 2025, 18(9), 1392; https://doi.org/10.3390/ph18091392 - 17 Sep 2025

Abstract

Mesoporous silica nanocarriers (MSNs) have emerged as significant candidates in the pharmaceutical industry for drug delivery systems, suitable for a wide variety of drugs. Absorbing the active pharmaceutical ingredients (APIs) into the pores can be beneficial in several ways. The narrow pores may stabilize the APIs in an amorphous state, thereby improving its aqueous solubility and providing protection for the encapsulated drug against various factors in the human body, including enzymatic or chemical degradation, which enhances the bioavailability of the product. Beside the overview of their main characteristics, the present review focuses on the recent findings on MSNs form therapeutic and drug formulation perspective, including functionalization possibilities, as the size and surface of the particles influence the interactions with the cell membrane; therefore, the epithelial permeability of and release rate from the carrier, and may offer even targeted delivery in an organ-, tissue- or cell-specific manner, improving the therapy, also avoiding drug-related side effects. Full article

(This article belongs to the Collection Feature Review Collection in Pharmaceutical Technology)

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25 pages, 3468 KB

Open AccessArticle

Baicalin–Myricetin-Coated Selenium Nanoparticles Mitigate Pathology in an Aβ1-42 Mice Model of Alzheimer’s Disease

by Rosa Martha Pérez Gutiérrez, Julio Téllez Gómez, José María Mota Flores, Mónica Corea Téllez and Alethia Muñiz Ramírez

Pharmaceuticals 2025, 18(9), 1391; https://doi.org/10.3390/ph18091391 - 17 Sep 2025

Abstract

Background: Current Alzheimer’s disease (AD) treatments primarily focus on symptom management and offer limited potential to arrest disease progression. To address this limitation, we developed baicalin–myricetin (BM) functionalized selenium nanoparticles (SeNPs), termed BMSe@BSA, aimed at multi-targeted neuroprotection. Materials and Methods: BMSe@BSA nanoparticles were synthesized via a gel–sol technique using bovine serum albumin (BSA), ascorbic acid, selenous acid, and BM. Interactions among BSA, BM, and SeNPs were characterized by microscopy and spectrometry. Cytotoxicity was assessed on RAW 264.7 and PC12 cells to determine biocompatibility. Neuroinflammation and cognitive function were evaluated in C57BL6/J mice challenged with Aβ1-42. Recognition memory was tested through open-field exploration, novel object recognition (NOR), and T-maze assays. Inflammatory markers (IL-1β and TNF-α) and microglial changes in the cerebral cortex were quantified, while amyloid fibril morphology was assessed using atomic force microscopy (AFM). Results: Spectroscopic analysis verified successful BM functionalization. Transmission electron microscopy revealed a spherical morphology with an average particle size of 90.57 nm, zeta potential of 27.2 mV, and a polydispersity index (PDI) of 0.270. BM entrapment efficiency reached approximately 90%. Cytotoxicity assays confirmed the nanoparticles’ safety, with no toxicity observed at concentrations up to 400 µg/mL after 4 h of incubation. BMSe@BSA effectively inhibited amyloid fibril formation, downregulated pro-inflammatory cytokine expression, preserved neuronal integrity, and significantly enhanced cognitive performance in AD mouse models. Conclusion: BMSe@BSA appear as a potential nanotherapeutic approach for targeted brain delivery and multi-pathway intervention in Alzheimer’s disease. Full article

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

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