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Pharmaceuticals
Volume 18
Issue 9
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Pharmaceuticals, Volume 18, Issue 9 (September 2025) – 183 articles

Cover Story (view full-size image): The 1,3,4-thiadiazole scaffold has emerged as a privileged structure in medicinal chemistry due to its unique electronic features, balanced physicochemical properties, and broad pharmacological potential. Its ability to modulate enzymes, interact with receptors, and disrupt microbial pathways underlies diverse antibacterial and antifungal effects. In recent years, numerous 1,3,4-thiadiazole derivatives have been synthesized and evaluated, demonstrating high levels of activity against Gram-positive and Gram-negative bacteria as well as a wide range of fungal species. This review highlights recent advances in the design, synthesis, and biological evaluation of such compounds. View this paper
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31 pages, 2784 KB  
Review
Obeticholic Acid and Other Farnesoid-X-Receptor (FXR) Agonists in the Treatment of Liver Disorders
by Stefano Fiorucci, Ginevra Urbani, Eleonora Distrutti and Michele Biagioli
Pharmaceuticals 2025, 18(9), 1424; https://doi.org/10.3390/ph18091424 - 22 Sep 2025
Viewed by 1270
Abstract
The Farnesoid-X-receptor (FXR) is a bile sensor involved in the regulation of bile acid homeostasis, fibrosis, inflammation, and metabolism. Obeticholic acid (OCA), a semisynthetic derivative of chenodeoxycholic acid (CDCA), initially named 6-ethyl-CDCA or INT-747, is the first in a class of FXR ligands [...] Read more.
The Farnesoid-X-receptor (FXR) is a bile sensor involved in the regulation of bile acid homeostasis, fibrosis, inflammation, and metabolism. Obeticholic acid (OCA), a semisynthetic derivative of chenodeoxycholic acid (CDCA), initially named 6-ethyl-CDCA or INT-747, is the first in a class of FXR ligands that have been approved for clinical use for the treatment of patients with primary biliary cholangitis (PBC) who are unresponsive or intolerant to ursodeoxycholic acid. In this narrative review, we will examine the current status and future perspective of clinical use of OCA. Based on results from phase 2 and 3 clinical trials, OCA received a conditional market approval for its use as a second-line treatment for the management of PBC in 2016. However, concerns over drug (OCA)-induced liver injury (DILI), including hepatic decompensation in cirrhotic and non-cirrhotic PBC patients, have led to discontinuation of OCA commercialization in the EU, but not in North America and the UK, in 2024. Based on positive results from preclinical models, OCA has been investigated also for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). Results from phase 2 and 3 trials, however, have shown that while OCA reduces liver fibrosis, the beneficial effects on steatosis are marginal, thus preventing its clinical approval under the current regulatory guidelines. Here, we review potential applications of OCA in PBC patients in the context of a highly competitive therapeutic landscape, generated by the approval for clinical use of safer and effective second-line therapies, including PPARs agonists such as elafibranor and seladelapar and increased off-label use of fibrates. The current status of development of second-generation FXR agonists such as cilofexor, tropifexor, and vonafexor and their potential in the treatment of liver fibrosis in MASH will be discussed and compared to recently approved therapies, resmetirom, and semaglutide, a GLP-1 agonist. Finally, since some of the novel candidates for treating MASH, have shown limited efficacy on liver fibrosis, we suggest that development of combinatorial therapies based on FXR ligands and agents acting on different molecular targets might offer the opportunity for the repositioning of drug candidates whose development has been abandoned for insufficient efficacy, minimizing/recovering costs linked to drug development. Full article
(This article belongs to the Special Issue Pharmacotherapy of Liver Fibrosis and Hepatitis: Recent Advances)
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14 pages, 848 KB  
Article
The Impact of 24-Month Etanercept Therapy on Changes in Adiponectin, Leptin and Tenascin C Levels in the Blood of Children with Juvenile Idiopathic Arthritis
by Jan Siwiec, Kornelia Kuźnik-Trocha, Katarzyna Winsz-Szczotka, Katarzyna Komosińska-Vassev, Andrzej Siwiec and Krystyna Olczyk
Pharmaceuticals 2025, 18(9), 1423; https://doi.org/10.3390/ph18091423 - 22 Sep 2025
Viewed by 268
Abstract
Background/Objectives: The most commonly diagnosed group of rheumatic diseases in children is juvenile idiopathic arthritis. It is characterized by a chronic inflammatory process that leads to the degradation of the bone and joint system and increased secretion of pro-inflammatory cytokines such as [...] Read more.
Background/Objectives: The most commonly diagnosed group of rheumatic diseases in children is juvenile idiopathic arthritis. It is characterized by a chronic inflammatory process that leads to the degradation of the bone and joint system and increased secretion of pro-inflammatory cytokines such as TNF-α, IL-1, and IL-6. These cytokines contribute to the dysregulation of adipocytokine metabolism, including adiponectin and leptin, as well as extracellular matrix components, such as tenascin C. While it is known that children with JIA exhibit TNF-α-stimulated degradation of most ECM cartilage components, the effect of TNF-α antagonists, such as etanercept, on these processes has not yet been evaluated. Therefore, the aim of our study was to assess the dynamics of changes in tenascin C, adiponectin, and leptin levels in the blood of children with JIA, both before and during therapy. Methods: The study material consisted of blood samples collected from 66 children of both sexes, including 40 girls and 26 boys diagnosed with juvenile idiopathic arthritis and treated with etanercept, as well as from 40 healthy children (22 girls and 18 boys). The quantitative assessment of adiponectin, leptin, and tenascin C levels was performed using commercial ELISA tests. Results: The conducted study revealed that untreated children with JIA exhibit altered plasma levels of all examined parameters—adiponectin, leptin, and tenascin C. Specifically, there was an increase in adiponectin concentration and a decrease in leptin as well as TNC levels compared to healthy children. The results demonstrated the beneficial effects of the TNF-α antagonist, i.e., etanercept, which not only improved the clinical condition of children with JIA but also positively influenced the metabolism of both adipokines and tenascin C. Conclusions: The obtained results suggest the potential use of adiponectin, leptin, and tenascin C as biochemical markers of the effectiveness of etanercept therapy in inhibiting the progression of degenerative joint changes in children with JIA treated with TNF-α inhibitors. Full article
(This article belongs to the Special Issue Biological Treatment for Rheumatic Diseases)
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30 pages, 4224 KB  
Article
Tracing Five Decades of Psoriasis Pharmacotherapy: A Large-Scale Bibliometric Investigation with AI-Guided Terminology Normalization
by Ada Radu, Andrei-Flavius Radu, Gabriela S. Bungau, Delia Mirela Tit and Paul Andrei Negru
Pharmaceuticals 2025, 18(9), 1422; https://doi.org/10.3390/ph18091422 - 21 Sep 2025
Viewed by 589
Abstract
Background/Objectives: Large-scale bibliometric assessments of psoriasis pharmacotherapy research remain limited despite significant research output in this rapidly evolving field. This study aimed to map the evolution of systemic psoriasis therapy research over five decades and demonstrate how systematic analysis of research trajectories [...] Read more.
Background/Objectives: Large-scale bibliometric assessments of psoriasis pharmacotherapy research remain limited despite significant research output in this rapidly evolving field. This study aimed to map the evolution of systemic psoriasis therapy research over five decades and demonstrate how systematic analysis of research trajectories can illuminate the transformation of specialized medical fields into central components of precision medicine. Methods: A comprehensive bibliometric analysis was conducted using Web of Science Core Collection as the single data source, examining 19,284 publications spanning 1975–2025. The methodology employed AI-enhanced terminology normalization for standardizing pharmaceutical nomenclature, VOSviewer version 1.6.20 for network visualization, and Bibliometrix package for temporal trend analysis and thematic evolution mapping. International collaboration networks, thematic evolution across three distinct periods (1975–2000, 2001–2010, 2011–2025), and citation impact patterns were systematically analyzed. Results: Four distinct developmental phases were identified, with publications growing from 9 articles in 1975 to 1638 in 2024. The United States dominated research output with 5959 documents, while Canada achieved the highest citation efficiency at 62.65 citations per document. Global collaboration encompassed 70 countries organized into four regional clusters, with a 28-nation Asia–Pacific–Africa–Middle East alliance representing the largest collaborative group. Citation impact peaked during 2001–2008, coinciding with revolutionary biological therapy introduction. Thematic evolution demonstrated systematic transformation from two foundational themes to nine specialized domains, ultimately consolidating into four core areas focused on targeted therapeutics and evidence-based methodologies. Keyword analysis demonstrated progression from basic immunological studies to sophisticated targeted interventions, evolving from tumor necrosis factor alpha inhibitors to contemporary interleukin-17/interleukin-23 pathway targeting and Janus kinase inhibitors. Conclusions: Over five decades, psoriasis therapeutics research has shifted from a niche dermatological discipline to a central model for innovation in immune-mediated diseases. This evolution illustrates how bibliometric approaches can capture the dynamics of scientific transformation, offering strategic insights for guiding pharmaceutical innovation, shaping research priorities, and informing precision medicine strategies across inflammatory conditions. Full article
(This article belongs to the Section Pharmacology)
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15 pages, 3565 KB  
Article
Interactions of Extracts from Selected Plant Materials Supporting the Treatment of Alzheimer’s Disease with Free Radicals—EPR and UV-Vis Studies
by Damian Łomankiewicz, Barbara Pilawa, Ewa Chodurek and Magdalena Zdybel
Pharmaceuticals 2025, 18(9), 1421; https://doi.org/10.3390/ph18091421 - 21 Sep 2025
Viewed by 396
Abstract
Background/objectives: Interactions of infusions of Ginkgo biloba, ginseng, Yerba Mate, and green tea, with free radicals, were examined. The aim of these studies was to determine quenching of free radicals by the extracts from the selected plant raw materials that are [...] Read more.
Background/objectives: Interactions of infusions of Ginkgo biloba, ginseng, Yerba Mate, and green tea, with free radicals, were examined. The aim of these studies was to determine quenching of free radicals by the extracts from the selected plant raw materials that are useful in the treatment of Alzheimer’s disease. Methods: The interactions were tested by an X-band (9.3 GHz) EPR spectroscopy and UV-Vis spectrophotometry. The model DPPH free radicals were used. The magnitude and changes with time of EPR and UV-Vis spectra of DPPH by the tested extracts were measured. Results: EPR and UV-Vis lines of DPPH free radicals decrease with increasing time of interactions of the extracts with DPPH, and after reaching the minimum value, it does not change with time. Ginseng infusion quenched free radicals the least. Ginkgo biloba extract quenches free radicals a little stronger than ginseng extract. Taking into account the tested extracts, Ginkgo biloba and ginseng extracts interact with free radicals less effectively compared to extracts of Yerba mate and green tea. Ginkgo biloba and ginseng extracts quench free radicals weaker than Yerba Mate and green tea extracts. Conclusions: Yerba Mate extract definitely had the strongest antioxidant properties. This extract quenches free radicals most effectively, what can be useful in the case of Alzheimer’s disease. Given its strong antioxidant properties, green tea extract can also be particularly recommended in the case of Alzheimer’s disease. Full article
(This article belongs to the Section Natural Products)
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22 pages, 3961 KB  
Article
In Vivo Antihypertensive and Ex Vivo Vasodilatory Studies of Taxifolin
by Xuye Wang, Xiangyang Xu, Wan Yin Tew, Liyun Ouyang, Xiaoning Yang, Hui Wei Loh, Wen Xu, Wei Xu and Mun Fei Yam
Pharmaceuticals 2025, 18(9), 1420; https://doi.org/10.3390/ph18091420 - 21 Sep 2025
Viewed by 423
Abstract
Background: Hypertension is a leading cause of cardiovascular morbidity and mortality. Taxifolin has shown cardiovascular benefits, but its antihypertensive mechanisms remain poorly defined. This study aimed to comprehensively elucidate the molecular mechanisms underlying Taxifolin’s blood pressure-lowering effects by integrating network pharmacology, molecular [...] Read more.
Background: Hypertension is a leading cause of cardiovascular morbidity and mortality. Taxifolin has shown cardiovascular benefits, but its antihypertensive mechanisms remain poorly defined. This study aimed to comprehensively elucidate the molecular mechanisms underlying Taxifolin’s blood pressure-lowering effects by integrating network pharmacology, molecular docking, ex vivo functional studies, and in vivo validation. Methods: Network pharmacology and molecular docking prioritized targets. Ex vivo thoracic aortas were obtained from healthy male Sprague–Dawley (SD) rats, and rings (3–4 mm) were prepared for vasorelaxation studies. Pathway-specific inhibitors, Western blotting, and ELISA were used to investigate mechanisms. In vivo, spontaneously hypertensive rats (SHRs) received oral Taxifolin 15, 30, or 60 mg/kg once daily for 28 days; propranolol (80 mg/kg) served as the positive control. Results: Taxifolin produced robust vasorelaxation in endothelium-intact rings (Rmax ≈ 121%), falling to ~72% after denudation. Relaxation was attenuated by LY294002, ODQ, indomethacin, and glibenclamide. In SHR aorta, Taxifolin increased NO by ~132% and cGMP by ~1.9-fold and upregulated p-Akt and eNOS; LY294002 abolished these effects. In vivo, Taxifolin reduced systolic blood pressure by ≈60 mmHg without adverse changes in hematology, biochemistry, or body weight. Conclusions: Taxifolin lowers blood pressure through multiple vascular mechanisms consistent with PI3K/Akt/eNOS, NO–sGC–cGMP, COX-2/PGI2 and calcium-handling pathways, supporting its potential as a safe antihypertensive candidate. Full article
(This article belongs to the Section Pharmacology)
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20 pages, 725 KB  
Review
An Overview of Target Membrane Proteins for Near-Infrared Photoimmunotherapy
by Motofumi Suzuki and Hirofumi Hanaoka
Pharmaceuticals 2025, 18(9), 1419; https://doi.org/10.3390/ph18091419 - 21 Sep 2025
Viewed by 938
Abstract
Near-infrared photoimmunotherapy (NIR-PIT) is a recently developed cancer treatment that utilizes antibody–photoabsorber (IRDye700DX [IR700]) conjugates and NIR light. Necrotic cell death associated with lethal membrane damage is induced when this conjugate binds to an antigen on cancer cells, and it is exposed to [...] Read more.
Near-infrared photoimmunotherapy (NIR-PIT) is a recently developed cancer treatment that utilizes antibody–photoabsorber (IRDye700DX [IR700]) conjugates and NIR light. Necrotic cell death associated with lethal membrane damage is induced when this conjugate binds to an antigen on cancer cells, and it is exposed to NIR light. Therefore, various membrane proteins are potential therapeutic targets for NIR-PIT, and many studies have described various target molecules and specific antibodies. To develop future drugs for NIR-PIT, the selection of appropriate target membrane proteins and monoclonal antibodies will be important. In this review, we summarize the membrane targets and antibodies for NIR-PIT used in previous studies, focusing on the characteristics of each molecule. Full article
(This article belongs to the Section Radiopharmaceutical Sciences)
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15 pages, 2669 KB  
Article
Integrative Study of Dipsaci Radix and Phlomidis Radix: Nomenclature, Morphology, DNA-Based Authentication, and Comparative Effects on Osteoclastogenesis
by Jun-Ho Song, Yun-Soo Seo, Yeseul Kim, Sohee Jeong, Sungyu Yang, Goya Choi, Joong-Sun Kim and Inkyu Park
Pharmaceuticals 2025, 18(9), 1418; https://doi.org/10.3390/ph18091418 - 20 Sep 2025
Viewed by 348
Abstract
Background/Objectives: Dipsaci Radix (Dipsacus asper) and Phlomidis Radix (Phlomoides umbrosa) are both traditional medicines used in Korea and China for various bone-associated diseases. However, the two are misused due to similarities in name and appearance. Additionally, D. japonicus [...] Read more.
Background/Objectives: Dipsaci Radix (Dipsacus asper) and Phlomidis Radix (Phlomoides umbrosa) are both traditional medicines used in Korea and China for various bone-associated diseases. However, the two are misused due to similarities in name and appearance. Additionally, D. japonicus root frequently contaminates Dipsaci Radix in Korean herbal markets. Methods: We examined morphological plant traits and performed a DNA barcoding analysis using ITS2 and matK sequences to differentiate between these three species. The effects of root extracts on bone resorption and osteoclast differentiation, measured as tartrate-resistant acid phosphatase (TRAP)-positive cell formation, were evaluated using mouse (5 weeks male ICR mice) bone marrow-derived macrophages. Cytotoxicity assays were conducted to assess extract safety. Results: Phlomoides umbrosa is easily distinguished by its verticillaster inflorescences and 2-labiate corollas. Dipsacus asper and D. japonicus, which share globose inflorescences, are distinguishable by flower color and leaf lobation. The ITS2 and matK sequences clearly differentiated the three species, with haplotype analysis supporting their genetic distinctiveness, enabling robust species discrimination. All three extracts decreased osteoclastic bone resorption and inhibited TRAP-positive cell formations in a dose-dependent manner. Only the D. japonicus extract demonstrated toxicity. Conclusions: This integrative study provides the current scientific names of the original species and proposes their use in the Korean Herbal Pharmacopoeia. Moreover, a reasonable molecular method for authenticating medicinal materials is suggested. Dipsacus japonicus shows promise as an additional origin species in the Korean Pharmacopoeia. However, processing methods that reduce toxicity must be discovered. Full article
(This article belongs to the Special Issue The Modes of Action of Herbal Medicines and Natural Products, 2nd Edition)
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27 pages, 5600 KB  
Article
Comparative Study of Ferrocene- and Indene-Based Tamoxifen Derivatives of Different Molecular Flexibility on High-Mortality Cancer Cell Lines
by Márton Kalabay, Zsófia Szász, Eszter Lajkó, Bálint Bagu, Éva Pállinger, Cintia Duró, Tamás Jernei, Antal Csámpai, Angéla Takács and László Kőhidai
Pharmaceuticals 2025, 18(9), 1417; https://doi.org/10.3390/ph18091417 - 20 Sep 2025
Viewed by 300
Abstract
Tamoxifen is a well-established selective estrogen receptor modulator (SERM) widely used in breast cancer treatment, yet its efficacy varies across tumor types. To enhance its antitumor potential, we previously synthesized and investigated novel ferrocene-linked (T5, T15) derivatives. This publication is a close continuation [...] Read more.
Tamoxifen is a well-established selective estrogen receptor modulator (SERM) widely used in breast cancer treatment, yet its efficacy varies across tumor types. To enhance its antitumor potential, we previously synthesized and investigated novel ferrocene-linked (T5, T15) derivatives. This publication is a close continuation of this work, introducing a new indene-based (T6) derivative. Objectives: The main aim of this study was to further broaden our knowledge of the mechanism behind the increased antitumor effect of the ferrocene-linked drugs (T5 and T15) and compare it with a new, indene-based tamoxifen derivative, T6. The indene moiety was selected as a rigid, hydrophobic aromatic unit to probe pharmacological effects independent of ferrocene’s redox activity. Methods: The compounds were tested on MCF7, MDA-MB231 and PANC1 cells. Cell viability was assessed with the AlamarBlue assay and the xCELLigence SP system. Reactive oxygen species (ROS) production was measured with the ROS Glo assay. Flow cytometry and RT-qPCR experiments were conducted to assess apoptosis and ROS regulation as well. Results: The modified compounds demonstrated an increased cell-viability-decreasing effect in breast (MCF7, MDA-MB-231) and pancreatic (PANC1) cancer cell lines, influencing both estrogen-receptor-dependent and -independent pathways. T6 led to G2/M phase arrest in PANC1 cells. Beyond cell cycle disruption, these derivatives significantly elevated ROS levels, contributing to apoptosis. Conclusions: Our findings suggest that these structural modifications retain tamoxifen’s pharmacophore properties while expanding its mechanism of action, particularly through universal interactions independent of the ER status of tumor cells. The enhanced antitumor effects highlight the potential of these derivatives as promising candidates for improved cancer therapies. Full article
(This article belongs to the Special Issue Chemotherapeutic and Targeted Drugs in Antitumor Therapy)
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24 pages, 9851 KB  
Article
Comprehensive Identification and Mechanistic Evaluation of Novel DHODH Inhibitors as Potent Broad-Spectrum Antiviral Agents
by Chao Zhang, Shiyang Sun, Huiru Xie, Yongzhao Ding, Chun Hu, Jialin Guo and Junhai Xiao
Pharmaceuticals 2025, 18(9), 1416; https://doi.org/10.3390/ph18091416 - 20 Sep 2025
Viewed by 383
Abstract
Background/Objectives: This study identifies novel dihydroorotate dehydrogenase (DHODH) inhibitors exhibiting potent broad-spectrum antiviral agents, particularly against influenza A virus (A/PR/8/34(H1N1)) and SARS-CoV-2. Methods: Structure-based virtual screening of 1.6 million compounds (ChemDiv and TargetMol databases) yielded 10 candidates, with compounds 6, [...] Read more.
Background/Objectives: This study identifies novel dihydroorotate dehydrogenase (DHODH) inhibitors exhibiting potent broad-spectrum antiviral agents, particularly against influenza A virus (A/PR/8/34(H1N1)) and SARS-CoV-2. Methods: Structure-based virtual screening of 1.6 million compounds (ChemDiv and TargetMol databases) yielded 10 candidates, with compounds 6, 9, and 10 demonstrating significant anti-influenza activity (IC50 = 4.85 ± 0.58, 7.35 ± 1.65, and 1.75 ± 0.28 μM, respectively). Building on these, molecular hybridization principles and scaffold hopping principles were applied to design and synthesize six novel compounds (11–16) through cyclization, coupling, and carboxylate deprotection. Prior to subsequent biological assays, the molecular structures of each compound were elucidated by NMR spectroscopy and MS. Their antiviral activities were subsequently assessed against both influenza virus and SARS-CoV-2. The compound 11, demonstrating the most potent antiviral activity, was further subjected to surface plasmon resonance (SPR) analysis to assess its binding affinity for human DHODH. Results: Compound 11 emerged as the most potent DHODH inhibitor (KD = 6.06 μM), exhibiting superior broad-spectrum antiviral activities (IC50 = 0.85 ± 0.05 μM, A/PR/8/34(H1N1); IC50 = 3.60 ± 0.67 μM, SARS-CoV-2) to the reported DHODH inhibitor (Teriflunomide, IC50 = 35.02 ± 3.33 μM, A/PR/8/34(H1N1); IC50 = 26.06 ± 4.32 μM, SARS-CoV-2). Mechanistic evaluations via 100 ns MD simulations and QM/MM calculations revealed stable binding interactions, particularly hydrogen bonds with GLN47 and ARG136, while alanine scanning mutagenesis confirmed these residues’ critical roles in binding stability. Conclusions: This work identifies compound 11 as a potent broad-spectrum antiviral compound, offering a promising strategy for broad-spectrum antiviral therapy against RNA viruses by depleting pyrimidine pools essential for viral replication. Full article
(This article belongs to the Section Medicinal Chemistry)
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51 pages, 2340 KB  
Review
Interventions for Neglected Diseases Caused by Kinetoplastid Parasites: A One Health Approach to Drug Discovery, Development, and Deployment
by Godwin U. Ebiloma, Amani Alhejeli and Harry P. de Koning
Pharmaceuticals 2025, 18(9), 1415; https://doi.org/10.3390/ph18091415 - 19 Sep 2025
Viewed by 757
Abstract
Kinetoplastids are protozoa that possess a unique organelle called a kinetoplast. These include the parasites Trypanosoma cruzi, T. brucei and related African trypanosomes, and Leishmania spp. These parasites cause a variety of neglected tropical diseases in humans and livestock, with devastating [...] Read more.
Kinetoplastids are protozoa that possess a unique organelle called a kinetoplast. These include the parasites Trypanosoma cruzi, T. brucei and related African trypanosomes, and Leishmania spp. These parasites cause a variety of neglected tropical diseases in humans and livestock, with devastating consequences. In the absence of any vaccine, pharmaceutical interventions are the mainstay of control, but these have historically been underfunded, fragmented, and inadequately aligned with the complex zoonotic and ecological realities of the parasites’ transmission dynamics. In this review, the landscape of current and emerging drugs for treating leishmaniasis, Chagas disease, and African trypanosomiasis is critically evaluated across both veterinary and human contexts. It examines the challenges of legacy compounds, the pharmacological shortcomings in multi-host, multi-tropic and multi-stage disease systems, and the gaps in veterinary therapeutics, specifically for African animal trypanosomiasis and canine leishmaniasis but also the animal reservoir of T. cruzi. Emphasis is placed on pharmacokinetic divergence between species, the accompanying risks with the use of off-label human drugs in animals, and the ecological effects of environmental drug exposure. We propose a far-reaching One Health framework for pharmaceutical research and development, promoting dual-indication co-development, ecological pharmacology, regulatory harmonisation, and integrated delivery systems. In this context, we argue that the drug development pipeline must be rationalised as a transdisciplinary and ecologically embedded process, able to interrupt parasite transmission to human, animal, and vector interfaces. Our findings reveal that we can bridge age-old therapeutic gaps, advance towards sustainable control, and eventually eliminate the neglected diseases caused by kinetoplastid protozoan parasites by aligning pharmaceutical innovation with One Health principles. This article aims to promote future research and development of innovative drugs that are sustainable under the One Health framework. Full article
(This article belongs to the Section Pharmacology)
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40 pages, 2388 KB  
Review
A Review on Sulfonamide Complexes with Metals: Their Pharmacological Potential as Anticancer Drugs
by Przemysław Rozbicki and Danuta Branowska
Pharmaceuticals 2025, 18(9), 1414; https://doi.org/10.3390/ph18091414 - 19 Sep 2025
Viewed by 426
Abstract
Sulfonamides represent a versatile class of biologically active compounds, best known for their antibacterial activity, but increasingly investigated for their potential in oncology. Free sulfonamides themselves display cytotoxic properties; however, coordination with metal ions often enhances both selectivity and potency, while also introducing [...] Read more.
Sulfonamides represent a versatile class of biologically active compounds, best known for their antibacterial activity, but increasingly investigated for their potential in oncology. Free sulfonamides themselves display cytotoxic properties; however, coordination with metal ions often enhances both selectivity and potency, while also introducing new mechanisms of action. Although numerous studies have reported sulfonamide–metal complexes with anticancer activity, a systematic overview linking biological properties to the central metal atom has been lacking. This review summarizes current research on sulfonamide complexes with transition metals and selected main-group elements, focusing on their pharmacological potential as anticancer agents. The compounds discussed include complexes of titanium, chromium, manganese, rhenium, ruthenium, osmium, iridium, palladium, platinum, copper, silver, gold, iron, cobalt, nickel, uranium, calcium, magnesium and bismuth. For each group, representative structures are presented along with cytotoxicity data against cancer cell lines, comparisons with reference drugs such as for example cisplatin, and where relevant, studies on carbonic anhydrase inhibition. The survey of available data demonstrates that many sulfonamide–metal complexes show cytotoxic activity comparable to or greater than existing chemotherapeutic agents, while in some cases exhibiting reduced toxicity toward non-cancerous cells. These findings highlight the promise of sulfonamide–metal complexes as a fertile area for anticancer drug development and provide a framework for future design strategies. This review covers the research on anti-cancer activity of sulfonamide complexes during the years 2007–2025. Full article
(This article belongs to the Special Issue Advances in the Synthesis and Application of Heterocyclic Compounds)
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19 pages, 1392 KB  
Article
Obesity-Related Cancers in Relation to Use of Statins and Testosterone Replacement Therapy Among Older Women: SEER-Medicare 2007–2015
by Maryam R. Hussain, Shannon Wu, Diane Saab, Biai Digbeu, Omer Abdelgadir, Jesus Gibran Hernandez-Perez, Luisa E. Torres-Sanchez, Tammy Leonard, Miguel Cano, Yong-Fang Kuo, Alejandro Villasante-Tezanos and David S. Lopez
Pharmaceuticals 2025, 18(9), 1413; https://doi.org/10.3390/ph18091413 - 19 Sep 2025
Viewed by 452
Abstract
Background/Objectives: The associations of statins and testosterone replacement therapy (TTh) with the risk of obesity-related cancers (ORC, breast [BrCa], colorectal [CRC], ovarian, and endometrial cancers) in older women remain poorly understood. This study examined the associations between the use of statins and [...] Read more.
Background/Objectives: The associations of statins and testosterone replacement therapy (TTh) with the risk of obesity-related cancers (ORC, breast [BrCa], colorectal [CRC], ovarian, and endometrial cancers) in older women remain poorly understood. This study examined the associations between the use of statins and TTh with risk of ORC and its cancer-specific sites in women aged 65 years and older. Methods: A retrospective cohort study was conducted using 2007–2015 SEER-Medicare data, including 142,772 women aged ≥ 65 years. We identified 52,086 women with incident ORC (BrCa [n = 32,707], CRC [n = 11,070], ovarian [n = 2601], and endometrial [n = 5708] cancers). The primary exposures were use of statins and TTh. Weighted multivariable time-dependent Cox proportional hazards and models were conducted to estimate hazard ratios (HRs) of incident ORC. Results: We found an inverse association of statins with incident [HR, 0.76; 95% CI: 0.74, 0.78], high-grade [HR, 0.75; 95% CI: 0.72, 0.78], and advanced-stage [HR, 0.91; 95% CI: 0.88, 0.95] ORC. Concurrent use of statins and TTh was associated with a reduced incidence of ORC and high-grade ORC. Similar associations were observed with BrCa. Statins were inversely associated with high-grade ovarian cancer and endometrial cancer (incident, high-grade, and advanced-stage). Conclusions: Use of statins was inversely associated with ORC, BrCa, and endometrial cancer (high-grade and advanced-stage) and high-grade ovarian cancer in older women. Concurrent use of statins and TTh was inversely associated with ORC and BrCa and their high-grade disease. Future prospective studies are needed to substantiate these findings, especially with a focus to examine time– and dose–response associations and to identify underlying biological mechanisms through which statins and TTh influence incidence of ORC. Full article
(This article belongs to the Section Pharmacology)
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25 pages, 1531 KB  
Review
Biosynthesized Silver Nanoparticles and Their Antidiabetic Potential
by Angélica Sofía González-Garibay, Omar Ricardo Torres-González, Iván Moisés Sánchez-Hernández and Eduardo Padilla-Camberos
Pharmaceuticals 2025, 18(9), 1412; https://doi.org/10.3390/ph18091412 - 19 Sep 2025
Viewed by 861
Abstract
Background/Objectives: Recent advances in nanotechnology have enabled the use of biosynthesized silver nanoparticles (AgNPs) in healthcare, including the management of diabetes mellitus, a metabolic disorder characterized by impaired glucose homeostasis. AgNPs have shown promising effects on enzymes, insulin signaling, gut hormones, and [...] Read more.
Background/Objectives: Recent advances in nanotechnology have enabled the use of biosynthesized silver nanoparticles (AgNPs) in healthcare, including the management of diabetes mellitus, a metabolic disorder characterized by impaired glucose homeostasis. AgNPs have shown promising effects on enzymes, insulin signaling, gut hormones, and in vivo models. Despite the availability of oral treatments, challenges persist, prompting interest in novel therapies such as AgNPs, which are currently under investigation in various in vitro and in vivo studies. Methods: This narrative review was conducted through a PubMed search using the terms “antidiabetic + activity + AgNPs” in April 2025. Relevant articles published in English were selected and analyzed, with emphasis on studies employing biosynthesized AgNPs from plants in in vitro and in vivo models. Information was extracted regarding the experimental approaches used to evaluate antidiabetic activity, the plant sources employed, nanoparticle characteristics, concentrations tested, and corresponding outcomes. Results: The biosynthesis of AgNPs employs bioactive compounds from plants, making it an environmentally friendly green synthesis method. Plant extracts are the most common biomaterial for AgNPs biosynthesis. Most of the in vitro studies evaluated the inhibitory effect of AgNPs on α-glucosidase or α-amylase; meanwhile, in animal studies, the main parameter evaluated is blood glucose level. Conclusions: The antidiabetic potential of AgNPs is becoming increasingly evident as ongoing research continues to explore their effects through both in vitro and in vivo studies. In this review, the current state of research regarding the potential use of AgNPs for diabetes management and treatment is presented, highlighting recent findings and discussing future perspectives in the field. Full article
(This article belongs to the Special Issue Therapeutic Potential of Silver Nanoparticles (AgNPs), 2nd Edition)
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26 pages, 2480 KB  
Review
Promising Norlabdane-Heterocyclic Hybrids: Synthesis, Structural Characterization and Antimicrobial Activity Evaluation
by Lidia Lungu, Alexandru Ciocarlan, Ionel I. Mangalagiu and Aculina Aricu
Pharmaceuticals 2025, 18(9), 1411; https://doi.org/10.3390/ph18091411 - 19 Sep 2025
Viewed by 465
Abstract
The terpeno-heterocyclic molecular hybrids are a new and promising class of modern organic and medicinal chemistry, because their molecules exhibit high and selective biological activity, natural origins, and good biocompatibility, and, usually, they are less toxic. The reported norlabdane-heterocyclic hybrids were synthesized by [...] Read more.
The terpeno-heterocyclic molecular hybrids are a new and promising class of modern organic and medicinal chemistry, because their molecules exhibit high and selective biological activity, natural origins, and good biocompatibility, and, usually, they are less toxic. The reported norlabdane-heterocyclic hybrids were synthesized by classical and new, original, and environmentally friendly methods, which include coupling reactions of norlabdane derivatives (such as carboxylic acids, acyl chlorides, or bromides) with individual heterocyclic compounds, as well as heterocyclization reactions of certain norlabdane intermediates like hydrazides, thiosemicarbazones, or hydrazinecarbothioamides. The aforementioned norlabdanes were derived from (+)-sclareolide 2, which is readily obtained from (−)-sclareol 1, a labdane-type diterpenoid extracted from the waste biomass of Clary sage (Salvia sclarea L.) that remains after essential oil extraction. All synthesized compounds were tested against various fungal strains and bacterial species, with many exhibiting significant antifungal and antibacterial activity. These findings support the potential application of the synthesized compounds in the treatment of diseases caused by fungi and bacteria. Additionally, the use of plant-based waste materials as starting resources highlights the economic and ecological value of this approach. This review summarizes experimental data on the synthesis and biological activity of norlabdane: diazine, 1,2,4-triazole and carbazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,3-thiazole, 1,3-benzothiazole and 1,3-benzimidazole hybrids performed by our research group covering the period from 2013 to the present. Full article
(This article belongs to the Special Issue Hybrid and Chimeric Heterocycles: A Promising Approach to Synthesizing Biologically Active Compounds)
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31 pages, 6901 KB  
Article
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 - 19 Sep 2025
Viewed by 458
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 [...] Read more.
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  
Article
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 - 19 Sep 2025
Viewed by 365
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 [...] Read more.
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  
Review
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
Viewed by 463
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 [...] Read more.
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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34 pages, 1843 KB  
Review
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
Viewed by 792
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 [...] Read more.
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  
Review
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
Viewed by 641
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 [...] Read more.
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  
Article
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-Moralesadd Show full author list remove Hide full author list
Pharmaceuticals 2025, 18(9), 1405; https://doi.org/10.3390/ph18091405 - 18 Sep 2025
Viewed by 515
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 [...] Read more.
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  
Article
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
Viewed by 391
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 [...] Read more.
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  
Article
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
Viewed by 338
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 [...] Read more.
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  
Reply
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
Viewed by 326
Abstract
Dear Editor, [...] Full article
5 pages, 212 KB  
Comment
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
Cited by 1 | Viewed by 458
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 [...] Read more.
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  
Retraction
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
Viewed by 279
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
40 pages, 3167 KB  
Opinion
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
Viewed by 573
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 [...] Read more.
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  
Article
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
Viewed by 458
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 [...] Read more.
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 (Ki 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  
Viewpoint
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
Viewed by 502
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 [...] Read more.
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  
Article
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
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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 [...] Read more.
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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Article
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
Viewed by 425
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 [...] Read more.
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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