Pharmaceuticals

22 pages, 2703 KiB

Open AccessReview

Chemical Composition and Biological Activities of Psilocybe Mushrooms: Gaps and Perspectives

by Mateus A. Luz, Hellen V. S. Guedes, Antônio B. M. Bisneto, Raquel A. de Jesus, Taynah P. Galdino, Lucas C. Oliveira, Victor Ignacio Afonso, Marcus Vinícius L. Fook, Antônio G. B. Lima, Suedina M. de L. Silva and Maria C. M. Torres

Pharmaceuticals 2025, 18(7), 989; https://doi.org/10.3390/ph18070989 (registering DOI) - 1 Jul 2025

Abstract

The Psilocybe genus is known for producing tryptamine alkaloids, specifically the compounds psilocybin and psilocin, which have shown antidepressant and anxiolytic potential. The presence of these alkaloids makes Psilocybe mushrooms promising sources of molecules with potential applications in the treatment of mental disorders. [...] Read more.

The Psilocybe genus is known for producing tryptamine alkaloids, specifically the compounds psilocybin and psilocin, which have shown antidepressant and anxiolytic potential. The presence of these alkaloids makes Psilocybe mushrooms promising sources of molecules with potential applications in the treatment of mental disorders. To explore this, a bibliographic study was conducted with the aim of synthesizing published data regarding the biological properties and chemical composition of Psilocybe mushrooms. Searches were performed on indexing platforms, and the articles found were processed using StArt software. These articles were then classified by score and selected based on inclusion and exclusion criteria. This survey yielded a total of 74 articles, and among them, 66 works showed the presence of psilocybin and/or psilocin alkaloids, indicating the psychoactivity of the mushrooms, and 4 works demonstrated the antimicrobial and antioxidant activities of the extract from certain species of the genus. Additionally, 37 chemical compounds were identified across the genus, 23 of which are alkaloids. Data regarding the temporal and chemical stability of these compounds were also observed, which could help optimize the handling of materials that contain indole alkaloids. Therefore, it is evident that species of this genus remain underexplored in terms of chemical diversity; only compounds classified as alkaloids, terpenoids and phenolic compounds were found, and, in total, only 36 compounds in a study range time of 67 years. Furthermore, most studies focused primarily on evaluating the tryptamine alkaloids responsible for the psychoactivity of the mushrooms, without any study focusing on demonstrating the biological activity of isolated compounds against any pathological factor, except for studies relating the whole extract to larvicidal, antimicrobial and antioxidant potential. So, this review provides a general overview of the molecules isolated from the genus and their biological activities and also suggests that researchers working with these mushroom species could focus their efforts on isolating new compounds and evaluating other types of biological activities that can improve the knowledge of mushrooms’ alternative applications. Full article

(This article belongs to the Special Issue Psychedelics: A New Drug Candidate for Treating Mental Illness)

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16 pages, 603 KiB

Open AccessArticle

Natural Honey-Propolis Combinations with Health-Promoting Potential: Antibacterial Activity Against Foodborne Pathogens

by Vanesa Sánchez-Martín, Marta B. López-Parra, Amaia Iriondo-DeHond, Aneta Wojdyło, Anna Michalska-Ciechanowska, Ana I. Haza, Paloma Morales and María Dolores del Castillo

Pharmaceuticals 2025, 18(7), 988; https://doi.org/10.3390/ph18070988 (registering DOI) - 1 Jul 2025

Abstract

Background/Objectives: Natural products such as honey and propolis have been widely studied for their antimicrobial properties. Combining these substances has shown synergistic effects against foodborne pathogens and has also demonstrated promising results in previous applications on fermented meat products. This study evaluated the [...] Read more.

Background/Objectives: Natural products such as honey and propolis have been widely studied for their antimicrobial properties. Combining these substances has shown synergistic effects against foodborne pathogens and has also demonstrated promising results in previous applications on fermented meat products. This study evaluated the antibacterial potential of Spanish thyme (Thymus spp.) and chestnut (Castanea sativa) honeys, enriched with 10% ethanolic extract of propolis, against two major foodborne pathogens: Listeria monocytogenes and Clostridium perfringens. Methods: Antibacterial activity was assessed using broth microdilution assays and colony-forming unit (CFU) counts. The phenolic composition of the most active samples was characterized by LC-MS-Q/TOF and UPLC-PDA to identify and quantify the bioactive compounds. Results: All samples exhibited differential responses depending on the pathogen, with C. perfringens being the most susceptible. Propolis addition significantly enhanced the bactericidal response of honey against L. monocytogenes and C. perfringens (p < 0.05). This effect correlated with higher levels of antimicrobial phenolic compounds, particularly cinnamic acid derivatives, pinobanksin-3-O-hexanoside, sakuranetin, quercetin, and quercetin-3,7-dimethyl ether. Conclusions: These findings support the synergistic antibacterial potential of honey-propolis combinations, highlighting their application as natural preservatives for reducing the risk of foodborne diseases, as well as bioactive ingredients in nutraceutical formulations with antibacterial properties and additional health benefits. Full article

(This article belongs to the Special Issue Natural Products in Health Promotion and Disease Prevention 2025)

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Graphical abstract

22 pages, 1595 KiB

Open AccessReview

Therapeutic Approaches of Viral Gene Silencing by Small Interfering RNA: Strategies to Prevent the Emergence of Antiviral Resistant Escape Mutants

by Hara Kang, Yun Ji Ga, Jung Won Kim, Chaeyeon Kim, Se-Hwan Son, Chaeeun Gwak and Jung-Yong Yeh

Pharmaceuticals 2025, 18(7), 987; https://doi.org/10.3390/ph18070987 (registering DOI) - 1 Jul 2025

Abstract

RNA interference (RNAi) was originally regarded as a mechanism of eukaryotic post-transcriptional gene regulation mediated by small interfering RNA (siRNA)-induced sequence-specific RNA degradation. It is well known to exert as an important antiviral defense mechanism in a wide range of organisms, from plants [...] Read more.

RNA interference (RNAi) was originally regarded as a mechanism of eukaryotic post-transcriptional gene regulation mediated by small interfering RNA (siRNA)-induced sequence-specific RNA degradation. It is well known to exert as an important antiviral defense mechanism in a wide range of organisms, from plants to invertebrates. The specificity, ease of design, and ability to target conserved gene regions make siRNA technology a promising approach to combat viral pathogenesis, allowing the targeting of multiple virus strains. The mechanism of sequence complementarity utilized by siRNAs against their targets presents a novel strategy to combat viral infections, as they can specifically target and degrade viral RNA. Consequently, siRNA-based therapeutics have been applied to various viral diseases. This is largely due to the design flexibility and rapid response potential of RNAi technologies, which provide advantages over traditional antiviral agents. However, the emergence of viral escape mutants poses a major barrier to the sustained antiviral activity of siRNA-based therapy. Therefore, devising strategies to overcome the emergence of escape mutants to antiviral siRNAs could enhance the efficacy of siRNA-based therapeutics in providing a rapid response to emerging viral infectious diseases. This review aims to comprehensively summarize the current knowledge on siRNA-based therapeutic approaches against viral infections and elucidate the challenges associated with implementing siRNA treatment, with a specific emphasis on antiviral resistance. Full article

(This article belongs to the Special Issue Design, Synthesis and Development of Novel Antiviral Agents)

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11 pages, 539 KiB

Open AccessArticle

A Novel Closo-Ortho-Carborane-Based Glucosamine Derivative as a Promising Agent for Boron Neutron Capture Therapy

by Daniela Imperio, Ian Postuma, Salvatore Villani, Erika Del Grosso, Laura Cansolino, Cinzia Ferrari, Silvia Fallarini, Silva Bortolussi and Luigi Panza

Pharmaceuticals 2025, 18(7), 986; https://doi.org/10.3390/ph18070986 (registering DOI) - 30 Jun 2025

Abstract

Background: Boron Neutron Capture Therapy (BNCT) is a promising cancer treatment that combines tumor-selective boron delivery agents with thermal neutrons to kill cancer cells while sparing normal tissue. BNCT requires boron-containing compounds that exhibit high tumor selectivity and achieve therapeutic boron concentrations within [...] Read more.

Background: Boron Neutron Capture Therapy (BNCT) is a promising cancer treatment that combines tumor-selective boron delivery agents with thermal neutrons to kill cancer cells while sparing normal tissue. BNCT requires boron-containing compounds that exhibit high tumor selectivity and achieve therapeutic boron concentrations within tumor cells. This work focuses on the early development of a novel boron cluster carbohydrate derivative based on the glucosamine structure. Our results indicate that this derivative may have advantages over the typical boron delivery agent used in clinical applications and may significantly improve boron delivery capacity at the cellular level. Methods: The performance of the compound in terms of boron uptake was tested in the U87-MG glioblastoma cell line employing neutron autoradiography imaging and quantification. Results: The compound was non-toxic for cells, and it showed a remarkable capacity to enrich cells with boron. The ratio between boron concentration provided in the culture medium and boron concentration achieved in cells was compared to that obtained with boronophenylalanine (BPA), the gold standard in BNCT. The result demonstrated a significantly better performance compared with BPA, showing that the novel agent can concentrate boron in cells more than in culture medium. Conclusions: The encouraging preliminary results provide a starting point for its potential application in in vivo tests. Full article

(This article belongs to the Special Issue Boron in Medicinal Chemistry: From Synthesis to Therapeutic Applications)

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Graphical abstract

2 pages, 5401 KiB

Open AccessCorrection

Correction: Fu et al. C16 Peptide and Ang-1 Improve Functional Disability and Pathological Changes in an Alzheimer’s Disease Model Associated with Vascular Dysfunction. Pharmaceuticals 2022, 15, 471

by Xiaoxiao Fu, Jing Wang, Huaying Cai, Hong Jiang and Shu Han

Pharmaceuticals 2025, 18(7), 985; https://doi.org/10.3390/ph18070985 (registering DOI) - 30 Jun 2025

Abstract

In the original publication [...] Full article

(This article belongs to the Section Biopharmaceuticals)

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16 pages, 1087 KiB

Open AccessArticle

Discovery of Cyclopentane-Based Phospholipids as Miltefosine Analogs with Superior Potency and Enhanced Selectivity Against Naegleria fowleri

by Ahmed H. E. Hassan, Hương Giang Lê, Tuấn Cường Võ, Minji Kim, Joo Hwan No, Mohamed H. Aboutaleb, Jaehoon Sim, Byoung-Kuk Na and Yong Sup Lee

Pharmaceuticals 2025, 18(7), 984; https://doi.org/10.3390/ph18070984 (registering DOI) - 30 Jun 2025

Abstract

Background/Objectives: Naegleria fowleri is a free-living amoeba that invades brain tissues causing fatal primary amoebic meningoencephalitis (PAM). An effective and tolerable therapeutic agent is still lacking. Methods: A series of conformationally restricted analogs of miltefosine with varied restriction positions, stereochemical configuration and lengths [...] Read more.

Background/Objectives: Naegleria fowleri is a free-living amoeba that invades brain tissues causing fatal primary amoebic meningoencephalitis (PAM). An effective and tolerable therapeutic agent is still lacking. Methods: A series of conformationally restricted analogs of miltefosine with varied restriction positions, stereochemical configuration and lengths of alkyl chain was investigated to discover more effective and less toxic agents than miltefosine. Results: Among tested compounds, derivatives 2a, 3b and 3d featuring 1,2- or 2,3-positional restriction with trans-configuration and tridecyl or behenyl alkyl chains were discovered as more potent and less cytotoxic agents. Compounds 2a, 3b and 3d elicited 3.49-, 3.58- and 6.03-fold relative potencies to miltefosine and 7.53, 3.90 and 3.49 selectivity indices, respectively. Furthermore, compounds 2a and 3b showed IC₉₀ values for N. fowleri lower than CC₅₀ against glial C6 cells. Compounds 2a, 3b and 3d induced morphological changes and programmed cell death of N. fowleri via the apoptosis-like pathway. The induced death of N. fowleri involved DNA fragmentation along with the loss of mitochondrial membrane potential. Conclusions: The current research presents compounds 2a and 3b as more potent, selective and effective agents than miltefosine against N. fowleri for further development. Full article

(This article belongs to the Special Issue Recent Advancements in the Development of Antiprotozoal Agents)

17 pages, 1586 KiB

Open AccessArticle

Natural Products for Drug Discovery in Cognitive Disabilities: Bibliometric Hotspots, Research Trends, Conceptual Framework, and Future Directions

by Mohammed Albratty, Maryam Halawi and Ali Mufraih Albarrati

Pharmaceuticals 2025, 18(7), 983; https://doi.org/10.3390/ph18070983 (registering DOI) - 30 Jun 2025

Abstract

Background: The therapeutic potential of natural products in cognitive disabilities has drawn growing attention, yet a comprehensive analysis of trends and key contributors is lacking. This study provides a bibliometric overview highlighting growth patterns, themes, and future directions. Methods: A comprehensive [...] Read more.

Background: The therapeutic potential of natural products in cognitive disabilities has drawn growing attention, yet a comprehensive analysis of trends and key contributors is lacking. This study provides a bibliometric overview highlighting growth patterns, themes, and future directions. Methods: A comprehensive Scopus search with multistep filtering was conducted by applying keywords related to natural products and cognitive disabilities to titles, abstracts, and keywords, initially retrieving 10,011 documents. Filters for original articles and English language reduced the results to 5688. Data extracted in October 2024 were analyzed using Excel and the R-package, yielding performance and citation indices. Differential proliferation was visualized using a Sankey diagram, while thematic maps highlighted key research themes, geographic trends, and subject clusters. Results: The field exhibited an annual growth rate of 12.36% from 1971 to 2024, with 2021 being the most productive year (497 articles). In recent decades, citation metrics have highlighted significant impacts. Thematic maps and Sankey diagrams revealed the research focus, geographic trends, and collaboration. Alzheimer’s disease dominates the field, alongside topics such as oxidative stress, neuroprotection, and molecular docking. Emerging trends include ferroptosis, UPLC-Q-TOF-MS, and network pharmacology, which have marked advancements in therapeutic and computational approaches. Conclusions: This analysis underscores the dynamic and interdisciplinary nature of this field, highlighting areas for future exploration, particularly underrepresented cognitive disorders and novel therapeutic approaches. Full article

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

23 pages, 5356 KiB

Open AccessArticle

A New In Silico Comparison of the Relative Affinity of Enantiomeric Chloroquine (CQ) and Hydroxychloroquine (HCQ) for ACE2

by Carlos Naranjo-Castañeda, Marco A. García-Revilla and Eusebio Juaristi

Pharmaceuticals 2025, 18(7), 982; https://doi.org/10.3390/ph18070982 (registering DOI) - 30 Jun 2025

Abstract

Background/Objectives: Chloroquine (CQ) and hydroxychloroquine (HCQ) have been the subject of debate in the treatment of COVID-19 due to the lack of conclusive evidence regarding their efficacy and safety. Our study aims to investigate the molecular interaction between the enantiomers of CQ [...] Read more.

Background/Objectives: Chloroquine (CQ) and hydroxychloroquine (HCQ) have been the subject of debate in the treatment of COVID-19 due to the lack of conclusive evidence regarding their efficacy and safety. Our study aims to investigate the molecular interaction between the enantiomers of CQ and HCQ with angiotensin-converting enzyme 2 (ACE2), focusing on the binding mechanism, affinity, and selectivity. Methods: We used in silico methods, including molecular docking, molecular dynamics, and binding free energy calculations using the MM-PBSA method, to evaluate the interaction between the enantiomers of CQ and HCQ with ACE2. Results: We identified three main interaction sites on ACE2 (α, β, and γ) with distinct characteristics based on the pocket size, hydrophilic/hydrophobic characteristics, and affinity energy. We observed that protonation states and ionic strength significantly influence the binding affinity and specificity. In particular, the selectivity of the β-site, characterized by its smaller size and hydrophilic residues, is preferential for species with the (R) configuration, whereas the α and γ binding sites, with a larger size and amphiphilic residues, have greater affinity for the (S) enantiomer of CQ and HCQ. Furthermore, ionic strength can affect ligand binding by modulating electrostatic interactions, molecular conformation, solvation, and the stability of the complex. Conclusions: Our findings reveal that protonation states and the ionic strength substantially impact the binding affinity and specificity, regulated by spatial and polar–electrostatic complementarity, as well as hydrophobic contributions. These results suggest that understanding the interaction between CQ and HCQ enantiomers with ACE2 could be useful for the design of novel therapies against COVID-19. Full article

(This article belongs to the Special Issue Chirality: The Important Factor for Drug Discovery and Development)

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29 pages, 1320 KiB

Open AccessSystematic Review

From Lab to Clinic: How Artificial Intelligence (AI) Is Reshaping Drug Discovery Timelines and Industry Outcomes

by Doni Dermawan and Nasser Alotaiq

Pharmaceuticals 2025, 18(7), 981; https://doi.org/10.3390/ph18070981 (registering DOI) - 30 Jun 2025

Abstract

Background/Objectives: Artificial intelligence (AI) is transforming drug discovery and development by enhancing the speed and precision of identifying drug candidates and optimizing their efficacy. This review evaluates the application of AI in various stages of drug discovery, from hit identification to lead optimization, [...] Read more.

Background/Objectives: Artificial intelligence (AI) is transforming drug discovery and development by enhancing the speed and precision of identifying drug candidates and optimizing their efficacy. This review evaluates the application of AI in various stages of drug discovery, from hit identification to lead optimization, and its impact on clinical outcomes. The objective is to provide insights into the role of AI across therapeutic areas and assess its contributions to improving clinical trial efficiency and pharmaceutical outcomes. Methods: A systematic review followed PRISMA guidelines to analyze studies published between 2015 and 2025, focusing on AI in drug discovery and development. A comprehensive search was performed across multiple databases to identify studies employing AI techniques. The studies were categorized based on AI methods, clinical phase, and therapeutic area. The percentages of AI methods used, clinical phase stages, and the therapeutic regions were analyzed to identify trends. Results: AI methods included machine learning (ML) at 40.9%, molecular modeling and simulation (MMS) at 20.7%, and deep learning (DL) at 10.3%. Oncology accounted for the majority of studies (72.8%), followed by dermatology (5.8%) and neurology (5.2%). In clinical phases, 39.3% of studies were in the preclinical stage, 23.1% in Clinical Phase I, and 11.0% in the transitional phase. Clinical outcome reporting was observed in 45% of studies, with 97% reporting industry partnerships. Conclusions: AI significantly enhances drug discovery and development, improving drug efficacy and clinical trial outcomes. Future work should focus on expanding AI applications into underrepresented therapeutic areas and refining models to handle complex biological systems. Full article

(This article belongs to the Special Issue Artificial Intelligence-Assisted Drug Discovery)

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17 pages, 3694 KiB

Open AccessArticle

Biodegradable Polylactide Nanocapsules Containing Quercetin for In Vitro Suppression of Mouse B16F10 and Human Sk-Mel-28 Melanoma Cell Lines

by Chenhui Zhao and Thomas Ming Swi Chang

Pharmaceuticals 2025, 18(7), 980; https://doi.org/10.3390/ph18070980 (registering DOI) - 30 Jun 2025

Abstract

Background: Quercetin is a flavonoid found in various dietary sources. It is a prodrug converted by overexpressed tyrosinase in melanoma into an active o-quinone that suppresses tumour growth. However, injected quercetin is rapidly cleared from the tumour site. Method: Our study aimed to [...] Read more.

Background: Quercetin is a flavonoid found in various dietary sources. It is a prodrug converted by overexpressed tyrosinase in melanoma into an active o-quinone that suppresses tumour growth. However, injected quercetin is rapidly cleared from the tumour site. Method: Our study aimed to enhance quercetin’s efficacy through nanoencapsulation using biodegradable nanocapsules, which were tested in both mouse and human melanoma cell lines in 2D and 3D models. Results: Nanoencapsulation achieved sustained release and improved bioavailability. In mouse 2D cultures, quercetin nanocapsules (Q-nanos) reduced cell viability to 28%, compared with 46% for free quercetin (Q-only) (p < 0.05). In 3D cultures simulating in vivo conditions, Q-nanos reduced viability to 43%, showing significant anti-melanoma activity, while Q-only resulted in 72% viability (p > 0.05 vs. control). A similar trend was observed in human melanotic melanoma, where both Q-nanos and Q-only were effective compared with the controls, with Q-nanos demonstrating superior tumour inhibition (p < 0.05). Conclusions: These findings show the superior efficacy of nanoencapsulated quercetin over free quercetin. Nanoencapsulation prolonged quercetin’s bioavailability, enhanced tumour regression, and addressed limitations associated with the rapid clearance of free quercetin. Full article

(This article belongs to the Special Issue Advances in Natural Extracts for Cancer Treatment: Targeting Melanoma Cells)

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16 pages, 634 KiB

Open AccessSystematic Review

Lurasidone for Pediatric Bipolar Disorder: A Systematic Review

by Alexia Koukopoulos, Claudia Calderoni, Georgios D. Kotzalidis, Tommaso Callovini, Lorenzo Moccia, Silvia Montanari, Gianna Autullo, Alessio Simonetti, Mario Pinto, Giovanni Camardese, Gabriele Sani and Delfina Janiri

Pharmaceuticals 2025, 18(7), 979; https://doi.org/10.3390/ph18070979 (registering DOI) - 30 Jun 2025

Abstract

Background/Objectives: Lurasidone ((3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-ylmethyl]cyclohexylmethyl}hexahydro-4,7-methano-2H-isoindole-1,3-dione) is a second-generation antipsychotic approved for schizophrenia and mood disorders. Adolescents and children with bipolar disorder receive treatments that expose them to weight gain and metabolic syndrome. Lurasidone is relatively free from such side effects, so it may constitute [...] Read more.

Background/Objectives: Lurasidone ((3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-ylmethyl]cyclohexylmethyl}hexahydro-4,7-methano-2H-isoindole-1,3-dione) is a second-generation antipsychotic approved for schizophrenia and mood disorders. Adolescents and children with bipolar disorder receive treatments that expose them to weight gain and metabolic syndrome. Lurasidone is relatively free from such side effects, so it may constitute a useful alternative for the treatment of these patients. We focused on the use of lurasidone in children and adolescents with bipolar disorder. Methods: On 11 June 2025, we used the following strategy on PubMed: lurasidone AND (“bipolar disorder” OR “bipolar depression” OR mania OR manic). We filtered for humans and ages 0–18 years and included case reports and clinical studies. Similar strategies adapted to each database were used to carry out our systematic review on CINAHL, PsycINFO/PsycARTICLES, Scopus, and the ClinicalTrials.gov register on the same date. We excluded reports without children/adolescent participants, those grouping adult participants with children/adolescents without providing data separately, reviews, and opinions/editorials with no data. Eligibility was determined through Delphi rounds; it was required that consensus was reached among all authors. We followed the PRISMA-2020 Statement. Results: Our search produced 38 results on PubMed on 11 June 2025. We included four case reports/series and five studies. One additional eligible study emerged from our Scopus inquiry, raising the number of eligible studies to six. One case series was moderately positive; one case report was neutral, another was positive, and one reported the induction of mania. The six longitudinal studies involved 16,735 participants and showed generally good efficacy. Conclusions: The use of lurasidone in adolescents/children with bipolar disorder obtains favorable results regarding the excitatory and depressive symptoms of bipolar disorder with no significant side effects. Full article

(This article belongs to the Special Issue Pediatric Drug Therapy: Safety, Efficacy, and Personalized Medicine)

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18 pages, 2204 KiB

Open AccessReview

Beyond the Limit: MYC Mediates Tumor Immune Escape

by Zhongyang Hong, Sitong Ming, Xin Luan, Zhe Sun and Weidong Zhang

Pharmaceuticals 2025, 18(7), 978; https://doi.org/10.3390/ph18070978 (registering DOI) - 29 Jun 2025

Abstract

MYC is an aberrantly regulated transcription factor implicated in approximately 70% of human tumors, where it extensively modulates signaling pathways associated with cancer progression. Inactivating MYC has been shown to inhibit tumor growth and even induce sustained tumor regression across various cancer types, [...] Read more.

MYC is an aberrantly regulated transcription factor implicated in approximately 70% of human tumors, where it extensively modulates signaling pathways associated with cancer progression. Inactivating MYC has been shown to inhibit tumor growth and even induce sustained tumor regression across various cancer types, a phenomenon referred to as oncogene addiction. However, in vitro studies reveal that the knockout or knockdown of MYC in numerous tumor cell lines does not necessarily result in cell death, despite these tumors exhibiting MYC addiction in vivo. This discrepancy suggests that the unique tumor microenvironment in vivo may play a critical role in facilitating MYC addiction in cancer cells. MYC is also widely acknowledged for its role in mediating the immune evasion of tumor cells. Nevertheless, due to the extensive regulation of cellular gene expression by MYC and the incomplete understanding of the mechanisms underlying tumor immune escape, the precise pathways through which MYC influences tumor immune evasion remain inadequately elucidated. Recent years have seen the identification of novel tumor immune escape mechanisms, some of which have been demonstrated to be directly or indirectly regulated by MYC. For instance, MYC may contribute to immune evasion by modulating the expression of argininosuccinate synthetase 1 (ASS1), a key enzyme involved in arginine biosynthesis. Herein, in this study, we explore some novel potential mechanisms through which MYC facilitates the immune evasion of tumor cells, alongside a combined therapeutic approach targeting MYC and employing immunotherapy based on this mechanism. Furthermore, we suggest that targeting proteins interacting with MYC to modulate its expression and function may serve as an alternative strategy to direct MYC targeting, thereby expediting the clinical translation of combination therapies. Full article

(This article belongs to the Section Biopharmaceuticals)

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25 pages, 6990 KiB

Open AccessArticle

Study on the Pharmacological Efficacy and Mechanism of Dual-Target Liposome Complex AD808 Against Alzheimer’s Disease

by Chang Liu, Xiaoqing Wang, Wei Xu, Songli Yu, Yueru Zhang, Qiming Xu and Xiangshi Tan

Pharmaceuticals 2025, 18(7), 977; https://doi.org/10.3390/ph18070977 (registering DOI) - 29 Jun 2025

Abstract

Background/Objectives: To study the efficacy and pharmacological mechanism of the dual-target liposome complex AD808 in the treatment of Alzheimer’s disease. Methods: Using APP/PS1 mouse models, the therapeutic efficacy and pharmacological mechanism of AD808 on Alzheimer’s disease were studied through water maze [...] Read more.

Background/Objectives: To study the efficacy and pharmacological mechanism of the dual-target liposome complex AD808 in the treatment of Alzheimer’s disease. Methods: Using APP/PS1 mouse models, the therapeutic efficacy and pharmacological mechanism of AD808 on Alzheimer’s disease were studied through water maze tests, brain tissue staining, immunofluorescence, and ELISA for inflammatory and neurotrophic factors. Results: AD808 exhibited significant pharmacodynamic effects in improving behavioral and cognitive abilities (70% reduction in escape latency) and repairing damaged nerve cells (90% reduction in Aβ plaque) in Alzheimer’s disease mice. The efficacy of the liposome complex AD808 was significantly better than that of ST707 or gh625-Zn₇MT3 alone. AD808 significantly reduced brain inflammation (57.3% and 61.5% reductions in TNF-α and IL-1β, respectively) in AD (Alzheimer’s disease) mouse models and promoted the upregulation of neurotrophic factors and nerve growth factors (142.8% increase in BDNF, 275.9% in GDNF, and 111.3% in NGF-1) in brain homogenates. By activating the PI3K/AKT signaling pathway in brain microglia, AD808 upregulated TREM2 protein expression and removed Aβ amyloid plaques in the brain. Additionally, it promoted the transition of microglia from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, regulated the M1/M2 balance, released anti-inflammatory and neurotrophic factors, reduced chronic inflammation, and enhanced neurological repair. Based on these results, the potential pharmacological mechanism of AD808 against Alzheimer’s disease was proposed. Conclusions: As a dual-target liposome complex, AD808 has shown promising therapeutic potential in the treatment of Alzheimer’s disease, providing a new strategy for innovative drug development. Full article

(This article belongs to the Special Issue Pharmacotherapy for Alzheimer’s Disease)

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20 pages, 5010 KiB

Open AccessArticle

Antimicrobial, Oxidant, Cytotoxic, and Eco-Safety Properties of Sol–Gel-Prepared Silica–Copper Nanocomposite Materials

by Lilia Yordanova, Lora Simeonova, Miroslav Metodiev, Albena Bachvarova-Nedelcheva, Yoanna Kostova, Stela Atanasova-Vladimirova, Elena Nenova, Iliana Ivanova, Lyubomira Yocheva and Elitsa Pavlova

Pharmaceuticals 2025, 18(7), 976; https://doi.org/10.3390/ph18070976 (registering DOI) - 28 Jun 2025

Abstract

Background: The present work is devoted to the biological effects of sol–gel-derived silica (Si)–copper (Cu) nanomaterials. Methods and Results: Tetraethyl orthosilane (TEOS) was used as a silica precursor; copper was introduced as a solution in ethanol with Cu(OH)₂. The obtained samples [...] Read more.

Background: The present work is devoted to the biological effects of sol–gel-derived silica (Si)–copper (Cu) nanomaterials. Methods and Results: Tetraethyl orthosilane (TEOS) was used as a silica precursor; copper was introduced as a solution in ethanol with Cu(OH)₂. The obtained samples were denoted as Si/Cu (gel) and Si/Cu/500 (500 °C heat-treated). Their phase formation and morphology were studied by XRD and SEM. The antibacterial activity was tested by two Gram-positive bacteria, three Gram-negative bacteria, and two types of eukaryotic species. Most bacteria were more sensitive to Si/Cu/500 materials than to Si/Cu (gel). The yeasts were more sensitive to Si/Cu (gel). The new nanomaterials were tested for oxidant activity at pH 7.4 (physiological) and pH 8.5 (optimal) in three model systems by the chemiluminescent method. They significantly inhibited the generation of free radicals and ROS. This result underlines their potential as regulators of the free radical processes in living systems. The epithelial tumor cell lines appeared more sensitive than the non-transformed fibroblasts, likely due to their metabolic activity and proliferation rates, leading to greater accumulation of the substances. Using Daphnia magna, the ecotoxicity study showed that the LC₅₀ was reached at 1 mg/L of Si/Cu/500. Si/Cu (gel) was more toxic. Conclusions: Our results reveal the potential of these nanohybrids to be applied in living, eukaryotic systems. The cytotoxicity evaluation showed higher tolerance of normal, non-transformed cells, in concurrence with the oxidation tests. Full article

(This article belongs to the Special Issue Nanotechnology in Biomedical Applications)

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18 pages, 1197 KiB

Open AccessArticle

Precision Enhanced Bioactivity Prediction of Tyrosine Kinase Inhibitors by Integrating Deep Learning and Molecular Fingerprints Towards Cost-Effective and Targeted Cancer Therapy

by Fatma Hilal Yagin, Yasin Gormez, Cemil Colak, Abdulmohsen Algarni, Fahaid Al-Hashem and Luca Paolo Ardigò

Pharmaceuticals 2025, 18(7), 975; https://doi.org/10.3390/ph18070975 (registering DOI) - 28 Jun 2025

Abstract

Background and Objective: Dysregulated tyrosine kinase signaling is a central driver of tumorigenesis, metastasis, and therapeutic resistance. While tyrosine kinase inhibitors (TKIs) have revolutionized targeted cancer treatment, identifying compounds with optimal bioactivity remains a critical bottleneck. This study presents a robust machine learning [...] Read more.

Background and Objective: Dysregulated tyrosine kinase signaling is a central driver of tumorigenesis, metastasis, and therapeutic resistance. While tyrosine kinase inhibitors (TKIs) have revolutionized targeted cancer treatment, identifying compounds with optimal bioactivity remains a critical bottleneck. This study presents a robust machine learning framework—leveraging deep artificial neural networks (dANNs), convolutional neural networks (CNNs), and structural molecular fingerprints—to accurately predict TKI bioactivity, ultimately accelerating the preclinical phase of drug development. Methods: A curated dataset of 28,314 small molecules from the ChEMBL database targeting 11 tyrosine kinases was analyzed. Using Morgan fingerprints and physicochemical descriptors (e.g., molecular weight, LogP, hydrogen bonding), ten supervised models, including dANN, SVM, CatBoost, and CNN, were trained and optimized through a randomized hyperparameter search. Model performance was evaluated using F1-score, ROC–AUC, precision–recall curves, and log loss. Results: SVM achieved the highest F1-score (87.9%) and accuracy (85.1%), while dANNs yielded the lowest log loss (0.25096), indicating superior probabilistic reliability. CatBoost excelled in ROC–AUC and precision–recall metrics. The integration of Morgan fingerprints significantly improved bioactivity prediction across all models by enhancing structural feature recognition. Conclusions: This work highlights the transformative role of machine learning—particularly dANNs and SVM—in rational drug discovery. By enabling accurate bioactivity prediction, our model pipeline can effectively reduce experimental burden, optimize compound selection, and support personalized cancer treatment design. The proposed framework advances kinase inhibitor screening pipelines and provides a scalable foundation for translational applications in precision oncology. By enabling early identification of bioactive compounds with favorable pharmacological profiles, the results of this study may support more efficient candidate selection for clinical drug development, particularly in regards to cancer therapy and kinase-associated disorders. Full article

(This article belongs to the Special Issue Integrating Machine Learning (ML) into Medicinal Chemistry and Cheminformatics)

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19 pages, 2746 KiB

Open AccessSystematic Review

Is Anlotinib and Radiotherapy Combination Effective for Non-Small-Cell Lung Cancer with Brain Metastases? A Systematic Scoping Review and Meta-Analysis

by Helal F. Hetta, Mostafa A. Sayed Ali, Saleh F. Alqifari, Hoda A. Salem, Khulood A. Qasem, Fawaz E. Alanazi, Amirah Alhowiti, Amirah M. Alatawi, Hyder Mirghani, Tariq Alrasheed, Salwa Q. Bukhari, Khalid A. Almazyad, Sultan A. Alhumaid, Noura H. Abd Ellah, Hashim M. Aljohani, Yasmin N. Ramadan and Reem Sayad

Pharmaceuticals 2025, 18(7), 974; https://doi.org/10.3390/ph18070974 (registering DOI) - 28 Jun 2025

Abstract

Background/Objectives: Non-small-cell lung cancer (NSCLC) frequently metastasizes to the brain, significantly impacting patient prognosis and quality of life. Anlotinib, a novel tyrosine kinase inhibitor, has shown promise in treating NSCLC with brain metastasis. So, we aimed to evaluate the clinical efficacy of [...] Read more.

Background/Objectives: Non-small-cell lung cancer (NSCLC) frequently metastasizes to the brain, significantly impacting patient prognosis and quality of life. Anlotinib, a novel tyrosine kinase inhibitor, has shown promise in treating NSCLC with brain metastasis. So, we aimed to evaluate the clinical efficacy of anlotinib and various types of radiotherapy combinations used to treat NSCLC patients with brain metastasis regarding overall survival and the treatment of internal and external lesions. Methods: A comprehensive literature search was conducted in the databases PubMed, Scopus, WoS, MedLine, and Cochrane Library up to April 2024. Studies assessing the efficacy of anlotinib combined with whole-brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), or other radiotherapy modalities in NSCLC patients with brain metastasis were included. The primary outcomes were (a) the efficacy of anlotinib and radiotherapy on the intracranial lesions and OS and (b) the effectiveness of combined anlotinib and radiotherapy versus radiotherapy alone in NSCLC patients with brain metastasis. The secondary outcome was the efficacy of anlotinib and radiotherapy on extracranial progression. We used a combination of keywords and MeSH terms including ‘non-small cell lung cancer’ OR ‘NSCLC’, ‘brain metastases’, ‘anlotinib’, ‘radiotherapy’, ‘radiation therapy’, and ‘combined treatment’, among others. Boolean operators (AND, OR) were applied as appropriate to optimize the search strategy across databases. Results: Nine studies met the inclusion criteria, comprising 210 patients in the combination group and 228 patients in the radiotherapy alone group. The combination of anlotinib with radiotherapy showed a significant improvement in iPFS compared to radiotherapy alone, with a pooled risk ratio (RR) for iORR of 1.18 (95% CI: 1.00–1.39) and a pooled SMD for OS of 0.03 (95% CI: −0.29, 0.36). Radiotherapy combined with anlotinib also demonstrated enhanced intracranial and extracranial control rates. Conclusions: Anlotinib combined with radiotherapy, especially WBRT, offers a promising treatment strategy for NSCLC patients with brain metastasis, improving intracranial control. Further large-scale randomized controlled trials are needed to confirm these findings and optimize treatment protocols. Full article

(This article belongs to the Section Radiopharmaceutical Sciences)

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16 pages, 764 KiB

Open AccessReview

3D Printing in Oral Drug Delivery: Technologies, Clinical Applications and Future Perspectives in Precision Medicine

by Zeena Saleh-Bey-Kinj, Yael Heller, Giannis Socratous and Panayiota Christodoulou

Pharmaceuticals 2025, 18(7), 973; https://doi.org/10.3390/ph18070973 (registering DOI) - 28 Jun 2025

Abstract

The recent advancement of 3D-printed drugs is an emerging technology that has the potential for effective and safe oral delivery of personalized treatment regimens to patients, replacing the current “one size fits all” philosophy. The objective of this literature review is to highlight [...] Read more.

The recent advancement of 3D-printed drugs is an emerging technology that has the potential for effective and safe oral delivery of personalized treatment regimens to patients, replacing the current “one size fits all” philosophy. The objective of this literature review is to highlight the importance of 3D-printing technology in the development of personalized treatments, focusing on Levetiracetam, the first FDA-approved 3D-printed drug, for the treatment of epilepsy. Levetiracetam serves as an ideal paradigm for exploring how precision medicine and 3D printing can be applied to improve treatment outcomes for other complex diseases such as diabetes, cardiovascular diseases, and cancer. 3D printing enables precise dosage and time-release profiles by modifying factors such as shape and size, and the combination of active pharmaceutical ingredients (APIs) and excipients, ensuring consistent therapeutic levels over the treatment period. Design of oral tablets with multiple compartments allows for simultaneous treatment with multiple APIs, each one with a different release profile, minimizing drug–drug interactions and side effects. This technology also supports on-demand production, making it particularly beneficial in resource-limited or urgent situations, and offers the flexibility to customize dosage forms. Additive manufacturing could be an important tool for developing personalized treatments to address the diverse medical needs of patients with complex diseases. Therefore, there is a need for more 3D-printed FDA-approved drugs in the biopharmaceutical industry to enable personalized treatment, improved patient compliance, and precise drug release control. Full article

(This article belongs to the Section Pharmaceutical Technology)

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Graphical abstract

31 pages, 5331 KiB

Open AccessArticle

Development of a Novel Drug Delivery System “Nanoemulfoam” for Topical Delivery of Terbinafine Hydrochloride as a Repurposed Therapy in Skin Cancer: Formulation, Optimization, In Vitro Characterization, Ex Vivo Transdermal Permeability, Cytotoxicity Studies, and In Silico Assessment

by Abeer A. Musallam, Reem A. Aldeeb, Riham M. Mansour, Manar Abd El-karim Kassem, Doaa Fayez Saeed, Mahmoud A. Mahdy, Rana M. Abdelnaby, Hanan M. Elnahas and Tarek M. Ibrahim

Pharmaceuticals 2025, 18(7), 972; https://doi.org/10.3390/ph18070972 (registering DOI) - 27 Jun 2025

Abstract

Background: Skin cancer has become a global health issue because of increasing exposure to environmental contaminants and UV radiation. Terbinafine hydrochloride (TRB), a broad-spectrum antifungal medication, has demonstrated notable anti-tumor properties in previous studies; however, its repurposing for skin cancer therapy remains underexplored. [...] Read more.

Background: Skin cancer has become a global health issue because of increasing exposure to environmental contaminants and UV radiation. Terbinafine hydrochloride (TRB), a broad-spectrum antifungal medication, has demonstrated notable anti-tumor properties in previous studies; however, its repurposing for skin cancer therapy remains underexplored. Objective: This study reports for the first time, the development of a new delivery system: a nanoemulsion (NE)–foam hybrid system, i.e., “nanoemulfoam” (NEF), designed to enhance the topical TRB delivery to the skin. The study applied this new hybrid system on TRB for managing skin cancer. Method: The TRB-loaded NEF was produced by loading TRB into a liquid NE. then this was incorporated into a liquid foam base and actuated into foam using a non-propellant mechanism. The NE was developed utilizing peppermint oil as the oil phase and Tween-20/ethanol as the surfactant/co-surfactant combination (Smix). The formulation underwent optimization using the D-optimal design that enabled the simultaneous evaluation of the impact of oil concentration and Tween 20 concentration in the Smix on the particle size (PS), zeta potential (ZP), and dissolution efficiency percent (DE%). Results: The optimal NE formula displayed a small PS of 186.60 ± 2.84 nm, ZP of −13.90 ± 0.99 mV, and DE% of 68.50 ± 1.78% (mean ± SD, n = 3). After incorporation into the foam system, the produced TRB-loaded NEF demonstrated a 7.43-fold increase in the drug transdermal flux in comparison with plain drug foam (p < 0.05). The TRB-loaded NEF showed no signs of inflammation or irritation when applied to abdominal rabbit skin, indicating its safety. The optimum formula exhibited a statistically significant 10-fold increase in cytotoxicity against A-431 skin cancer cells compared to TRB alone, along with a 1.54-fold increase in apoptosis (p < 0.05). Molecular docking studies targeting CDK2, a key regulator of cell proliferation and a known TRB target, revealed that TRB displayed highly favorable binding scores compared to the reference drug. Conclusions: The TRB-loaded NEF represents a promising nanotechnology-based approach for the topical treatment of skin cancer, supporting further investigation toward clinical translation. Full article

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Graphical abstract

22 pages, 2803 KiB

Open AccessArticle

Pharmacogenomics and Pharmacometabolomics in Precision Tramadol Prescribing for Enhanced Pain Management: Evidence from QBB and EMR Data

by Dhoha Dhieb, Najeha Anwardeen, Dinesh Velayutham, Mohamed A. Elrayess, Puthen Veettil Jithesh and Kholoud Bastaki

Pharmaceuticals 2025, 18(7), 971; https://doi.org/10.3390/ph18070971 (registering DOI) - 27 Jun 2025

Abstract

Background/Objectives: Tramadol is an opioid frequently prescribed for moderate to severe pain and has seen a global increase in use. This presents numerous challenges in clinical management. This study aims to elucidate metabolic signatures associated with tramadol consumption, enhancing predictive capabilities for [...] Read more.

Background/Objectives: Tramadol is an opioid frequently prescribed for moderate to severe pain and has seen a global increase in use. This presents numerous challenges in clinical management. This study aims to elucidate metabolic signatures associated with tramadol consumption, enhancing predictive capabilities for therapeutic outcomes and optimizing patient-specific treatment plans. Methods: Data were obtained from the Qatar Biobank (QBB), focusing on pharmacogenomic variants associated with tramadol use and prescription trends. A cohort of 27 individuals who were administered daily tramadol doses between 100 and 400 mg with available metabolomic profiles were selected. The pharmacokinetics of tramadol were evaluated in relation to specific CYP2D6 genetic variants. Comparative pharmacometabolomic profiles were generated for tramadol users versus a control group of 54 non-users. Additionally, prescription data encompassing tramadol formulations were collected from the electronic medical records (EMR) system of the major public hospital network in Qatar (Hamad Medical Corporation) to discern prescribing patterns. Results: From January 2019 to December 2022, tramadol prescriptions varied, with chronic pain as the primary indication, followed by acute pain. Pharmacogenomic analysis indicated that CYP2D6 allele variations significantly impacted tramadol and O-desmethyltramadol glucuronide levels, notably in ‘normal metabolizers’. Metabolomic analysis revealed distinct metabolic profiles in tramadol users, with significant variations in phosphatidylcholine, histidine, and lysine pathways compared to controls, highlighting tramadol’s unique biochemical impacts. Conclusions: This study underscores the importance of integrating genetic and omics-based approaches to enhance tramadol’s efficacy and safety. These findings support personalized pain management strategies, enhancing treatment outcomes for both chronic and acute pain. Full article

(This article belongs to the Special Issue Pharmacogenomics for Precision Medicine)

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