Pharmaceuticals

21 pages, 5953 KB

Open AccessArticle

Network Pharmacology and Experimental Validation Identify Paeoniflorin as a Novel SRC-Targeted Therapy for Castration-Resistant Prostate Cancer

by Meng-Yao Xu, Jun-Biao Zhang, Yu-Zheng Peng, Mei-Cheng Liu, Si-Yang Ma, Ye Zhou, Zhi-Hua Wang and Sheng Ma

Pharmaceuticals 2025, 18(8), 1241; https://doi.org/10.3390/ph18081241 - 21 Aug 2025

Viewed by 605

Abstract

Background: Despite advances in prostate cancer treatment, castration-resistant prostate cancer (CRPC) remains clinically challenging due to inherent therapy resistance and a lack of durable alternatives. Although traditional Chinese medicine offers untapped potential, the therapeutic role of paeoniflorin (Pae), a bioactive compound derived from [...] Read more.

Background: Despite advances in prostate cancer treatment, castration-resistant prostate cancer (CRPC) remains clinically challenging due to inherent therapy resistance and a lack of durable alternatives. Although traditional Chinese medicine offers untapped potential, the therapeutic role of paeoniflorin (Pae), a bioactive compound derived from Paeonia lactiflora, in prostate cancer has yet to be investigated. Methods: Using an integrative approach (network pharmacology, molecular docking, and experimental validation), we identified Pae key targets, constructed protein–protein interaction networks, and performed GO/KEGG pathway analyses. A Pae-target-based prognostic model was developed and validated. In vitro and in vivo assays assessed Pae effects on proliferation, migration, invasion, apoptosis, and tumor growth. Results: Pae exhibited potent anti-CRPC activity, inhibiting cell proliferation by 60% and impairing cell migration by 65% compared to controls. Mechanistically, Pae downregulated SRC proto-oncogene, non-receptor tyrosine kinase (SRC) mRNA expression by 68%. The Pae-target-based prognostic model stratified patients into high- and low-risk groups with distinct survival outcomes. Organoid and xenograft studies confirmed Pae-mediated tumor growth inhibition and SRC downregulation. Conclusions: Pae overcomes CRPC resistance by targeting SRC-mediated pathways, presenting a promising therapeutic strategy. Our findings underscore the utility of network pharmacology-guided drug discovery and advocate for further clinical exploration of Pae in precision oncology. Full article

(This article belongs to the Section Pharmacology)

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29 pages, 3696 KB

Open AccessArticle

Smart Formulation: AI-Driven Web Platform for Optimization and Stability Prediction of Compounded Pharmaceuticals Using KNIME

by Artur Grigoryan, Stefan Helfrich, Valentin Lequeux, Benjamine Lapras, Chloé Marchand, Camille Merienne, Fabien Bruno, Roseline Mazet and Fabrice Pirot

Pharmaceuticals 2025, 18(8), 1240; https://doi.org/10.3390/ph18081240 - 21 Aug 2025

Viewed by 493

Abstract

Background/Objectives: Smart Formulation is an artificial intelligence-based platform designed to predict the Beyond Use Dates (BUDs) of compounded oral solid dosage forms. The study aims to develop a decision-support tool for pharmacists by integrating molecular, formulation, and environmental parameters to assist in [...] Read more.

Background/Objectives: Smart Formulation is an artificial intelligence-based platform designed to predict the Beyond Use Dates (BUDs) of compounded oral solid dosage forms. The study aims to develop a decision-support tool for pharmacists by integrating molecular, formulation, and environmental parameters to assist in optimizing the stability of extemporaneous preparations. Methods: A tree ensemble regression model was trained using a curated dataset of 55 experimental BUD values collected from the Stabilis database. Each formulation was encoded with molecular descriptors, excipient composition, packaging type, and storage conditions. The model was implemented using the KNIME platform, allowing the integration of cheminformatics and machine learning workflows. After training, the model was used to predict BUDs for 3166 APIs under various formulation and storage scenarios. Results: The analysis revealed a significant impact of excipient type, number, and environmental conditions on API stability. APIs with lower LogP values generally exhibited greater stability, particularly when formulated with a single excipient. Excipients such as cellulose, silica, sucrose, and mannitol were associated with improved stability, whereas HPMC and lactose contributed to faster degradation. The use of two excipients instead of one frequently resulted in reduced BUDs, possibly due to moisture redistribution or phase separation effects. Conclusions: Smart Formulation represents a valuable contribution to computational pharmaceutics, bridging theoretical formulation design with practical compounding needs. The platform offers a scalable, cost-effective alternative to traditional stability testing and is already available for use by healthcare professionals. Its implementation in hospital and community pharmacies may help mitigate drug shortages, support formulation standardization, and improve patient care. Future developments will focus on real-time stability monitoring and adaptive learning for enhanced precision. Full article

(This article belongs to the Section Pharmaceutical Technology)

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28 pages, 31113 KB

Open AccessArticle

Multi-Omics and Molecular Docking Studies on Caffeine for Its Skin Rejuvenating Potentials

by Peng Shu, Nan Zhao, Qi Zhou, Yuan Wang and Lanyue Zhang

Pharmaceuticals 2025, 18(8), 1239; https://doi.org/10.3390/ph18081239 - 21 Aug 2025

Cited by 1 | Viewed by 482

Abstract

Background: Caffeine (CA) exhibits promising reparative effects against UV-induced skin aging, but the specific mechanisms, including differences in gene and metabolite regulation and the involvement of signaling pathways, are still insufficiently elucidated. Methods: This study is on the repairing capability of [...] Read more.

Background: Caffeine (CA) exhibits promising reparative effects against UV-induced skin aging, but the specific mechanisms, including differences in gene and metabolite regulation and the involvement of signaling pathways, are still insufficiently elucidated. Methods: This study is on the repairing capability of CA to ultraviolet (UV)-induced skin aging and explores the ferroptosis pathway through in vitro cell experiments, a UV-aged mouse skin model, and molecular docking. Results: CA enhanced the vitality and proliferation of HaCaT cells, delayed cell aging, reduced reactive oxygen species levels, increased mitochondrial membrane potential, and activated the peroxisome proliferator-activated receptor pathway, as well as repaired UVB-induced cytoskeletal disorders. Simultaneously, CA reduced other related but undesirable biological mechanisms. Moreover, multi-omics and network pharmacology studies suggested that CA mitigated aging by modulating related metabolic and ferroptosis pathways. Additionally, CA effectively reduced lipid peroxidation and intracellular ferrous ion levels and regulated the expression of key ferroptosis proteins, and its potential anti-aging effects were also confirmed through the modulation of ferroptosis pathways. In addition, molecular docking revealed strong interactions between CA and related key proteins, further supporting the potentiality of CA. Conclusions: This study elucidates the effectiveness and potential mechanism of CA to reduce the UV-induced skin aging. Full article

(This article belongs to the Section Pharmacology)

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18 pages, 3771 KB

Open AccessArticle

VDR Decrease Enhances the Efficacy of 1,25-Dihydroxyvitamin D3 Inhibiting Gefitinib Resistance by Regulating EGFR/FASN Loop in NSCLC Cells

by Junqing Yang, Mingyu Fang, Mengjun Hou, Yalei Duan, Jiali Wang, Kaiyong Hu, Shuo Liu, Xiaoying Liu, Xiaohan Peng, Xuansheng Ding and Zhirong Jia

Pharmaceuticals 2025, 18(8), 1238; https://doi.org/10.3390/ph18081238 - 21 Aug 2025

Viewed by 467

Abstract

Background: Gefitinib is a first-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) targeting EGFR-mutated non-small cell lung cancer (NSCLC) and is a current first-line treatment for NSCLC. However, acquired resistance leads to the failure of treatment and remains a challenge. Therefore, [...] Read more.

Background: Gefitinib is a first-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) targeting EGFR-mutated non-small cell lung cancer (NSCLC) and is a current first-line treatment for NSCLC. However, acquired resistance leads to the failure of treatment and remains a challenge. Therefore, identifying novel therapeutic approaches to combat EGFR-TKI resistance is crucial. Methods: The Cancer Genome Atlas (TCGA) database analysis and gefitinib-resistant cell lines were used to analyze VDR expression in NSCLC. Cell proliferation and apoptosis were assessed via MTT assay, colony formation assay, and flow cytometry. Immunofluorescence, qPCR, and Western blotting were used to measure mRNA and protein expression levels of VDR and other related molecules. Xenograft tumors in BALB/c nude mice were employed to investigate the effects of VDR and 1,25-dihydroxyvitamin D3 (1,25(OH)₂D₃) on gefitinib-resistant tumors in vivo. Results: We found that VDR was significantly upregulated in EGFR-TKI-resistant NSCLC cells. Patients with high VDR expression exhibited poor prognosis. VDR knockdown significantly inhibited cell proliferation, tumor growth, and reduced gefitinib resistance, whereas VDR overexpression enhanced resistance. VDR knockdown downregulated EGFR and FASN expression. Silencing either EGFR or FASN confirmed the existence of a positive feedback regulatory loop involving VDR, EGFR, and FASN. Treatment with 1,25(OH)₂D₃ increased VDR levels but decreased EGFR and FASN expression. VDR knockdown significantly enhanced the inhibitory effect of 1,25(OH)₂D₃ on gefitinib resistance. The combination of VDR knockdown and 1,25(OH)₂D₃ treatment was more effective than either treatment alone in suppressing EGFR and FASN expression. Conclusions: VDR promotes NSCLC resistance to EGFR-TKIs by regulating EGFR and FASN expression through a positive feedback loop. Knocking down VDR effectively enhances the ability of 1,25(OH)₂D₃ to overcome gefitinib resistance, mediated by the synergistic downregulation of EGFR and FASN expression. Targeting VDR represents a potential strategy to enhance the efficacy of 1,25(OH)₂D₃ in overcoming EGFR-TKI resistance. Full article

(This article belongs to the Special Issue Epithelial Plasticity and Therapy Resistance in Cancer)

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24 pages, 4992 KB

Open AccessArticle

Identification of Potential Pteridin Reductase-1 Inhibitors for the Treatment of Leishmaniasis: A Bioinformatics Approach

by Paulo R. da S. R. Júnior, Lúcio R. de Lima, Luciane B. Silva, Ryan S. Ramos, Vitor H. da S. Sanches, Njogu M. Kimani, Gustavo H. G. Trossini, Joaquín M. Campos, Cleison C. Lobato and Cleydson B. R. Santos

Pharmaceuticals 2025, 18(8), 1237; https://doi.org/10.3390/ph18081237 - 21 Aug 2025

Viewed by 486

Abstract

Background/Objectives: Leishmaniasis is an infectious disease caused by digenetic protozoa of the genus Leishmania, transmitted by infected female sandflies of the Phlebotominae subfamily. Current treatments are limited, relying on drugs that were not specifically developed for this disease and are often associated [...] Read more.

Background/Objectives: Leishmaniasis is an infectious disease caused by digenetic protozoa of the genus Leishmania, transmitted by infected female sandflies of the Phlebotominae subfamily. Current treatments are limited, relying on drugs that were not specifically developed for this disease and are often associated with high toxicity and elevated costs. Among alternative therapeutic strategies, antifolate compounds have been investigated due to their ability to inhibit dihydrofolate reductase (DHFR), an enzyme essential for folate metabolism in the parasite. However, the parasite circumvents DHFR inhibition through the activity of pteridine reductase-1 (PTR-1), which maintains folate reduction and ensures parasite survival. In this context, this study aimed to identify potential PTR-1 inhibitors in Leishmania major through in silico approaches. Methods: The methodology included virtual screening of molecular databases, Tanimoto similarity analysis, pharmacokinetic and toxicological predictions, and biological activity evaluation in silico. The most promising compounds were further analyzed via molecular docking. Results: The virtual screening resulted in 474 molecules, of which 4 structures (M601, M692, M700, and M703) showed high potential as PTR-1 inhibitors in Leishmania major throughout all stages of the methodology employed, especially in the results of molecular docking where they exhibited strong binding affinities and significant interactions with key residues of the target enzymes. Conclusions: This work provides a solid foundation for advancing these molecules into experimental validation, contributing to the development of safer and more effective therapeutic alternatives for the treatment of leishmaniasis. Full article

(This article belongs to the Special Issue Drug Target Exploration and Drug Design & Development Based on Small Molecule)

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18 pages, 5778 KB

Open AccessArticle

Pharmacologic Potential of Statins in Cancer Prevention: Colo-Rectal Cancer Risk in Dyslipidemic Patients from a Korean Nationwide Cohort

by Ho Suk Kang, Joo-Hee Kim, Heejin Kim, Joong Seob Lee, Hyo Geun Choi, Dae Myoung Yoo, Kyeong Min Han, Nan Young Kim, Kyueng-Whan Min and Mi Jung Kwon

Pharmaceuticals 2025, 18(8), 1236; https://doi.org/10.3390/ph18081236 - 21 Aug 2025

Viewed by 474

Abstract

Background/Objectives: Colorectal cancer (CRC) is a growing public health concern in South Korea, with incidence rising alongside dyslipidemia. Statins, widely prescribed for lipid control, have been proposed to reduce CRC risk, but evidence remains inconsistent, particularly in Asian populations. Methods: Using [...] Read more.

Background/Objectives: Colorectal cancer (CRC) is a growing public health concern in South Korea, with incidence rising alongside dyslipidemia. Statins, widely prescribed for lipid control, have been proposed to reduce CRC risk, but evidence remains inconsistent, particularly in Asian populations. Methods: Using Korean National Health Insurance Service data (2002–2019), we conducted a nested case–control study of 9920 CRC patients and 39,680 matched controls. To reduce confounding, we applied a matching process with a propensity score and overlap weighting based on demographic and clinical variables. Statin use within two years before CRC diagnosis was categorized by type (lipophilic vs. hydrophilic) and duration. Lifestyle data such as smoking and diet were not available. Results: Short-term statin use was associated with a 17% reduced CRC risk, particularly in younger, metabolically healthier Korean males. Lipophilic statins were consistently associated with lower CRC risk and mortality. However, hydrophilic statins showed mixed results: while short-term use lowered CRC risk, long-term use was linked to increased all-cause mortality. These associations varied by patient subgroup. Conclusion: Among Korean adults, short-term statin use—especially lipophilic agents—was associated with favorable CRC outcomes. However, the observational design, the absence of lifestyle data, and increased mortality linked to long-term hydrophilic statin use limit causal interpretation. Further research using clinically enriched or prospective datasets is warranted to validate these findings and guide personalized preventive strategies. Full article

(This article belongs to the Special Issue Pharmacotherapy of Dyslipidemias, 2nd Edition)

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42 pages, 1918 KB

Open AccessSystematic Review

Molecular Basis of BRAF Inhibitor Resistance in Melanoma: A Systematic Review

by Ilaria Cosci, Valentina Salizzato, Paolo Del Fiore, Jacopo Pigozzo, Valentina Guarneri, Simone Mocellin, Alberto Ferlin, Sara Mathlouthi, Luisa Piccin and Mariangela Garofalo

Pharmaceuticals 2025, 18(8), 1235; https://doi.org/10.3390/ph18081235 - 21 Aug 2025

Viewed by 965

Abstract

Background: Melanoma, the deadliest human skin cancer, frequently harbors activating BRAF mutations, with V600E being the most prevalent. These alterations drive constitutive activation of the MAPK pathway, promoting uncontrolled cell proliferation, survival, and dissemination. The advent of BRAFi and MEKi has significantly [...] Read more.

Background: Melanoma, the deadliest human skin cancer, frequently harbors activating BRAF mutations, with V600E being the most prevalent. These alterations drive constitutive activation of the MAPK pathway, promoting uncontrolled cell proliferation, survival, and dissemination. The advent of BRAFi and MEKi has significantly improved outcomes in BRAF V600-mutant melanoma. However, therapeutic resistance remains a major clinical barrier. Methods: This review integrates recent findings from preclinical and clinical studies to delineate resistance mechanisms to BRAF-targeted therapy. It categorizes resistance into primary (intrinsic), adaptive, and acquired forms, and analyzes their molecular underpinnings, including genetic and epigenetic alterations, pathway reactivation, and microenvironmental interactions. Results: Primary resistance is linked to pre-existing genetic and epigenetic changes that activate alternative signaling pathways, such as PI3K-AKT. Adaptive and acquired resistance includes secondary BRAF mutations, pathway redundancy, phenotype switching, and immune and stromal interactions. High-throughput sequencing has revealed novel mutations, including NRAS, NF1, and PTEN alterations, that contribute to resistance. Discussion: Understanding the multifaceted nature of resistance is critical to improving outcomes in advanced melanoma. This review highlights emerging strategies to overcome resistance, including combinatorial therapies, metabolic targeting, and biomarker-driven approaches, aiming to inform future therapeutic development and precision oncology strategies. Full article

(This article belongs to the Section Pharmacology)

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3 pages, 152 KB

Open AccessCorrection

Correction: Qin et al. Metabolites from the Dendrobium Endophyte Pseudomonas protegens CM-YJ44 Alleviate Insulin Resistance in HepG2 Cells via the IRS1/PI3K/Akt/GSK3β/GLUT4 Pathway. Pharmaceuticals 2025, 18, 817

by Luqi Qin, Yixia Zhou, Bei Fan, Jiahuan Zheng, Rao Diao, Jiameng Liu and Fengzhong Wang

Pharmaceuticals 2025, 18(8), 1234; https://doi.org/10.3390/ph18081234 - 21 Aug 2025

Viewed by 299

Abstract

In the original publication [...] Full article

(This article belongs to the Special Issue 20th Anniversary of Pharmaceuticals—Therapeutic Mechanisms of Nature Products against Insulin Resistance)

4 pages, 184 KB

Open AccessComment

Comment on Somnin et al. Study of Interactions Between Gadolinium-Based Contrast Agents and Collagen by Taylor Dispersion Analysis and Frontal Analysis Continuous Capillary Electrophoresis. Pharmaceuticals 2024, 17, 1633

by Nicol Guidolin, Federico Maisano, Fabio Tedoldi and Zsolt Baranyai

Pharmaceuticals 2025, 18(8), 1233; https://doi.org/10.3390/ph18081233 - 21 Aug 2025

Cited by 1 | Viewed by 334

Abstract

With great interest, we read the recent paper published in Pharmaceuticals, titled “Study of Interactions Between Gadolinium-Based Contrast Agents and Collagen by Taylor Dispersion Analysis and Frontal Analysis Continuous Capillary Electrophoresis” [...] Full article

(This article belongs to the Section Pharmaceutical Technology)

10 pages, 975 KB

Open AccessArticle

Neuromuscular System of Nematodes Is a Target of Synergistic Pharmacological Effects of Carvacrol and Geraniol

by Maja Stojković, Djordje S. Marjanović, Dragana Medić, Claude L. Charvet and Saša M. Trailović

Pharmaceuticals 2025, 18(8), 1232; https://doi.org/10.3390/ph18081232 - 20 Aug 2025

Viewed by 510

Abstract

Background: The active ingredients of essential plant oils appear as potentially effective antinematodal drugs or substances that can potentiate the action of already-existing anthelmintics. So far, we have verified that, aside from the direct effect on the neuromuscular system of nematodes, some of [...] Read more.

Background: The active ingredients of essential plant oils appear as potentially effective antinematodal drugs or substances that can potentiate the action of already-existing anthelmintics. So far, we have verified that, aside from the direct effect on the neuromuscular system of nematodes, some of them can potentiate the effects of drugs that are agonists or antagonists of nematode cholinergic receptors. Methods: In this study, the antinematodal effects of geraniol and carvacrol were compared, as well as their interaction in the experimental model Caenorhabditis elegans, on the contractile properties of Ascaris suum neuromuscular preparations and on the ACR-16 nicotinic acetylcholine receptor (nAChR) of A. suum expressed in Xenopus leavis oocytes. Results: The combination of geraniol and carvacrol showed a synergistic nematocidal effect in the tests on C. elegans, reducing the value of individual LC₅₀ by almost 10-times. This combination also exerted a synergistic inhibitory effect on the contractions of A. suum, significantly increased the EC₅₀ of ACh and reduced the maximal contractile effect. The synergistic interaction of these two monoterpenes on Asu-ACR-16 nAChR expressed in Xenopus oocytes resulted in a significant decrease in the maximum current, while the ACh EC₅₀ value remained unchanged. Conclusions: Our findings provide a better understanding of the mode of action of monoterpene plant compounds. The possible antiparasitic application of active ingredients of essential plant oils that exhibit a synergistic anthelmintic effect represents an important basis for the development of new drugs and new therapeutic procedures. Full article

(This article belongs to the Special Issue Advancements in the Study of Biological Activities of Plant Extracts and Components)

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24 pages, 1620 KB

Open AccessArticle

Novel Indole-Based Sulfonylhydrazones as Potential Anti-Breast Cancer Agents: Synthesis, In Vitro Evaluation, ADME, and QSAR Studies

by Violina T. Angelova, Rositsa Mihaylova, Zvetanka Zhivkova, Nikolay Vassilev, Boris Shivachev and Irini Doytchinova

Pharmaceuticals 2025, 18(8), 1231; https://doi.org/10.3390/ph18081231 - 20 Aug 2025

Viewed by 604

Abstract

Background: Breast cancer continues to pose a significant global health challenge despite advances in early detection and targeted therapies. The development of novel chemotherapeutic agents remains crucial, particularly those with selective cytotoxicity toward specific breast cancer subtypes. Methods: A series of [...] Read more.

Background: Breast cancer continues to pose a significant global health challenge despite advances in early detection and targeted therapies. The development of novel chemotherapeutic agents remains crucial, particularly those with selective cytotoxicity toward specific breast cancer subtypes. Methods: A series of ten hybrid indolyl-methylidene phenylsulfonylhydrazones and one bis-indole derivative were designed, synthesized, and structurally characterized using NMR and high-resolution mass spectrometry (HRMS). Prior to synthesis, in silico screening was performed to assess drug likeness and ADME-related properties. Single-crystal X-ray diffraction was conducted for compound 3e. The cytotoxic potential of the synthesized compounds was evaluated using the MTT assay against MCF-7 (ER-α⁺) and MDA-MB-231 (triple-negative) breast cancer cell lines. Additionally, quantitative structure–activity relationship (QSAR) analysis was conducted to identify key structural features contributing to activity. Results: Most compounds exhibited selective cytotoxicity against MCF-7 cells. Notably, compound 3b demonstrated the highest potency with an IC₅₀ of 4.0 μM and a selectivity index (SI) of 20.975. Compound 3f showed strong activity against MDA-MB-231 cells (IC₅₀ = 4.7 μM). QSAR analysis revealed that the presence of a non-substituted phenyl ring and specific indolyl substituents (5-methoxy, 1-acetyl, 5-chloro) significantly contributed to enhanced cytotoxic activity and ligand efficiency. Conclusion: The synthesized phenylsulfonylhydrazone hybrids exhibit promising and selective cytotoxicity, particularly against ER-α⁺ breast cancer cells. Structural insights from QSAR analysis provide a valuable foundation for the further optimization of this scaffold as a potential source of selective anticancer agents. Full article

(This article belongs to the Special Issue Advances in Hydrazone Compounds with Anticancer Activity)

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21 pages, 12972 KB

Open AccessReview

The Rise of a Legend: Lithium and the Extraordinary Story of Its Discovery

by Konstantinos N. Fountoulakis

Pharmaceuticals 2025, 18(8), 1230; https://doi.org/10.3390/ph18081230 - 20 Aug 2025

Viewed by 847

Abstract

Lithium is still the gold standard in the treatment of Bipolar disorder in adults. Despite the recent advances and the continuous increase in the use of antipsychotics and specific antiepileptics, it is still widely used despite not being promoted by the industry. Lithium [...] Read more.

Lithium is still the gold standard in the treatment of Bipolar disorder in adults. Despite the recent advances and the continuous increase in the use of antipsychotics and specific antiepileptics, it is still widely used despite not being promoted by the industry. Lithium was discovered in the early 19th century in a Swedish mine, and only a few decades later, it was discovered that it could be added to water so that urea could be dissolved with the formation of lithium urate. This was considered in the frame of the uric acid diathesis theory, which, during the 19th century, was considered a strong etiopathogenetic theory for many pathological conditions, including mental disorders. The first attempts to use lithium as a treatment modality in psychiatry appeared in the late 19th century by Hammond and the Lange brothers, and during the late 19th century and the early 20th century, lithium was used in various remedies and beverages until its toxicity became evident. Lithium was established as a valid treatment option for Bipolar disorder only during the second half of the 20th century after the works of John Cade, Mogens Schou, Poul Baastrup, and others who pursued a line of research, frequently against the scientific opinion of the majority of colleagues. Full article

(This article belongs to the Special Issue Lithium in Psychiatric Therapy: Celebrating 75th Anniversary)

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23 pages, 1138 KB

Open AccessArticle

Phytochemical Profile, Antioxidant Capacity, and Photoprotective Potential of Brazilian Humulus Lupulus

by Gabriela Catuzo Canonico Silva, Fabiana Pereira Alves da Silva, Gabriel Augusto Rodrigues Beirão, José Júnior Severino, Mariane de Almeida Machado, Marina Pereira da Silva Bocchio Barbosa, Giulia Boito Reyes, Max Emerson Rickli, Ana Daniela Lopes, Ezilda Jacomassi, Maria Graciela Iecher Faria Nunes, João Paulo Francisco, Beatriz Cervejeira Bolanho Barros, Juliana Silveira do Valle, José Eduardo Gonçalves and Zilda Cristiani Gazim

Pharmaceuticals 2025, 18(8), 1229; https://doi.org/10.3390/ph18081229 - 20 Aug 2025

Viewed by 446

Abstract

Background and Objectives: The cultivation of Humulus lupulus has been encouraged in Brazil, despite the country’s climate generally being unfavorable for its development. This study aimed to evaluate the chemical composition, antioxidant activity, and photoprotective potential of four H. lupulus varieties, Cascade, [...] Read more.

Background and Objectives: The cultivation of Humulus lupulus has been encouraged in Brazil, despite the country’s climate generally being unfavorable for its development. This study aimed to evaluate the chemical composition, antioxidant activity, and photoprotective potential of four H. lupulus varieties, Cascade, Columbus, Comet, and Nugget, cultivated in the northwestern region of Paraná State, Brazil. Methods: The varieties were grown in experimental plots. Crude extracts (CEs) of cones and leaves were obtained through dynamic maceration with solvent renewal (96% ethanol), followed by concentration in a rotary evaporator. Assays for sun protection factor (SPF), total phenolic content (TPC), total flavonoid content (TFC), ferric reducing antioxidant power (FRAP), 2.2-diphenyl-1-picrylhydrazyl (DPPH^•) radical scavenging activity, and 2.2′-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS^•⁺) were performed to assess antioxidant activity. Chemical profiling was performed using UHPLC-MS/MS. Results: UHPLC-MS/MS analysis revealed the presence of phenolic and organic acids, flavonoids, phenolic aldehydes, alkaloids, and α-benzopyrone-type lactones, with high concentrations of rutin (>500 µg/g) in both cones and leaves. Total phenolic content ranged from 69.70 to 95.95 µg gallic acid equivalent/mg CE; flavonoids from 170.53 to 696.67 µg quercetin equivalent/mg CE; DPPH^• EC₅₀ values ranged from 1.34 to 3.13 mg/mL; FRAP from 1.19 to 2.52 µM ferrous sulfate/mg; ABTS^•⁺ from 5.11 to 22.60 mM Trolox/mg CE; and SPF ranged from 16.02 to 39.48 in the CE of H. lupulus cones and leaves. Conclusions: These findings demonstrate that the cultivated varieties possess antioxidant and photoprotective properties, encouraging further studies to explore their potential applications. Full article

(This article belongs to the Special Issue Advancements in the Study of Biological Activities of Plant Extracts and Components)

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24 pages, 3945 KB

Open AccessArticle

Eupatorium lindleyanum DC Ameliorates Carbon Tetrachloride-Induced Hepatic Inflammation and Fibrotic Response in Mice

by Jinbao Yang, Yufei Wang, Lijuan Zhuo, Guijun Lu, Meiting Zhang, Jiabin Huang, Yehaomin Li, Wenwen Liu, Jing Qi, An Zhu and Zixiong Zhou

Pharmaceuticals 2025, 18(8), 1228; https://doi.org/10.3390/ph18081228 - 20 Aug 2025

Viewed by 505

Abstract

Background/Objectives: Eupatorium lindleyanum DC (Eup), a traditional Chinese medicinal herb, is widely used for treating inflammation-mediated diseases, including pneumonia. However, its potential therapeutic effects on inflammation-driven liver fibrosis remain to be elucidated. This study aimed to investigate the effects of Eup on [...] Read more.

Background/Objectives: Eupatorium lindleyanum DC (Eup), a traditional Chinese medicinal herb, is widely used for treating inflammation-mediated diseases, including pneumonia. However, its potential therapeutic effects on inflammation-driven liver fibrosis remain to be elucidated. This study aimed to investigate the effects of Eup on carbon tetrachloride (CCl₄)-induced liver fibrosis and elucidate its underlying mechanisms. Methods: The chemical constituents of Eup were analyzed using ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF-LC/MS). A CCl₄-induced liver fibrosis murine model and LX-2 cells were used in study. Serum biochemical assays, histological analysis, qRT-PCR, ELISA, and Western blot were used to assess Eup’s anti-inflammatory and anti-fibrotic properties. RNA sequencing (RNA-seq) was employed to identify potential mechanisms, with validation by Western blot. Results: 89 and 49 compounds were identified in Eup under positive and negative ion modes, respectively. In vivo, Eup treatment decreased collagen deposition and expression levels of fibrosis-related genes, including collagen I and α-smooth muscle actin. Additionally, Eup alleviated hepatic inflammation. In vitro, Eup inhibited FBS-induced hepatic stellate cell (HSCs) activation. Gene set enrichment analysis (GSEA) indicated that Eup significantly downregulated the platelet-derived growth factor (PDGF)/platelet-derived growth factor receptor-beta (PDGFR-β) signaling pathway, which was further validated in both CCl₄-induced fibrotic livers and PDGF-BB-activated HSCs using western blot. Conclusions: Eup attenuated liver fibrosis by inhibiting inflammation and suppressing HSCs activation via downregulating PDGF/PDGFR-β signaling pathway. Full article

(This article belongs to the Section Natural Products)

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15 pages, 1101 KB

Open AccessArticle

Multi-Objective Drug Molecule Optimization Based on Tanimoto Crowding Distance and Acceptance Probability

by Yuxin Wang, Cai Dai and Xiujuan Lei

Pharmaceuticals 2025, 18(8), 1227; https://doi.org/10.3390/ph18081227 - 20 Aug 2025

Viewed by 412

Abstract

Background: Traditional molecular optimization methods struggle with high data dependency and significant computational demands. Additionally, conventional genetic algorithms often produce solutions with high similarity, leading to potential local optima and reduced molecular diversity, thereby limiting the exploration of chemical space. Methods: [...] Read more.

Background: Traditional molecular optimization methods struggle with high data dependency and significant computational demands. Additionally, conventional genetic algorithms often produce solutions with high similarity, leading to potential local optima and reduced molecular diversity, thereby limiting the exploration of chemical space. Methods: In order to address the above issues, this paper proposes an improved genetic algorithm for multi-objective drug molecular optimization (MoGA-TA). It uses the Tanimoto similarity-based crowding distance calculation and a dynamic acceptance probability population update strategy. The study employs a decoupled crossover and mutation strategy within chemical space for molecular optimization. The proposed crowding distance calculation method better captures molecular structural differences, enhancing search space exploration, maintaining population diversity, and preventing premature convergence. The dynamic acceptance probability strategy balances exploration and exploitation during evolution. Optimization continues until a predefined stopping condition is met. To assess MoGA-TA’s effectiveness, the algorithm is evaluated using metrics like success rate, dominating hypervolume, geometric mean, and internal similarity. Results: Experimental results show that compared to the comparative method, MoGA-TA performs better in drug molecule optimization and significantly improves the efficiency and success rate. Conclusions: The method described in this paper has been proven to be an effective and reliable method for multi-objective molecular optimization tasks. Full article

(This article belongs to the Section Medicinal Chemistry)

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13 pages, 2063 KB

Open AccessArticle

SIRT1 Modulates the Photodynamic Anticancer Activity of 5,10,15-Triethoxycarbonyl P(V) Corrole in Hepatocellular Carcinoma

by Yan Liu, Jian Zheng, Jiayi Zhu, Xuemin Xian, Zhao Zhang and Haitao Zhang

Pharmaceuticals 2025, 18(8), 1226; https://doi.org/10.3390/ph18081226 - 20 Aug 2025

Viewed by 427

Abstract

Background: Hepatocellular carcinoma (HCC) remains a global health challenge with limited therapeutic efficacy. Photodynamic therapy (PDT) using 5,10,15-triethoxycarbonyl P(V) corrole (1-P) shows promise, but its molecular mechanisms and regulatory factors, particularly the role of SIRT1, are poorly understood. Methods: [...] Read more.

Background: Hepatocellular carcinoma (HCC) remains a global health challenge with limited therapeutic efficacy. Photodynamic therapy (PDT) using 5,10,15-triethoxycarbonyl P(V) corrole (1-P) shows promise, but its molecular mechanisms and regulatory factors, particularly the role of SIRT1, are poorly understood. Methods: The effects of 1-P combined with red light irradiation (625 nm) on HCC cells (HepG2, PLC/PRF5, MHCC97H) were evaluated via MTT, clonogenic assays, flow cytometry (apoptosis, mitochondrial membrane potential, ROS), and Western blotting (p53, Bax, Bcl-2, cleaved caspase-3, SIRT1). SIRT1-overexpressing cells and xenograft mouse models were used to validate its regulatory role. Results: 1-P with irradiation dose-dependently inhibited cell viability (IC50: 0.965–1.478 μM), suppressed clonogenicity, induced apoptosis (up to 68.8%), reduced mitochondrial membrane potential, and elevated ROS. Mechanistically, 1-P upregulated Bax/p53/cleaved caspase-3 and downregulated Bcl-2/SIRT1. SIRT1 overexpression rescued 1-P-induced apoptosis (30–50% reduction), restored mitochondrial function, and attenuated ROS accumulation. In vivo, 1-P significantly inhibited tumor growth in mice, but SIRT1 overexpression diminished this effect (p < 0.05). Conclusions: 1-P exerts potent photodynamic anticancer effects via mitochondrial dysfunction, oxidative stress, and apoptosis induction. SIRT1 is a critical modulator of 1-P activity, highlighting its potential as a therapeutic target to enhance PDT efficacy in HCC. Full article

(This article belongs to the Section Pharmacology)

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34 pages, 7320 KB

Open AccessReview

Benzimidazole–Pyrimidine Hybrids: Synthesis and Medicinal Properties

by Maria Marinescu and Christina Zalaru

Pharmaceuticals 2025, 18(8), 1225; https://doi.org/10.3390/ph18081225 - 19 Aug 2025

Viewed by 877

Abstract

Background: Heterocyclic compounds represent a key class of compounds in medicinal chemistry. Both benzimidazoles and pyrimidines are essential heterocycles in medicinal chemistry, with various therapeutic properties. Recent literature presents a series of hybrid heterocyclic compounds, as their medicinal properties are generally improved [...] Read more.

Background: Heterocyclic compounds represent a key class of compounds in medicinal chemistry. Both benzimidazoles and pyrimidines are essential heterocycles in medicinal chemistry, with various therapeutic properties. Recent literature presents a series of hybrid heterocyclic compounds, as their medicinal properties are generally improved compared to those of single heterocyclic rings. Methods: A literature search was conducted across relevant scientific literature from peer-reviewed sources, using keywords, including “benzimidazole”, “pyrimidine”, “Biginelli”, “benzimidazole-pyrimidine hybrids”, “anticancer”, “antiviral”, “antimicrobial”, and “anti-inflammatory”. Results: In this review, benzimidazole–pyrimidine hybrids are reported as anticancer, antimicrobial, antiviral, anti-inflammatory, analgesic, antiulcer, antidepressant, anti-Alzheimer’s, or antioxidant agents, with activities even better than those of existing drugs. The IC₅₀ values for these anticancer hybrids are in the nanomolar range, which signifies potent anticancer agents. It can be mentioned here that the anticancer hybrid Abemaciclib, as a CDK4/6 inhibitor for the treatment of certain types of breast cancer, was approved in 2017. The antimicrobial activity of these hybrids proved especially potent against a broad variety of infections, with MIC values in the range of µM or even nM. Moreover, these hybrids exhibited good antiviral properties against SARS-CoV-2, HIV-1, and the hepatitis C virus. The hybrids also functioned as JAK3 inhibitors, COX-1 inhibitors, and MAO-A inhibitors. Conclusions: This review presents synthesis methods of benzimidazole–pyrimidine hybrids, their medicinal properties, and SAR studies reported in the last 20 years. For almost every therapeutic activity, SAR studies have revealed the essential presence of a substituent on the aromatic rings or between the two benzimidazole and pyrimidine nuclei. Full article

(This article belongs to the Special Issue Novel Heterocyclic Compounds as Potential Anti-Inflammatory and/or Anticancer Agents)

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24 pages, 4654 KB

Open AccessArticle

Drug Combination Recommendation Model for Systemic Lupus Erythematosus and Antiphospholipid Syndrome

by Ling Wang, Zhengyang Zhang, Ziheng Zhang, Tie Hua Zhou and Keun Ho Ryu

Pharmaceuticals 2025, 18(8), 1224; https://doi.org/10.3390/ph18081224 - 19 Aug 2025

Viewed by 633

Abstract

Background: Systemic Lupus Erythematosus (SLE) and Antiphospholipid Syndrome (APS) are two common autoimmune disorders for which the choice of drug regimen is clinically crucial. However, due to drug-drug interactions and individual differences, the therapeutic process faces greater risks. Methods: In this [...] Read more.

Background: Systemic Lupus Erythematosus (SLE) and Antiphospholipid Syndrome (APS) are two common autoimmune disorders for which the choice of drug regimen is clinically crucial. However, due to drug-drug interactions and individual differences, the therapeutic process faces greater risks. Methods: In this study, we propose a drug recommendation model that combines drug combination frequency, risk assessment, and genetic interaction information with the aim of providing personalized, low-risk treatment options for patients with lupus erythematosus and antiphospholipid syndrome. We extracted drug combination frequencies and drug-gene interaction information from data sources, such as the MIMIC-III clinical database, Drug Bank, and Gene Expression Omnibus. The model comprehensively evaluates the frequency of drug combinations, the risk level, and the gene interaction information through a greedy algorithm to recommend the optimal drug alternatives. Results: The experimental results show that the model is able to effectively reduce the potential risk between drugs while ensuring the drug treatment effect. In addition, the performance evaluation of the drug recommendation model shows that the model performs well under different drug combinations and clinical scenarios, and can provide clinicians with effective drug substitution suggestions. Conclusions: This study provides an important theoretical basis and technical support for advancing the realization of personalized therapy and precision medicine. Full article

(This article belongs to the Section Pharmacology)

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24 pages, 5298 KB

Open AccessArticle

Therapeutic Potential of Ozonated Ocimum basilicum L. from Saudi Arabia: Phytochemical Characterization and Enhanced Bioactivities

by Husam Qanash, Sulaiman A. Alsalamah, Abdulrahman S. Bazaid, Mohammed Ibrahim Alghonaim, Amro Duhduh and Ibtisam Hudani

Pharmaceuticals 2025, 18(8), 1223; https://doi.org/10.3390/ph18081223 - 19 Aug 2025

Viewed by 542

Abstract

Background/Objectives: Medicinal plants are an abundant source of bioactive molecules, particularly in arid environments, such as Saudi Arabia, where Ocimum basilicum L. (Saudi basil) has long been used for its therapeutic properties. This study aimed to examine the phytochemical profile and bioactivities [...] Read more.

Background/Objectives: Medicinal plants are an abundant source of bioactive molecules, particularly in arid environments, such as Saudi Arabia, where Ocimum basilicum L. (Saudi basil) has long been used for its therapeutic properties. This study aimed to examine the phytochemical profile and bioactivities of non-ozonated (untreated) and ozonated methanolic extracts of O. basilicum and to determine whether ozonation enhances their biological effects, with a focus on antidiabetic, anti-Alzheimer, anti-inflammatory, antimicrobial, and cytotoxic properties. Methods: Fresh leaves of O. basilicum were extracted with methanol, subjected to ozonation, and analyzed by HPLC. In vitro assays were conducted to evaluate α-amylase, α-glucosidase, and BChE inhibition, RBC membrane stabilization, antibacterial activity against Helicobacter pylori and cytotoxicity using normal lung fibroblasts (WI-38) and human colorectal adenocarcinoma cell line (Caco-2). Results: Ozonation modified the phytochemical profile, enriching chlorogenic and rosmarinic acids. Ozonated extracts exhibited stronger inhibition of α-amylase with an IC₅₀ of 5.09 µg/mL compared to 13.6 µg/mL of untreated Saudi basil and α-glucosidase (IC₅₀ 6.15 µg/mL vs. 9.42 µg/mL). They also showed enhanced BChE inhibition with an IC₅₀ of 13.4 µg/mL compared to 31.8 µg/mL of non-ozonated extract. In addition, ozonated extracts produced significant anti-inflammatory effects by stabilizing RBCs, with an IC₅₀ of 8.04 µg/mL compared to 8.44 µg/mL for untreated extracts and 4.41 µg/mL for indomethacin. Ozonated extracts produced larger H. pylori inhibition zones (26.7 mm) and an MBC/MIC ratio of 1. Cytotoxicity testing revealed that ozonated extracts were less toxic to WI-38 cells, with IC₅₀ values of 437.89 µg/mL versus 191.06 µg/mL, and 149.14 µg/mL compared to 103.7 µg/mL of untreated Saudi basil in Caco-2 cells. Conclusions: Ozonation enriches the phytochemical composition of O. basilicum, enhancing antidiabetic, neuroprotective, anti-inflammatory, and antibacterial activities while reducing cytotoxicity on normal cells. These findings support the potential of ozonated O. basilicum as a safe and promising natural therapeutic candidate for metabolic, neurodegenerative, and infectious diseases. Full article

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

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28 pages, 2605 KB

Open AccessReview

Exercise-Induced Muscle–Fat Crosstalk: Molecular Mediators and Their Pharmacological Modulation for the Maintenance of Metabolic Flexibility in Aging

by Amelia Tero-Vescan, Hans Degens, Antonios Matsakas, Ruxandra Ștefănescu, Bianca Eugenia Ősz and Mark Slevin

Pharmaceuticals 2025, 18(8), 1222; https://doi.org/10.3390/ph18081222 - 19 Aug 2025

Viewed by 1121

Abstract

Regular physical activity induces a dynamic crosstalk between skeletal muscle and adipose tissue, modulating the key molecular pathways that underlie metabolic flexibility, mitochondrial function, and inflammation. This review highlights the role of myokines and adipokines—particularly IL-6, irisin, leptin, and adiponectin—in orchestrating muscle–adipose tissue [...] Read more.

Regular physical activity induces a dynamic crosstalk between skeletal muscle and adipose tissue, modulating the key molecular pathways that underlie metabolic flexibility, mitochondrial function, and inflammation. This review highlights the role of myokines and adipokines—particularly IL-6, irisin, leptin, and adiponectin—in orchestrating muscle–adipose tissue communication during exercise. Exercise stimulates AMPK, PGC-1α, and SIRT1 signaling, promoting mitochondrial biogenesis, fatty acid oxidation, and autophagy, while also regulating muscle hypertrophy through the PI3K/Akt/mTOR and Wnt/β-catenin pathways. Simultaneously, adipose-derived factors like leptin and adiponectin modulate skeletal muscle metabolism via JAK/STAT3 and AdipoR1-mediated AMPK activation. Additionally, emerging exercise mimetics such as the mitochondrial-derived peptide MOTS-c and myostatin inhibitors are highlighted for their roles in increasing muscle mass, the browning of white adipose tissue, and improving systemic metabolic function. The review also addresses the role of anti-inflammatory compounds, including omega-3 polyunsaturated fatty acids and low-dose aspirin, in mitigating NF-κB and IL-6 signaling to protect mitochondrial health. The resulting metabolic flexibility, defined as the ability to efficiently switch between lipid and glucose oxidation, is enhanced through repeated exercise, counteracting age- and disease-related mitochondrial and functional decline. Together, these adaptations demonstrate the importance of inter-tissue signaling in maintaining energy homeostasis and preventing sarcopenia, obesity, and insulin resistance. Finally, here we propose a stratified treatment algorithm based on common age-related comorbidities, offering a framework for precision-based interventions that may offer a promising strategy to preserve metabolic plasticity and delay the age-associated decline in cardiometabolic health. Full article

(This article belongs to the Section Pharmacology)

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15 pages, 2101 KB

Open AccessArticle

Anesthetic-Induced Disruption of Amino Acid and Carnitine Profiles: A Metabolomic Comparison of Propofol and Thiopental in Hepatocytes

by Veli F. Pehlivan, Basak Pehlivan, Erdogan Duran, Ismail Koyuncu and Hamza Erdogdu

Pharmaceuticals 2025, 18(8), 1221; https://doi.org/10.3390/ph18081221 - 19 Aug 2025

Viewed by 427

Abstract

Background/Objectives: Propofol and Thiopental are widely used anesthetic agents, yet their cumulative and high-dose effects on hepatic metabolism remain insufficiently characterized. This study aimed to evaluate the impact of supra-therapeutic concentrations of these agents on carnitine and amino acid metabolism in AML12 hepatocytes, [...] Read more.

Background/Objectives: Propofol and Thiopental are widely used anesthetic agents, yet their cumulative and high-dose effects on hepatic metabolism remain insufficiently characterized. This study aimed to evaluate the impact of supra-therapeutic concentrations of these agents on carnitine and amino acid metabolism in AML12 hepatocytes, with a focus on their toxicometabolic profiles. Methods: AML12 mouse hepatocytes were exposed to escalating concentrations (2.5–500 µg/mL) of Propofol and Thiopental to assess cytotoxicity. IC₅₀ values (~255 µg/mL for both) were determined, and two high-dose concentrations (100 µg/mL and 200 µg/mL) were selected for metabolic profiling. Cell viability was assessed via the MTT assay. Intracellular carnitine and amino acid levels were quantified using LC-MS/MS. Statistical analyses included one-way ANOVA with post hoc tests, unpaired t-tests, and effect size estimations (Cohen’s d). Results: Propofol significantly suppressed carnitine metabolism in a dose-dependent manner, with a 79% reduction in free carnitine (C0), indicative of impaired mitochondrial β-oxidation. Thiopental, however, preserved or partially restored several acylcarnitines, including C16:1. While both agents reduced intracellular amino acid levels, 200 µg/mL Thiopental partially restored key metabolites such as glutamine, alanine, and histidine. Propofol exhibited broader metabolic suppression. Effect size analysis further confirmed the stronger inhibitory impact of Propofol. Conclusion: Although the concentrations used exceed typical clinical plasma levels, they may reflect prolonged or high-dose exposure scenarios observed in ICU settings. The findings highlight distinct toxicometabolic signatures for each agent and underscore the utility of metabolite profiling in modeling anesthetic-induced hepatic stress and guiding anesthetic selection in vulnerable populations. Full article

(This article belongs to the Section Pharmacology)

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24 pages, 2238 KB

Open AccessReview

Antifungal Drugs for the Treatment of Invasive Fungal Infections—A Limited Therapeutic Toolbox Facing Growing Resistances

by Victoria Susan, Mylène Lang, Marcela Sabou and Line Bourel-Bonnet

Pharmaceuticals 2025, 18(8), 1220; https://doi.org/10.3390/ph18081220 - 19 Aug 2025

Viewed by 1243

Abstract

Invasive fungal infections (IFIs) are one of the most significant public health challenges worldwide. Yet, research and communication thereof were left behind for a long time, until the WHO published a priority pathogens list to guide research, development, and public health action in [...] Read more.

Invasive fungal infections (IFIs) are one of the most significant public health challenges worldwide. Yet, research and communication thereof were left behind for a long time, until the WHO published a priority pathogens list to guide research, development, and public health action in October 2022. Indeed, due to the rising number of immunocompromised patients at risk and the high level of morbidity, mortality, and economic burden they entail, especially in low- and middle-income countries, IFIs are a serious public health threat. Fungal infections due to dimorphic fungi face additional challenges such as limited knowledge outside of endemic areas and restricted availability of antifungal molecules in areas affected by these infections. The number of related deaths per year is estimated at 2.5 million, but non-governmental organisations make a wider estimation, due to the difficulties in early in vitro diagnostic and troublesome collection and analysis of epidemiological data. Despite this fact, the therapeutic toolbox addressing these infections remains limited, with only four main families of molecules available so far. The antifungal therapeutic supply is composed of very toxic polyenes, the weakly selective and nearly unused 5-fluorocytosine, and azoles, some of which are becoming increasingly inefficient against IFIs. In the 2000–2020s, the fourth arising family consisted of safer semisynthetic echinocandins. Unfortunately, nowadays, more and more fungal isolates encountered in intensive care units exhibit a low susceptibility to echinocandins or are even multiresistant. In this review, we expose the current treatments available to fight against invasive fungal infections. We recall the discovery and physico-chemical aspects of these substances leading to structure/activity and structure/properties relationships. We particularly focus on the to-date resistances and their molecular mechanisms. We finally list some of the most relevant antifungal drug candidates, as they were freshly overviewed by the World Health Organization in April 2025, highlighting the importance of the molecular dimension of this pursuit toward the expansion of the antifungal therapeutic toolbox. Full article

(This article belongs to the Section Pharmacology)

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2 pages, 446 KB

Open AccessCorrection

Correction: Malebari et al. Synthesis and Antiproliferative Evaluation of 3-Chloroazetidin-2-ones with Antimitotic Activity: Heterocyclic Bridged Analogues of Combretastatin A-4. Pharmaceuticals 2021, 14, 1119

by Azizah M. Malebari, Shu Wang, Thomas F. Greene, Niamh M. O’Boyle, Darren Fayne, Mohemmed Faraz Khan, Seema M. Nathwani, Brendan Twamley, Thomas McCabe, Daniela M. Zisterer and Mary J. Meegan

Pharmaceuticals 2025, 18(8), 1219; https://doi.org/10.3390/ph18081219 - 19 Aug 2025

Viewed by 296

Abstract

In the original publication [...] Full article

(This article belongs to the Section Medicinal Chemistry)

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2 pages, 991 KB

Open AccessCorrection

Correction: Wang et al. Antiproliferative and Tubulin-Destabilising Effects of 3-(Prop-1-en-2-yl)azetidin-2-Ones and Related Compounds in MCF-7 and MDA-MB-231 Breast Cancer Cells. Pharmaceuticals 2023, 16, 1000

by Shu Wang, Azizah M. Malebari, Thomas F. Greene, Shubhangi Kandwal, Darren Fayne, Seema M. Nathwani, Daniela M. Zisterer, Brendan Twamley, Niamh M. O’Boyle and Mary J. Meegan

Pharmaceuticals 2025, 18(8), 1218; https://doi.org/10.3390/ph18081218 - 19 Aug 2025

Viewed by 313

Abstract

In the original publication [...] Full article

(This article belongs to the Section Medicinal Chemistry)

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13 pages, 506 KB

Open AccessReview

Oritavancin a Therapeutic Option for Periprosthetic Joint Infections in Selected Cases: A Comprehensive Review

by Rares-Mircea Birlutiu and Victoria Birlutiu

Pharmaceuticals 2025, 18(8), 1217; https://doi.org/10.3390/ph18081217 - 18 Aug 2025

Viewed by 631

Abstract

Background: Periprosthetic joint infections (PJIs) remain among the most challenging complications in orthopedic surgery, often requiring prolonged antibiotic therapy and complex surgical interventions. Oritavancin, a long-acting semisynthetic lipoglycopeptide approved for acute bacterial skin and skin structure infections, has emerged as a potential off-label [...] Read more.

Background: Periprosthetic joint infections (PJIs) remain among the most challenging complications in orthopedic surgery, often requiring prolonged antibiotic therapy and complex surgical interventions. Oritavancin, a long-acting semisynthetic lipoglycopeptide approved for acute bacterial skin and skin structure infections, has emerged as a potential off-label agent in PJI treatment due to its favorable pharmacokinetic properties, potent Gram-positive coverage, and documented antibiofilm activity. Objectives: This comprehensive review aims to assess the current clinical and preclinical data regarding the potential use of oritavancin in the management of PJIs. Methods: A comprehensive literature search was conducted in three major databases. Results: Six studies were included. In vitro data demonstrated strong activity of oritavancin against methicillin-resistant Staphylococcus aureus and S. epidermidis biofilms, particularly in synergy with rifampin. Clinical reports described successful outcomes in both acute and chronic PJI cases, including those with limited surgical options. Weekly or monthly dosing regimens were well-tolerated and effective in suppressive and curative contexts. Adverse events were infrequent but included infusion-related reactions. Conclusions: Oritavancin represents a promising adjunct or alternative to conventional antimicrobial regimens in PJIs, particularly for outpatient management or in patients with multidrug-resistant Gram-positive infections. Further prospective studies are needed to define its role, optimal dosing, and long-term efficacy in this complex clinical setting. Full article

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

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20 pages, 4379 KB

Open AccessArticle

Network Pharmacology and Experiment Verification-Based Strategy for Exploring the Mechanisms of Shuqing Granule in the Treatment of COVID-19

by Xiaoping Guo, Haoyu Zheng, Yiming An, Yuemeng Song, Tianqi Liu, Zhengjie Zhou, Chuangui Liu, Guoqiang Wang and Fang Wang

Pharmaceuticals 2025, 18(8), 1216; https://doi.org/10.3390/ph18081216 - 18 Aug 2025

Viewed by 454

Abstract

Background/Objectives: Coronavirus disease 2019 (COVID-19) has been a global pandemic since 2019, but effective therapeutic treatments for it remain limited. Shuqing Granule (SG) is a traditional Chinese medicine containing ingredients such as indirubin, shinpterocarpin, naringenin, and quercetin. It exhibits anti-inflammatory and antiviral activities [...] Read more.

Background/Objectives: Coronavirus disease 2019 (COVID-19) has been a global pandemic since 2019, but effective therapeutic treatments for it remain limited. Shuqing Granule (SG) is a traditional Chinese medicine containing ingredients such as indirubin, shinpterocarpin, naringenin, and quercetin. It exhibits anti-inflammatory and antiviral activities as well as broad-spectrum antiviral effects, yet its potential role in the treatment of COVID-19 remains unclear. This study thus aimed to explore the therapeutic effects of SG on COVID-19, with a focus on its potential anti-SARS-CoV-2 activity linked to these bioactive ingredients. Methods: The potential therapeutic ability of SG was investigated by combining network pharmacology, molecular docking, and experimental verification. First, key ingredients in SG and their corresponding targets, as well as COVID-19-related targets, were identified. Then, enrichment analyses were performed to highlight potential key pathways. Additionally, molecular docking was conducted to assess the binding capacity of the key ingredients to ACE2. Finally, experiments such as Western blot and ELISA were conducted to verify the effect of SG. Results: The results showed that 15 key ingredients such as quercetin in SG could affect overlapping targets such as RELA. Molecular docking results showed that key ingredients in SG, such as isoliquiritigenin, formononetin, shinpterocarpin, indirubin, naringenin, kaempferol, and 7-Methoxy-2-methylisoflavone, might bind to angiotensin-converting enzyme II (ACE2)—a critical receptor in the process of COVID-19 infection—thereby exerting antiviral effects. Experiments such as Western blot and ELISA further demonstrated that SG could reduce inflammation induced by the SARS-CoV-2 S1 protein by 50%. This effect might be achieved by downregulating ACE2 expression by 1.5 times and inhibiting the NF-κB signaling pathway. Conclusions: This study confirmed that SG has potential as a candidate for COVID-19 treatment. It also provided a new approach for the application of traditional Chinese medicine in combating the virus. Full article

(This article belongs to the Section Pharmacology)

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22 pages, 1009 KB

Open AccessReview

Targeted Alpha Therapy: Exploring the Clinical Insights into [225Ac]Ac-PSMA and Its Relevance Compared with [177Lu]Lu-PSMA in Advanced Prostate Cancer Management

by Wael Jalloul, Vlad Ghizdovat, Alexandra Saviuc, Despina Jalloul, Irena Cristina Grierosu and Cipriana Stefanescu

Pharmaceuticals 2025, 18(8), 1215; https://doi.org/10.3390/ph18081215 - 18 Aug 2025

Viewed by 1245

Abstract

Targeted alpha therapy (TAT) has recently emerged as a highly promising approach for the management of metastatic castration-resistant prostate cancer (mCRPC), especially in patients with disease progression despite standard treatments. Among alpha-emitter radiopharmaceuticals, actinium-225-labelled prostate-specific membrane antigen ([225Ac]Ac-PSMA) has shown remarkable potential due [...] Read more.

Targeted alpha therapy (TAT) has recently emerged as a highly promising approach for the management of metastatic castration-resistant prostate cancer (mCRPC), especially in patients with disease progression despite standard treatments. Among alpha-emitter radiopharmaceuticals, actinium-225-labelled prostate-specific membrane antigen ([225Ac]Ac-PSMA) has shown remarkable potential due to its high linear energy transfer (LET), short path length, and ability to induce potent, localised cytotoxic effects. This review summarises current clinical evidence regarding [225Ac]Ac-PSMA radioligand therapy (RLT), emphasising its efficacy, safety profile, and position relative to beta-emitter therapy with lutetium-177 ([177Lu]Lu-PSMA). Data from compassionate-use programs and small clinical trials demonstrate that [225Ac]Ac-PSMA produces significant biochemical and imaging responses, including > 50% declines in prostate-specific antigen (PSA) and lesion regression on [68Ga]Ga-PSMA PET/CT, even in heavily pre-treated mCRPC cohorts. Xerostomia, renal toxicity, and haematological adverse effects remain the main safety challenges, necessitating optimisation of patient selection, dosing strategies, and salivary gland protection protocols. Compared with [177Lu]Lu-PSMA, [225Ac]Ac-PSMA appears effective even in cases of beta-refractory disease, highlighting its complementary role rather than a competitive alternative. However, limited availability, high production costs, and the lack of large-scale, randomised trials hinder widespread clinical adoption. Future directions include combination protocols, improved radiopharmaceutical design, and trials evaluating its use in earlier disease stages. This review provides a comprehensive overview of the clinical aspects of [225Ac]Ac-PSMA RLT and its evolving role in advanced prostate cancer management. Full article

(This article belongs to the Special Issue Production, Development and Theranostic Applications of Radiopharmaceuticals for Nuclear Medicine)

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42 pages, 31030 KB

Open AccessArticle

Unlocking Therapeutic Potential of Novel Thieno-Oxazepine Hybrids as Multi-Target Inhibitors of AChE/BChE and Evaluation Against Alzheimer’s Disease: In Vivo, In Vitro, Histopathological, and Docking Studies

by Khulood H. Oudah, Mazin A. A. Najm, Triveena M. Ramsis, Maha A. Ebrahim, Nirvana A. Gohar, Karema Abu-Elfotuh, Ehsan Khedre Mohamed, Ahmed M. E. Hamdan, Amira M. Hamdan, Reema Almotairi, Shaimaa R. Abdelmohsen, Khaled Ragab Abdelhakim, Abdou Mohammed Ahmed Elsharkawy and Eman A. Fayed

Pharmaceuticals 2025, 18(8), 1214; https://doi.org/10.3390/ph18081214 - 17 Aug 2025

Viewed by 830

Abstract

Background: Alzheimer’s disease (AD) is largely linked with oxidative stress, the accumulation of amyloid-β plaques, and hyperphosphorylated τ-protein aggregation. Alterations in dopaminergic and serotonergic neurotransmission have also been implicated in various AD-related symptoms. Methods: To explore new therapeutic agents, a [...] Read more.

Background: Alzheimer’s disease (AD) is largely linked with oxidative stress, the accumulation of amyloid-β plaques, and hyperphosphorylated τ-protein aggregation. Alterations in dopaminergic and serotonergic neurotransmission have also been implicated in various AD-related symptoms. Methods: To explore new therapeutic agents, a series of bicyclic and tricyclic thieno-oxazepine derivatives were synthesized as potential acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. The resultant compounds were purified via HPLC and characterized using spectral analysis techniques. Histopathological examinations, other antioxidants, and anti-inflammatory biomarkers were evaluated, and in silico ADMET calculations were performed for synthetic hybrids. Molecular docking was utilized to validate the new drugs’ binding mechanisms. Results: The most powerful AChE inhibitors were 14 and 16, with respective values of IC₅₀ equal to 0.39 and 0.76 µM. Derivative 15 demonstrated remarkable BChE-inhibitory efficacy, on par with tacrine, with IC₅₀ values of 0.70 µM. Hybrids 13 and 15 showed greater selectivity towards BChE, despite substantial inhibition of AChE. Compounds 13 and 15 reduced escape latency and raised residence time, with almost equal activity to donepezil. Conclusions: According to these findings, the designed hybrids constitute multipotent lead compounds that could be used in the creation of novel anti-AD medications. Full article

(This article belongs to the Special Issue Heterocyclic Chemistry in Modern Drug Development)

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19 pages, 417 KB

Open AccessReview

Analytical Biomarkers for Inflammation Status Monitoring of Psychotropic and Antiepileptic Drugs

by Wiktoria Jiers, Karina Sommerfeld-Klatta, Mehmet Gumustas, Paul Mozdziak, Magdalena Łukasik-Głębocka, Artur Teżyk, Zbigniew Żaba, Czesław Żaba and Hanna Piotrowska-Kempisty

Pharmaceuticals 2025, 18(8), 1213; https://doi.org/10.3390/ph18081213 - 17 Aug 2025

Viewed by 631

Abstract

In recent years, an increasing amount of research has investigated the impact of chronic inflammation on the development and progression of both neurological and psychiatric disorders, including epilepsy, depression, schizophrenia, and bipolar disorder. Moreover, growing attention is being paid to how inflammatory processes [...] Read more.

In recent years, an increasing amount of research has investigated the impact of chronic inflammation on the development and progression of both neurological and psychiatric disorders, including epilepsy, depression, schizophrenia, and bipolar disorder. Moreover, growing attention is being paid to how inflammatory processes contribute to disease mechanisms, influence symptom severity, and interact with pharmacological treatments in these conditions. Changes in the levels of inflammatory biomarkers, such as cytokines and C-reactive protein, may signal the early stages of neurological disorder development. Furthermore, specific biomarker profiles have been identified for individual diseases, and chronic treatment may affect their blood levels. Over the last two decades, significant progress in the study of inflammatory biomarkers in psychiatric disorders and epilepsy has been achieved, demonstrating an association between biomarkers with symptoms, a potential prognostic role, and possible use in personalising therapy. Furthermore, widely used methods for biomarker evaluation, such as immunoenzymatic assays and flow cytometry, remain essential tools for current research. Despite numerous indications of the importance of inflammation in psychiatry and neurology, the available studies are characterised by considerable heterogeneity in terms of both population selection and methodology. Based on the available data, inflammatory biomarkers represent a promising diagnostic and therapeutic tool for epilepsy and psychiatric disorders. Although existing studies suggest a correlation between inflammation and the symptoms of various disorders, inconsistent results highlight the need for further research to enable wider implementation of these findings in psychiatric and epilepsy practice. Advancing knowledge of inflammatory biomarkers is essential for improving treatment outcomes and promoting the development of targeted interventions. Full article

(This article belongs to the Special Issue Potential Pharmacotherapeutic Targets in Neurodegenerative Diseases)

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18 pages, 690 KB

Open AccessReview

Old Therapy, New Questions: Rethinking Phlebotomy in a Pharmacologic Landscape

by Andrea Duminuco, Patrick Harrington, Vittorio Del Fabro, Elvira Scalisi, Gabriella Santuccio, Annalisa Santisi, Arianna Sbriglione, Bruno Garibaldi, Uros Markovic, Francesco Di Raimondo, Giuseppe Alberto Palumbo, Novella Pugliese and Calogero Vetro

Pharmaceuticals 2025, 18(8), 1212; https://doi.org/10.3390/ph18081212 - 16 Aug 2025

Viewed by 1029

Abstract

Therapeutic phlebotomy remains a key intervention in the management of erythrocytosis and iron overload disorders, particularly polycythemia vera (PV) and hereditary hemochromatosis. Despite its historical origins as an ancient practice, venesection continues to be recommended in international guidelines for the reduction of hematocrit [...] Read more.

Therapeutic phlebotomy remains a key intervention in the management of erythrocytosis and iron overload disorders, particularly polycythemia vera (PV) and hereditary hemochromatosis. Despite its historical origins as an ancient practice, venesection continues to be recommended in international guidelines for the reduction of hematocrit and iron burden, thereby mitigating thrombotic and organ-related complications. However, the evolving landscape of targeted pharmacologic therapies is reshaping the therapeutic paradigm. This review examines the current role of therapeutic phlebotomy, with a particular focus on PV, outlining its physiological rationale, clinical benefits, and well-documented limitations—including iron deficiency, procedural burden, and incomplete hematocrit control between sessions. Comparative insights are provided between phlebotomy and red cell apheresis, highlighting differences in efficacy, tolerability, and accessibility. The emergence of disease-modifying agents—such as interferons, JAK inhibitors, hepcidin mimetics, and epigenetic modulators like givinostat and bomedemstat—promises more sustained hematologic control with the potential to reduce or eliminate the need for repeated phlebotomies. While phlebotomy remains indispensable in early-stage or low-risk PV, its future utility will likely shift toward complementary or bridge therapy in the context of individualized, pharmacologically driven strategies, redefining the role of phlebotomy in the era of precision medicine. Full article

(This article belongs to the Section Pharmacology)

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Pharmaceuticals, Volume 18, Issue 8 (August 2025) – 162 articles

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