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26 pages, 3951 KiB  
Article
Exploring the Bioactive Potential and Chemical Profile of Schinus molle Essential Oil: An Integrated In Silico and In Vitro Evaluation
by Rómulo Oses, Matías Ferrando, Flavia Bruna, Patricio Retamales, Myriam Navarro, Katia Fernández, Waleska Vera, María José Larrazábal, Iván Neira, Adrián Paredes, Manuel Osorio, Osvaldo Yáñez, Martina Jacobs and Jessica Bravo
Plants 2025, 14(15), 2449; https://doi.org/10.3390/plants14152449 - 7 Aug 2025
Abstract
Chilean Schinus molle has been used in traditional medicine for effects such as antibacterial, antifungal, anti-inflammatory, analgesic, antiviral, antitumoral, antioxidant, antispasmodic, astringent, antipyretic, cicatrizant, cytotoxic, diuretic, among others. In this study, we evaluated the pharmacological potential of Schinus molle seed essential oil extract [...] Read more.
Chilean Schinus molle has been used in traditional medicine for effects such as antibacterial, antifungal, anti-inflammatory, analgesic, antiviral, antitumoral, antioxidant, antispasmodic, astringent, antipyretic, cicatrizant, cytotoxic, diuretic, among others. In this study, we evaluated the pharmacological potential of Schinus molle seed essential oil extract (SM_EO) through in vitro and in silico approaches. In vitro, the antioxidant potential was analyzed, and antitumor activity was evaluated in non-tumor and human epithelial tumor cell lines. Caenorhabditis elegans was used as a model for evaluating toxicity, and the chemical composition of the SM_EO was analyzed using gas chromatography–mass spectrometry. The oil contained four major monoterpenes: α-phellandrene (34%), β-myrcene (23%), limonene (13%), and β-phellandrene (7%). Based on quantum mechanical calculations, the reactivity of the molecules present in the SM_EO was estimated. The results indicated that α- phellandrene, β-phellandrene, and β-myrcene showed the highest nucleophilic activity. In addition, the compounds following these as candidates for antioxidant and antiproliferative activities were α-phellandrene, β-phellandrene, ρ-cymene, sabinene, caryophyllene, l-limonene, and α-pinene, highlighting β-myrcene. Based on ADME-Tox properties, it is feasible to use these compounds as new drug candidates. Moreover, the antibacterial activity MIC value obtained for B. cereus was equivalent to 2 μg/mL, and for Y. enterocolitica, S. enteritidis, and S. typhimurium, the MIC value was 32.5 μg/μL. SM_EO could selectively inhibit the proliferation of human epithelial mammary tumor MCF7 cells treated with SM_EOs at 64 and 16 ug/mL—a significant increase in BCL-2 in a dose-dependent manner—and showed low toxicity against Caenorhabditis elegans (from 10 to 0.078 mg·mL−1). These findings suggest that SM_EO may be a potential source of bioactive compounds, encouraging further investigation for applications in veterinary medicine, cosmetics, and sanitation. Full article
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23 pages, 882 KiB  
Review
Toward Precision Medicine: Molecular Biomarkers of Response to Tofacitinib in Inflammatory Bowel Disease
by Anja Bizjak, Boris Gole, Gregor Jezernik, Uroš Potočnik and Mario Gorenjak
Genes 2025, 16(8), 908; https://doi.org/10.3390/genes16080908 - 29 Jul 2025
Viewed by 307
Abstract
Ulcerative colitis (UC), a subtype of inflammatory bowel disease (IBD), is a chronic, relapsing inflammatory condition that significantly impairs the patient’s quality of life. While biologics have transformed disease management, a substantial number of patients remain unresponsive or lose efficacy over time. Tofacitinib [...] Read more.
Ulcerative colitis (UC), a subtype of inflammatory bowel disease (IBD), is a chronic, relapsing inflammatory condition that significantly impairs the patient’s quality of life. While biologics have transformed disease management, a substantial number of patients remain unresponsive or lose efficacy over time. Tofacitinib (TOFA), an oral Janus kinase (JAK) inhibitor, introduces a novel therapeutic class of small-molecule drugs with a unique oral administration route, offering enhanced patient convenience and broader accessibility compared to parenterally administered biologics. As the first oral treatment approved for moderate to severe UC in years, TOFA acts by modulating the JAK/STAT pathway, influencing critical inflammatory mediators such as IL-6, IL-17, and IFN-γ. However, response rates are variable and appear dose-dependent, with up to 60% of patients showing inadequate therapeutic outcomes. This review represents the first comprehensive synthesis focused specifically on biomarkers of TOFA response in UC. Drawing on multi-omics data—epigenomics, transcriptomics, proteomics, and cellular profiling, we highlight emerging predictors of responsiveness, including CpG methylation signatures (e.g., LRPAP1 and FGFR2), transcriptomic regulators (e.g., REG3A and CLDN3), immune and epithelial cell shifts, and the cationic transporter MATE1. TOFA demonstrates a dual mechanism by modulating immune responses while supporting epithelial barrier restoration. Despite being promising, TOFA’s dose-dependent efficacy and interpatient variability underscore the critical need for non-invasive, predictive biomarkers to guide personalized treatment. As the first review of its kind, this work establishes a basis for precision medicine approaches to optimize the clinical utility of TOFA in UC management. Full article
(This article belongs to the Section Human Genomics and Genetic Diseases)
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31 pages, 4404 KiB  
Review
Recent Advances in the Use of Ganoderma lucidum and Coriolus versicolor Mushrooms to Enhance the Anticancer Efficacy of EGFR-Targeted Drugs in Lung Cancer
by Hang Zhang, Longling Wang, Yuet Wa Chan, William C. Cho, Zhong Zuo and Kenneth K. W. To
Pharmaceutics 2025, 17(7), 917; https://doi.org/10.3390/pharmaceutics17070917 - 15 Jul 2025
Viewed by 717
Abstract
Lung cancer is the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) is the major subtype, accounting for more than 85% of all lung cancer cases. Recent advances in precision oncology have allowed NSCLC patients bearing specific oncogenic epidermal growth [...] Read more.
Lung cancer is the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) is the major subtype, accounting for more than 85% of all lung cancer cases. Recent advances in precision oncology have allowed NSCLC patients bearing specific oncogenic epidermal growth factor receptor (EGFR) mutations to respond well to EGFR tyrosine kinase inhibitors (TKIs). Due to the high EGFR mutation frequency (up to more than 50%) observed particularly in Asian NSCLC patients, EGFR-TKIs have produced unprecedented clinical responses. Depending on their binding interactions with EGFRs, EGFR-TKIs are classified as reversible (first-generation: gefitinib and erlotinib) or irreversible inhibitors (second-generation: afatinib and dacomitinib; third-generation: osimertinib). While the discovery of osimertinib represents a breakthrough in the treatment of NSCLC, most patients eventually relapse and develop drug resistance. Novel strategies to overcome osimertinib resistance are urgently needed. In Asian countries, the concomitant use of Western medicine and traditional Chinese medicine (TCM) is very common. Ganoderma lucidum (Lingzhi) and Coriolus versicolor (Yunzhi) are popular TCMs that are widely consumed by cancer patients to enhance anticancer efficacy and alleviate the side effects associated with cancer therapy. The bioactive polysaccharides and triterpenes in these medicinal mushrooms are believed to contribute to their anticancer and immunomodulating effects. This review presents the latest update on the beneficial combination of Lingzhi/Yunzhi and EGFR-TKIs to overcome drug resistance. The effects of Lingzhi/Yunzhi on various oncogenic signaling pathways and anticancer immunity, as well as their potential to overcome EGFR-TKI resistance, are highlighted. The potential risk of herb–drug interactions could become critical when cancer patients take Lingzhi/Yunzhi as adjuvants during cancer therapy. The involvement of drug transporters and cytochrome P450 enzymes in these herb–drug interactions is summarized. Finally, we also discuss the opportunities and future prospects regarding the combined use of Lingzhi/Yunzhi and EGFR-TKIs in cancer patients. Full article
(This article belongs to the Special Issue Combination Therapy Approaches for Cancer Treatment)
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28 pages, 3811 KiB  
Article
In Vivo and In Vitro Experimental Study Comparing the Effect of a Combination of Sodium Dichloroacetate and Valproic Acid with That of Temozolomide on Adult Glioblastoma
by Rūta Skredėnienė, Donatas Stakišaitis, Angelija Valančiūtė and Ingrida Balnytė
Int. J. Mol. Sci. 2025, 26(14), 6784; https://doi.org/10.3390/ijms26146784 - 15 Jul 2025
Viewed by 312
Abstract
To date, there is no effective treatment for glioblastoma (GBM). This study aimed to compare the effectiveness of sodium dichloroacetate (NaDCA), a valproic acid and NaDCA combination (VPA–NaDCA), or temozolomide (TMZ) on U87 and T98G cell tumors on the chick embryo chorioallantoic membrane [...] Read more.
To date, there is no effective treatment for glioblastoma (GBM). This study aimed to compare the effectiveness of sodium dichloroacetate (NaDCA), a valproic acid and NaDCA combination (VPA–NaDCA), or temozolomide (TMZ) on U87 and T98G cell tumors on the chick embryo chorioallantoic membrane (CAM), and on the expression of proliferating cell nuclear antigen (PCNA), polycomb inhibitory complex catalytic subunit 2 (EZH2), and TP53 gene-encoded p53 protein (p53) in tumors on the CAM, and SLC12A2 (gene encoding Na+-K+-2Cl (NKCC1) co-tarnsporter), SLC12A5 (gene encoding K+-Cl (KCC2) co-transporter), SLC5A8 (gene encoding Na+-dependent monocarboxylate transporter) and CDH1 (gene encoding the E-cadherin protein) and CDH2 (gene encoding the N-cadherin protein) in cells. VPA–NaDCA and TMZ reduced the invasion of U87 and T98G tumors, as well as the expression of PCNA and EZH2 in the tumor. TMZ reduced p53 expression in tumors from both cell lines, whereas VPA–NaDCA did not affect the expression of this marker. VPA–NaDCA, but not TMZ, reduced SLC12A2 expression in T98G cells. However, VPA–NaDCA and TMZ did not affect SLC12A2 expression in U87 cells. VPA–NaDCA increased SLC5A8 expression only in U87 cells, and TMZ did not affect gene expression in either cell line. Only VPA–NaDCA increased CDH1 expression and decreased CDH2 expression in T98G cells, whereas TMZ had no effect on gene expression in the study cells. This study demonstrated that VPA–NaDCA exhibits a more effective anticancer effect than NaDCA. The data suggest that VPA–NaDCA has a more effective impact than TMZ; however, the effect of investigational medicines on carcinogenesis varies depending on the cell line. The study of the efficacy of drugs used to treat tumors on the CAM and cells demonstrates that it is essential to assess the effectiveness of treatment, which should be personalized, before administering chemotherapy. Full article
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35 pages, 10190 KiB  
Article
Molecular Mechanisms of Lobelia nummularia Extract in Breast Cancer: Targeting EGFR/TP53 and PI3K-AKT-mTOR Signaling via ROS-Mediated Apoptosis
by Fahu Yuan, Yu Qiao, Zhongqiang Chen, Huihuang He, Fuyan Wang and Jiangyuan Chen
Curr. Issues Mol. Biol. 2025, 47(7), 546; https://doi.org/10.3390/cimb47070546 - 14 Jul 2025
Viewed by 414
Abstract
Lobelia nummularia Lam. is a traditional medicinal herb of which the anticancer mechanisms remain largely unexplored. Here, we demonstrated that its ethanolic extract (LNE) exerts potent anti-breast cancer activity by inducing ROS-dependent mitochondrial apoptosis in MDA-MB-231 cells, a mechanism confirmed via rescue experiments [...] Read more.
Lobelia nummularia Lam. is a traditional medicinal herb of which the anticancer mechanisms remain largely unexplored. Here, we demonstrated that its ethanolic extract (LNE) exerts potent anti-breast cancer activity by inducing ROS-dependent mitochondrial apoptosis in MDA-MB-231 cells, a mechanism confirmed via rescue experiments with the antioxidant N-acetylcysteine (NAC). This pro-apoptotic program is driven by a dual mechanism: potent suppression of the pro-survival EGFR/PI3K/AKT signaling pathway and simultaneous activation of the TP53-mediated apoptotic cascade, culminating in the cleavage of executor caspase-3. Phytochemical analysis identified numerous flavonoids, and quantitative HPLC confirmed that key bioactive compounds, including luteolin and apigenin, are substantially present in the extract. These mechanisms translated to significant in vivo efficacy, where LNE administration suppressed primary tumor growth and lung metastasis in a 4T1 orthotopic model in BALB/c mice. Furthermore, a validated molecular docking protocol provided a plausible structural basis for these multi-target interactions. Collectively, this study provides a comprehensive, multi-layered validation of LNE’s therapeutic potential, establishing it as a mechanistically well-defined candidate for natural product-based anticancer drug discovery. Full article
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24 pages, 4756 KiB  
Review
Mechanistic Insights into Autophagy-Dependent Cell Death (ADCD): A Novel Avenue for Cancer Therapy
by Md Ataur Rahman, Maroua Jalouli, Mohammed Al-Zharani, Ehsanul Hoque Apu and Abdel Halim Harrath
Cells 2025, 14(14), 1072; https://doi.org/10.3390/cells14141072 - 13 Jul 2025
Viewed by 750
Abstract
Autophagy-dependent cell death (ADCD) presents a promising but challenging therapeutic strategy in cancer treatment. Autophagy regulates cellular breakdown and stress responses, serving a dual function—either inhibiting tumorigenesis or facilitating the survival of cancer cells in advanced stages. This paradox presents both opportunities and [...] Read more.
Autophagy-dependent cell death (ADCD) presents a promising but challenging therapeutic strategy in cancer treatment. Autophagy regulates cellular breakdown and stress responses, serving a dual function—either inhibiting tumorigenesis or facilitating the survival of cancer cells in advanced stages. This paradox presents both opportunities and challenges in the exploration of autophagy as a potential target for cancer treatment. In this review, we explore various pharmacological agents, including autophagy inhibitors (e.g., chloroquine, 3-MA) and activators (e.g., rapamycin, metformin), which have demonstrated effectiveness in modulating autophagy-dependent cell death (ADCD). These agents either enhance cancer cell apoptosis or sensitize tumors to conventional therapies. Combination therapies, such as the use of autophagy modulators alongside chemotherapy, immunotherapy, or radiation therapy, offer enhanced therapeutic potential by overcoming drug resistance and improving overall treatment efficacy. Nonetheless, significant challenges remain, including tumor heterogeneity, treatment resistance, and off-target effects of autophagy-targeting agents. Future progress in biomarker discovery, precision medicine, and targeted medication development will be crucial for enhancing ADCD-based methods. Although autophagy-dependent cell death presents significant potential in cancer treatment, additional studies and clinical validation are necessary to confirm its position as a conventional therapeutic approach. Therefore, this review aims to identify the existing restrictions that will facilitate the development of more effective and personalized cancer therapies, hence enhancing patient survival and outcomes. Full article
(This article belongs to the Special Issue Cell Death: Cell–Cell Interactions and Signaling Networks)
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19 pages, 9060 KiB  
Article
Targeting CDK4/6 in Cancer: Molecular Docking and Cytotoxic Evaluation of Thottea siliquosa Root Extract
by Maruthamuthu Rathinam Elakkiya, Mohandas Krishnasreya, Sureshkumar Tharani, Muthukrishnan Arun, L. Vijayalakshmi, Jiseok Lim, Ayman A. Ghfar and Balasundaramsaraswathy Chithradevi
Biomedicines 2025, 13(7), 1658; https://doi.org/10.3390/biomedicines13071658 - 7 Jul 2025
Viewed by 441
Abstract
Background: Cyclin-dependent kinases 4 and 6 (CDK4/6) are pivotal regulators of the cell cycle, whose dysregulation is closely linked to cancer progression. While synthetic CDK4/6 inhibitors such as Palbociclib and Ribociclib are clinically effective, their use is limited by significant adverse effects. [...] Read more.
Background: Cyclin-dependent kinases 4 and 6 (CDK4/6) are pivotal regulators of the cell cycle, whose dysregulation is closely linked to cancer progression. While synthetic CDK4/6 inhibitors such as Palbociclib and Ribociclib are clinically effective, their use is limited by significant adverse effects. Methods: In this study, the aqueous root extract of Thottea siliquosa, a traditionally used medicinal plant, was evaluated for its potential as a natural CDK4/6 inhibitor. Phytochemical profiling using GC-MS identified bioactive compounds, which were subsequently subjected to molecular docking, ADME prediction, and in vitro cell-based assays using HCT116 and L929 cells. Results: The docking results revealed that Isocorydine (−7.4 kcal/mol for CDK4 and −7.2 kcal/mol for CDK6) and Thunbergol (−6.5 kcal/mol for CDK4 and −7.0 kcal/mol for CDK6) exhibited promising binding affinities comparable to standard CDK inhibitors, Palbociclib (−7.2, −8.3 kcal/mol) and Ribociclib (−7.1, −8.1 kcal/mol). Among the other tested natural compounds, Squalene (−7.1 kcal/mol for CDK4) and 2-palmitoylglycerol (−5.2 kcal/mol for CDK4, −4.9 kcal/mol for CDK6) demonstrated moderate binding affinities. ADME analysis confirmed favorable drug-like properties with minimal toxicity alerts. The extract displayed dose-dependent cytotoxicity with an IC50 of 140 μg/mL and reduced cell migration in HCT116 cells, indicating potential anti-proliferative effects. These findings suggest that T. siliquosa root extract, through synergistic phytochemical interactions, holds promise as a multi-targeted, plant-based therapeutic candidate for CDK4/6-associated cancers, warranting further in vitro and in vivo validation. Full article
(This article belongs to the Special Issue Progress in Cytotoxicity of Biomaterials)
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16 pages, 3597 KiB  
Article
Towards a Customized Oral Drug Therapy for Pediatric Applications: Chewable Propranolol Gel Tablets Printed by an Automated Extrusion-Based Material Deposition Method
by Kristiine Roostar, Andres Meos, Ivo Laidmäe, Jaan Aruväli, Heikki Räikkönen, Leena Peltonen, Sari Airaksinen, Niklas Sandler Topelius, Jyrki Heinämäki and Urve Paaver
Pharmaceutics 2025, 17(7), 881; https://doi.org/10.3390/pharmaceutics17070881 - 4 Jul 2025
Viewed by 445
Abstract
Background: Automated semi-solid extrusion (SSE) material deposition is a promising new technology for preparing personalized medicines for different patient groups and veterinary applications. The technology enables the preparation of custom-made oral elastic gel tablets of active pharmaceutical ingredient (API) by using a semi-solid [...] Read more.
Background: Automated semi-solid extrusion (SSE) material deposition is a promising new technology for preparing personalized medicines for different patient groups and veterinary applications. The technology enables the preparation of custom-made oral elastic gel tablets of active pharmaceutical ingredient (API) by using a semi-solid polymeric printing ink. Methods: An automated SSE material deposition method was used for generating chewable gel tablets loaded with propranolol hydrochloride (-HCl) at three different API content levels (3.0 mg, 4.0 mg, 5.0 mg). The physical appearance, surface morphology, dimensions, mass and mass variation, process-derived solid-state changes, mechanical properties, and in-vitro drug release of the gel tablets were studied. Results: The inclusion of API (1% w/w) in the semi-solid CuraBlendTM printing mixture decreased viscosity and increased fluidity, thus promoting the spreading of the mixture on the printed (material deposition) bed and the printing performance of the gel tablets. The printed gel tablets were elastic, soft, jelly-like, chewable preparations. The mechanical properties of the gel tablets were dependent on the printing ink composition (i.e., with or without propranolol HCl). The maximum load for the final deformation of the CuraBlend™-API (3.0 mg) gel tablets was very uniform, ranging from 73 N to 80 N. The in-vitro dissolution test showed that more than 85% of the drug load was released within 15–20 min, thus verifying the immediate-release behavior of these drug preparations. Conclusions: Automated SSE material deposition as a modified 3D printing method is a feasible technology for preparing customized oral chewable gel tablets of propranolol HCl. Full article
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18 pages, 1158 KiB  
Article
Ten-Year Trend in the Potentially Inappropriate Prescribing of Renally-Dependent Medicines in Australian General Practice Patients with Dementia
by Saad Alhumaid, Woldesellassie M. Bezabhe, Mackenzie Williams and Gregory M. Peterson
J. Clin. Med. 2025, 14(13), 4734; https://doi.org/10.3390/jcm14134734 - 4 Jul 2025
Viewed by 429
Abstract
Background: There is limited published evidence on the prevalence of potentially inappropriate prescribing of medicines in relation to kidney function in older Australians, particularly those with dementia. Objectives: To examine the prevalence, temporal trends and factors associated with potentially inappropriate prescribing of renally-dependent [...] Read more.
Background: There is limited published evidence on the prevalence of potentially inappropriate prescribing of medicines in relation to kidney function in older Australians, particularly those with dementia. Objectives: To examine the prevalence, temporal trends and factors associated with potentially inappropriate prescribing of renally-dependent medicines in patients with dementia, using Australian general practice data. Methods: This comparative study was reported in accordance with the STROBE guidelines for cohort studies. Retrospective analyses of the National Prescribing Service (NPS) MedicineInsight dataset were performed to determine the proportion of patients aged ≥ 65 years with a recorded diagnosis of dementia, along with matched controls, who had potentially inappropriate prescribing based on their estimated glomerular filtration rate (eGFR) during the study period (2011–2020). Each patient was included only once throughout the study. Potentially inappropriate prescribing was evaluated for 33 commonly used medicines, using the Cockcroft-Gault equation for estimated creatinine clearance or eGFR, in accordance with the guidelines from the Australian Medicines Handbook (AMH). Each patient’s medicines were included if they were prescribed within 180 days after the most recent recorded lowest eGFR value for the patient. Medicines having prescribed doses exceeding those recommended for an individual’s renal function were classified as ‘inappropriate dosage’, while those whose use was advised against were labelled ‘contraindicated’. Both categories were regarded as inappropriate prescriptions. Descriptive statistics were used to summarise patient characteristics and medication use. Temporal trends were displayed in graphs, with statistical significance determined using the Cochran-Armitage test. Binary logistic regression models were used to examine the associations between sociodemographic and clinical factors and the prescribing of medicines inconsistent with AMH guidelines. Results: The unmatched cohorts included 33,101 patients, comprising 4092 with dementia and 29,009 without. Among them, 58.4% were female, and the overall median age was 82 years [interquartile range (IQR): 77–87]. After propensity score matching, there were 4041 patients with dementia and 8031 without dementia. Over the study period, potentially inappropriate prescribing increased slightly, but insignificantly, in both groups of patients; the prevalence of inappropriate use of at least one of the 33 drugs of interest rose from 6.5% (95% CI 4.5–9.1%) in 2011 to 8.9% (95% CI 6.0–12.7%; p for trend: 0.966) in 2020 in the dementia group, and 9.2% (95% CI 8.0–10.5%) to 11.1% (95% CI 10.3–12.0%; p for trend: 0.224) in the matched controls. Over the ten-year period, approximately 9.3% (377) of patients with dementia in the matched cohort received at least one potentially inappropriate prescription. Among these, 154 (40.8%) were for contraindicated medicines, and 223 (59.1%) were for inappropriate doses based on renal function. Among patients with dementia in the matched cohort, fenofibrate, nitrofurantoin, and moxonidine were the most frequently prescribed medicines at doses inconsistent with AMH guidelines. In the unmatched dementia cohort, potentially inappropriate prescribing was not significantly associated with demographic characteristics or most comorbidities; however, it occurred more frequently in patients with an eGFR below 30 mL/min/1.73 m2 or those with concomitant diabetes. Conclusions: Positively, the prevalence of potentially inappropriate prescribing of renally-dependent medicines in primary care patients with dementia in Australia was similar to their matched controls. However, there was room for improvement in the prescribing of these drugs in both patients with and without dementia. Full article
(This article belongs to the Special Issue Clinical Epidemiology in Chronic Kidney Disease)
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19 pages, 1219 KiB  
Review
Carboxylesterase Factors Influencing the Therapeutic Activity of Common Antiviral Medications Used for SARS-CoV-2 Infection
by Yue Shen, William Eades, Linh Dinh and Bingfang Yan
Pharmaceutics 2025, 17(7), 832; https://doi.org/10.3390/pharmaceutics17070832 - 26 Jun 2025
Viewed by 588
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, remains a major global health threat. The virus enters host cells by binding to the angiotensin-converting enzyme 2 (ACE2) receptor. Several small-molecule antiviral drugs, including molnupiravir, favipiravir, remdesivir, and nirmatrelvir have [...] Read more.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, remains a major global health threat. The virus enters host cells by binding to the angiotensin-converting enzyme 2 (ACE2) receptor. Several small-molecule antiviral drugs, including molnupiravir, favipiravir, remdesivir, and nirmatrelvir have been shown to inhibit SARS-CoV-2 replication and are approved for treating SARS-CoV-2 infections. Nirmatrelvir inhibits the viral main protease (Mpro), a key enzyme for processing polyproteins in viral replication. In contrast, molnupiravir, favipiravir, and remdesivir are prodrugs that target RNA-dependent RNA polymerase (RdRp), which is crucial for genome replication and subgenomic RNA production. However, undergoing extensive metabolism profoundly impacts their therapeutic effects. Carboxylesterases (CES) are a family of enzymes that play an essential role in the metabolism of many drugs, especially prodrugs that require activation through hydrolysis. Molnupiravir is activated by carboxylesterase-2 (CES2), while remdesivir is hydrolytically activated by CES1 but inhibits CES2. Nirmatrelvir and remdesivir are oxidized by the same cytochrome P450 (CYP) enzyme. Additionally, various transporters are involved in the uptake or efflux of these drugs and/or their metabolites. It is well established that drug-metabolizing enzymes and transporters are differentially expressed depending on the cell type, and these genes exhibit significant polymorphisms. In this review, we examine how CES-related cellular and genetic factors influence the therapeutic activities of these widely used COVID-19 medications. This article highlights implications for improving product design, targeted inhibition, and personalized medicine by exploring genetic variations and their impact on drug metabolism and efficacy. Full article
(This article belongs to the Special Issue ADME Properties in the Drug Delivery)
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19 pages, 1287 KiB  
Article
Exploring the Phytochemical Profile and Therapeutic Potential of Saudi Native Santolina chamaecyparissus L. Essential Oil
by Hanan Y. Aati, Wedad Sarawi, Hala Attia, Rehab Ghazwani and Lama Aldmaine
Pharmaceutics 2025, 17(7), 830; https://doi.org/10.3390/pharmaceutics17070830 - 26 Jun 2025
Viewed by 524
Abstract
Background/Objectives: Medicinal plants such as Santolina chamaecyparissus L., an evergreen shrub from the Asteraceae family, have long been valued for their bioactive compounds and traditional therapeutic uses. Materials: In this study, the essential oil of S. chamaecyparissus (EOSC) was isolated via hydrodistillation and [...] Read more.
Background/Objectives: Medicinal plants such as Santolina chamaecyparissus L., an evergreen shrub from the Asteraceae family, have long been valued for their bioactive compounds and traditional therapeutic uses. Materials: In this study, the essential oil of S. chamaecyparissus (EOSC) was isolated via hydrodistillation and then comprehensively evaluated for its phytochemical composition and antioxidant, anti-inflammatory, hemolytic, and cytotoxic properties, as well as its in silico bioactivity. Results: In total, 89.5% of the essential oil composition was successfully identified using GC-MS analysis. Hydrocarbon sesquiterpenes constituted the largest fraction (36.0%), followed by oxygenated sesquiterpenes (19.7%). Phytochemical screening revealed high phenolic content (839.50 ± 5.0 mg GAE/g E.O), while the Total Antioxidant Capacity (TAC) assay confirmed its strong antioxidant potential. The oil showed moderate hemolytic activity and significant lipoxygenase inhibition, indicating anti-inflammatory capability. The cytotoxic effects of the EOSC were evaluated using the MTT assay and HepG2 liver cancer cells. A dose-dependent reduction in cell viability was observed, confirming the oil’s strong anticancer activity. Molecular docking and ADMET analyses supported the bioactivity of the identified compounds, which showed good drug-likeness and pharmacokinetic properties. Conclusions: These findings demonstrate that EOSC has promising antioxidant and anti-inflammatory properties, suggesting that it could have potential as a safe natural substance for use in drug development and food preservation. Full article
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17 pages, 4743 KiB  
Article
Uncovering Anti-Melanoma Mechanisms of Bambusa stenostachya Leaf Compounds via Network Pharmacology and Molecular Docking
by Gen Maxxine C. Darilag, Hsuan-Chieh Liu, Cheng-Yang Hsieh, Lemmuel L. Tayo, Nicholas Dale D. Talubo, Shu-Ching Yang, Ching-Hui Chang, Ying-Pin Huang, Shih-Chi Lee, Yung-Chuan Liu and Po-Wei Tsai
Int. J. Mol. Sci. 2025, 26(13), 6120; https://doi.org/10.3390/ijms26136120 - 25 Jun 2025
Viewed by 588
Abstract
Skin cancer, particularly melanoma, remains a major public health concern due to its high mortality rate. Current treatment options, including chemotherapy with dacarbazine and doxorubicin, have shown limited efficacy, achieving only a 20% objective response rate over six months, along with severe side [...] Read more.
Skin cancer, particularly melanoma, remains a major public health concern due to its high mortality rate. Current treatment options, including chemotherapy with dacarbazine and doxorubicin, have shown limited efficacy, achieving only a 20% objective response rate over six months, along with severe side effects such as cardiotoxicity. Given these limitations, there is a growing interest in herbal medicine as a source of novel anticancer compounds. Bambusa stenostachya, a bamboo species native to Taiwan, was investigated for its potential anti-melanoma properties using network pharmacology and molecular docking. LC-MS analysis identified seven bioactive compounds, including quinic acid and isovitexin, which satisfied Lipinski’s drug-likeness criteria. Among the seven bioactive compounds identified, five belong to the flavonoid family, while two are classified as phenolic compounds that modulate signaling pathways related to cancer and exhibit antioxidant activity, respectively. Through pathway enrichment analysis, four key melanoma-associated genes (PIM1, MEK1, CDK2, and PDK1) were identified as potential therapeutic targets. Ensemble docking results demonstrated that naringin-7-rhamnoglucoside exhibited the highest binding affinity (−6.30 kcal/mol) with phosphoinositide-dependent kinase-1, surpassing the affinities of standard chemotherapeutic agents. Additionally, the average docking scores for naringin-7-rhamnoglucoside and the remaining three proteins were as follows: PIM1 (−5.92), MEK1 (−6.07), and CDK2 (−5.26). These findings suggest that the bioactive compounds in B. stenostachya may play a crucial role in inhibiting melanoma progression by modulating metabolic and signaling pathways. Further in vitro and in vivo studies are necessary to validate these computational findings and explore the potential of B. stenostachya as a complementary therapeutic agent for melanoma. Full article
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48 pages, 8758 KiB  
Review
Targeting Cancer Cell Fate: Apoptosis, Autophagy, and Gold Nanoparticles in Treatment Strategies
by Maria Anthi Kouri, Alexandra Tsaroucha, Theano-Marina Axakali, Panagiotis Varelas, Vassilis Kouloulias, Kalliopi Platoni and Efstathios P. Efstathopoulos
Curr. Issues Mol. Biol. 2025, 47(6), 460; https://doi.org/10.3390/cimb47060460 - 14 Jun 2025
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Abstract
At the intersection of nanotechnology and cancer biology, gold nanoparticles (AuNPs) have emerged as more than passive carriers—they are active agents capable of reshaping cellular fate. Among their most promising attributes is the potential to modulate apoptosis and autophagy, two intricately linked pathways [...] Read more.
At the intersection of nanotechnology and cancer biology, gold nanoparticles (AuNPs) have emerged as more than passive carriers—they are active agents capable of reshaping cellular fate. Among their most promising attributes is the potential to modulate apoptosis and autophagy, two intricately linked pathways that determine tumor response to stress, damage, and treatment. Apoptosis serves as the principal mechanism of programmed cell death, while autophagy offers a dualistic role—preserving survival under transient stress or contributing to cell death under sustained insult. Thus, understanding how these mechanisms interact—and how AuNPs influence this crosstalk—may be key to unlocking more effective oncologic therapies. This review explores the molecular interplay between apoptosis and autophagy in cancer and evaluates how AuNPs impact these pathways. By enhancing radiosensitization in radiation therapy and improving drug delivery and chemotherapeutic precision, AuNPs offer a unique strategy to circumvent resistance in aggressive or refractory tumors towards shaping their biological behavior and cellular pathways and, therefore, forming a patient-centered personalized therapeutic potential. Yet, clinical translation remains challenging. The dynamic physicochemical nature of AuNPs makes their biological behavior highly context-dependent. Combined with the complexity of apoptotic and autophagic signaling and tumor heterogeneity, this creates a triad of profound intricacy. However, within this complexity lies therapeutic opportunity. Framing AuNPs, apoptosis, and autophagy as a synergistic axis may enable mechanism-informed, adaptable, and patient-specific cancer therapies. This paradigm shift invites a more strategic integration of nanotechnology with molecular oncology, advancing the frontier of precision medicine. Full article
(This article belongs to the Special Issue Effects of Nanoparticles on Living Organisms, 3rd Edition)
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12 pages, 426 KiB  
Article
Post-Marketing Surveillance of Nirsevimab: Safety Profile and Adverse Event Analysis from Spain’s 2023–2024 RSV Immunisation Campaign
by Pablo Estrella-Porter, Elisa Correcher-Martínez, Alejandro Orrico-Sánchez and Juan José Carreras
Vaccines 2025, 13(6), 623; https://doi.org/10.3390/vaccines13060623 - 10 Jun 2025
Cited by 1 | Viewed by 1376
Abstract
Background: Respiratory syncytial virus (RSV) poses a significant health burden in children, being the major cause of lower respiratory tract infection (LRTI), including bronchiolitis. During the 2023–2024 RSV season, Spain introduced nirsevimab, a monoclonal antibody for universal RSV prophylaxis in infants. This study [...] Read more.
Background: Respiratory syncytial virus (RSV) poses a significant health burden in children, being the major cause of lower respiratory tract infection (LRTI), including bronchiolitis. During the 2023–2024 RSV season, Spain introduced nirsevimab, a monoclonal antibody for universal RSV prophylaxis in infants. This study reviews the safety of nirsevimab through post-marketing surveillance. Material and Methods: A descriptive pharmacovigilance study was made based on spontaneous reporting data of suspected adverse events (SAEs) from the Spanish Pharmacovigilance System for Medicinal Products for Human Use (SEFV-H) and industry reports. SAEs reported between September 2023 and May 2024 were extracted from the Spanish Pharmacovigilance Adverse Reactions Data (FEDRA) database. Cases were analysed by sex, age, severity, and SAEs classification using the Preferred Terms (PT) level of the Medical Dictionary for Regulatory Activities (MedDRA). Reporting rates were estimated based on immunization coverage and birth data. Results: Sixty-seven cases reported 141 SAEs, yielding an overall rate of 23.1 cases per 100,000 doses. Common events included rash (8.51%), drug ineffectiveness (7.09%), and pyrexia (7.09%). Serious events constituted 53.70% of reports, including two fatalities (3.00%). No new safety signals or unexpected risks, such as antibody-dependent enhancement (ADE), were identified. Discussion: SAEs reported peaked early in the campaign, reflecting heightened reporting in new immunization programs. The safety profile aligns with clinical trial findings and regulatory expectations, confirming nirsevimab’s benefit–risk balance. Continued pharmacovigilance is critical for maintaining public trust in RSV prophylaxis. Nirsevimab demonstrated a favorable safety profile during Spain’s initial universal RSV immunization campaign in infants, supporting its continued use in reducing RSV-related morbidity. Full article
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16 pages, 2016 KiB  
Article
A Deep Learning-Based Model Approach for Quantitative Analysis of Cell Chemotaxis in a Microfluidic Chip
by Hongxuan Wu, Fei Zhang and Mingji Wei
Sensors 2025, 25(11), 3515; https://doi.org/10.3390/s25113515 - 3 Jun 2025
Viewed by 570
Abstract
The rapid and accurate quantitative analysis of cell chemotaxis, which is essential in biology, medicine, and drug development, enables the evaluation of the directional migration capability of cells and the simulation of in vivo cell chemotaxis. However, traditional methods for studying cell chemotaxis [...] Read more.
The rapid and accurate quantitative analysis of cell chemotaxis, which is essential in biology, medicine, and drug development, enables the evaluation of the directional migration capability of cells and the simulation of in vivo cell chemotaxis. However, traditional methods for studying cell chemotaxis often depend on complex experimental procedures, which are not only time-consuming and labor-intensive but also prone to human error. Recently, the rapid advancement of microfluidic technology and deep learning has provided a new way for evaluation of cell chemotaxis. In this study, a chemotaxis evaluation method based on microfluidics and deep learning is proposed. A microfluidic device was designed to simulate cell chemotaxis, allowing for the controlled assessment of cell chemotaxis by generating chemical gradients within microchannels and shear stress. Concurrently, deep learning technology was introduced to identify the migrated and non-migrated states of cell images, thereby enabling the automatic counting and analysis of chemotactic cells. Compared with traditional manual assays, this method not only reduced time and labor costs but also achieved higher accuracy and reproducibility. This innovative approach, which integrates microfluidics and deep learning, provides a novel perspective and tool for cell chemotaxis research. This method not only offers a fresh perspective on cell migration analysis but also has the potential to significantly advance the field of biomedical research, particularly in biosensor development related to drug discovery and disease diagnosis. Full article
(This article belongs to the Section Biosensors)
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