Pharmaceuticals

24 pages, 3712 KiB

Open AccessArticle

Elucidation of Artemisinin as a Potent GSK3β Inhibitor for Neurodegenerative Disorders via Machine Learning-Driven QSAR and Virtual Screening of Natural Compounds

by Hassan H. Alhassan, Malvi Surti, Mohd Adnan and Mitesh Patel

Pharmaceuticals 2025, 18(6), 826; https://doi.org/10.3390/ph18060826 (registering DOI) - 31 May 2025

Abstract

Background/Objectives: Glycogen synthase kinase-3 beta (GSK3β) is a key enzyme involved in neurodegenerative diseases such as Alzheimer’s and Parkinson’s, contributing to tau hyperphosphorylation, amyloid-beta (Aβ) aggregation, and neuronal dysfunction. Methods: This study applied a machine learning-driven virtual screening approach to identify potent [...] Read more.

Background/Objectives: Glycogen synthase kinase-3 beta (GSK3β) is a key enzyme involved in neurodegenerative diseases such as Alzheimer’s and Parkinson’s, contributing to tau hyperphosphorylation, amyloid-beta (Aβ) aggregation, and neuronal dysfunction. Methods: This study applied a machine learning-driven virtual screening approach to identify potent natural inhibitors of GSK3β. A dataset of 3092 natural compounds was analyzed using Support Vector Machine (SVM), Random Forest (RF), and K-Nearest Neighbors (KNN), with feature selection focusing on key molecular descriptors, including lipophilicity (ALogP: −0.5 to 5.0), hydrogen bond acceptors (0–10), and McGowan volume (0.5–2.5). RF outperformed SVM and KNN, achieving the highest test accuracy (83.6%), specificity (87%), and lowest RMSE (0.3214). Results: Virtual screening using AutoDock Vina and molecular dynamics simulations (100 ns, GROMACS 2022) identified artemisinin as the top GSK3β inhibitor, with a binding affinity of −8.6 kcal/mol, interacting with key residues ASP200, CYS199, and LEU188. Dihydroartemisinin exhibited a binding affinity of −8.3 kcal/mol, reinforcing its neuroprotective potential. Pharmacokinetic predictions confirmed favorable drug-likeness (TPSA: 26.3–70.67 Å²) and non-toxicity. Conclusions: While these findings highlight artemisinin-based inhibitors as promising candidates, experimental validation and structural optimization are needed for clinical application. This study demonstrates the effectiveness of machine learning and computational screening in accelerating neurodegenerative drug discovery. Full article

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

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30 pages, 1146 KiB

Open AccessReview

Antimicrobial Smart Dressings for Combating Antibiotic Resistance in Wound Care

by Alina-Georgiana Cristea (Hohotă), Elena-Lăcrămioara Lisă, Simona Iacob (Ciobotaru), Ionut Dragostin, Claudia Simona Ștefan, Iuliu Fulga, Andra Monica Anghel (Ștefan), Maria Dragan, Ionela Daniela Morariu and Oana-Maria Dragostin

Pharmaceuticals 2025, 18(6), 825; https://doi.org/10.3390/ph18060825 (registering DOI) - 30 May 2025

Abstract

Wound healing is a complex, tightly regulated process essential for maintaining skin barrier function. Chronic wounds, often complicated by biofilm-forming bacteria and elevated oxidative stress, pose significant challenges in clinical management. The rise of antibiotic-resistant bacteria has further exacerbated the problem, limiting therapeutic [...] Read more.

Wound healing is a complex, tightly regulated process essential for maintaining skin barrier function. Chronic wounds, often complicated by biofilm-forming bacteria and elevated oxidative stress, pose significant challenges in clinical management. The rise of antibiotic-resistant bacteria has further exacerbated the problem, limiting therapeutic options and complicating wound treatment. Traditional wound care approaches frequently fail to provide real-time accurate insights into wound status, leading to delayed or suboptimal treatments. Recent advancements in modern and smart wound dressings, which integrate various biosensors, different new drug delivery systems, and wireless communication technology, offers promising solutions for monitoring wound progression over time. These innovations enable early detection of adverse events such as bacterial infections and inflammation, facilitating more effective, on-demand treatment. This review highlights the current state of antibiotic-embedded wound dressings, discusses their limitations, and explores the potential of next-generation wound dressings incorporating microelectronic sensors for real-time monitoring and adaptive therapeutic responses to support healing and combat antimicrobial resistance. Full article

(This article belongs to the Section Biopharmaceuticals)

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24 pages, 5444 KiB

Open AccessArticle

Identification of HMOX-1-Targeting Natural Compounds in Camellia nitidissima Chi for NSCLC Therapy: Integrating Bioassay and In Silico Screening Approaches

by Lingqiu Zhang, Fan Zhang, Haimei Liang, Xiangling Qin, Chunmei Liang, Manlu Zhong, Yuemi Mo, Jinling Xie, Xiaotao Hou, Jiagang Deng, Erwei Hao and Zhengcai Du

Pharmaceuticals 2025, 18(6), 824; https://doi.org/10.3390/ph18060824 - 30 May 2025

Abstract

Background/Objectives: Camellia nitidissima Chi (C. nitidissima), a traditional Chinese “food and medicine homology” plant, has demonstrated potential anti-tumor properties. However, its mechanisms of anti-lung cancer activity via ferroptosis remain unclear. This study aimed to construct an integrated research system of [...] Read more.

Background/Objectives: Camellia nitidissima Chi (C. nitidissima), a traditional Chinese “food and medicine homology” plant, has demonstrated potential anti-tumor properties. However, its mechanisms of anti-lung cancer activity via ferroptosis remain unclear. This study aimed to construct an integrated research system of “natural product extraction-purification, bioactivity evaluation, and computational drug screening” to explore the bioactive compounds in C. nitidissima leaves targeting HMOX-1-mediated ferroptosis and their anti-lung cancer mechanisms. Methods: Active fractions were prepared using ethanol extraction combined with polyamide column chromatography. The anti-lung cancer activity was evaluated using the NCI-H1975 cell model. Ferroptosis was verified via transmission electron microscopy (TEM), biochemical indicators, a PCR Array, and immunofluorescence. The bioactive compounds were identified using UPLC-Q Exactive MS, and their binding affinity to HMOX-1 was evaluated via molecular docking and dynamics simulations, followed by cellular validation. Results: The 95% F1 fraction from the extracts of C. nitidissima leaves exhibited the strongest anti-lung cancer activity, which could be significantly reversed by Ferrostatin-1. Furthermore, it induced typical ferroptosis-related structural damage in mitochondria, including shrinkage and a reduction in size, increased membrane density, and a reduction or even the disappearance of cristae structures. At the molecular level, this fraction significantly increased the levels of oxidative stress markers (ROS↑, MDA↑, Fe²⁺↑, and GSH↓) and upregulated the expression of key ferroptosis-related genes, including HMOX-1, CHAC1, and NOX1. Using UPLC-Q Exactive MS combined with computational simulation methods, four bioactive compounds with high affinity for HMOX1 were successfully identified, including isochlorogenic acid A (−8.4 kcal/mol), isochlorogenic acid C (−8.4 kcal/mol), apigenin (−7.8 kcal/mol), and chrysin (−7.3 kcal/mol). Cellular experiments validated that these compounds exhibited dose-dependent anti-proliferative effects. Conclusions: The leaves of C. nitidissima induce anti-lung cancer effects via HMOX-1-mediated ferroptosis. Isochlorogenic acid A/C, apigenin, and chrysin were identified as key bioactive components. These findings lay the foundation for the development of natural ferroptosis-targeted drugs. Full article

(This article belongs to the Section Natural Products)

28 pages, 3397 KiB

Open AccessArticle

Molecular Mechanisms of Panax japonicus var. major Against Gastric Cancer: Metabolite Analysis, Signaling Pathways, and Protein Targets

by Chao Huang, Ge Li, Xiuxiang Yan, Terd Disayathanoowat, Angkhana Inta, Lu Gao and Lixin Yang

Pharmaceuticals 2025, 18(6), 823; https://doi.org/10.3390/ph18060823 - 30 May 2025

Abstract

Background/Objectives: Ginseng (Panax japonicus var. major) is a traditional medicinal plant with anticancer properties. We aimed to assess the biological activity, potential targets, and molecular mechanisms of P. japonicus var. major in resisting gastric cancer. Methods: We developed a model that [...] Read more.

Background/Objectives: Ginseng (Panax japonicus var. major) is a traditional medicinal plant with anticancer properties. We aimed to assess the biological activity, potential targets, and molecular mechanisms of P. japonicus var. major in resisting gastric cancer. Methods: We developed a model that combines network pharmacology, molecular docking, untargeted metabolomics, and molecular dynamics simulations to predict which compounds from P. japonicus var. major might be active in the treatment of gastric cancer. We conducted in vitro experiments and immunoblot validation to test these predictions. Results: We identified 44 main active compounds from P. japonicus var. major and 29 core targets. These compounds showed anti-gastric cancer activity against the HGC-27 cell line by acting on TNF and T-cell receptor signaling pathways to diminish inflammatory factor production and promote apoptosis of gastric cancer cells. Clinical survival analysis identified four core proteins (CASP3, TNF, AKT1, and EGFR) whose abundance was associated with survival status in gastric cancer patients. Molecular docking, along with molecular dynamics simulations, revealed that these core proteins could be stably bound by the identified active compounds. The anti-gastric cancer effects of P. japonicus var. major compounds involved a lower Bcl-2/Bax ratio and upregulation of CASP3 and CASP9 levels, highlighting significant differences in anti-gastric cancer activity between extracts prepared from fresh versus dried P. japonicus var. major. Conclusions: Our results provide background for the indigenous medicinal use of P. japonicus var. major to treat gastric cancer and lay the foundation for further pharmacological experiments and clinical tests. Full article

(This article belongs to the Section Natural Products)

16 pages, 11480 KiB

Open AccessArticle

Dasatinib and Quercetin Combination Increased Kidney Damage in Acute Folic Acid-Induced Experimental Nephropathy

by Antonio Battaglia-Vieni, Vanessa Marchant, Lucia Tejedor-Santamaria, Cristina García-Caballero, Elena Flores-Salguero, María Piedad Ruiz-Torres, Sandra Rayego-Mateos, Ana Belen Sanz, Alberto Ortiz and Marta Ruiz-Ortega

Pharmaceuticals 2025, 18(6), 822; https://doi.org/10.3390/ph18060822 - 30 May 2025

Abstract

Background/Objectives: Acute kidney injury (AKI) remains an unsolved medical problem due to the lack of effective treatments, high mortality, and increased susceptibility to progression to chronic kidney disease (CKD), especially in the elderly. Cellular senescence has been described in AKI, CKD, and [...] Read more.

Background/Objectives: Acute kidney injury (AKI) remains an unsolved medical problem due to the lack of effective treatments, high mortality, and increased susceptibility to progression to chronic kidney disease (CKD), especially in the elderly. Cellular senescence has been described in AKI, CKD, and aging and has been proposed as a promising therapeutic target. The senolytic drug combination of dasatinib plus quercetin (D&Q) is beneficial in some pathological conditions, including experimental CKD, but there are no data for AKI. Methods: The effect of D&Q combination was tested in folic acid-induced nephrotoxicity (FAN-AKI), a murine AKI model. Results: D&Q pretreatment did not prevent renal dysfunction in the acute phase of FAN-AKI, as determined by serum creatinine and BUN levels at 48 h. Moreover, gene expression of the kidney damage biomarkers Lcn2 and Havcr1, the Cdkn1a gene, which encodes p21, and some genes encoding components of the senescent cell secretome were significantly increased in response to D&Q treatment. The number of senescent p21-positive cells in injured kidneys was similar in untreated or D&Q-treated FAN mice. In addition, D&Q did not prevent the downregulation of the antiaging factor Klotho in damaged kidneys. Conclusions: D&Q treatment was not protective in FAN-AKI, exacerbating some deleterious responses. These results suggest caution when exploring the clinical translation of D&Q senolytic activity. Full article

(This article belongs to the Section Biopharmaceuticals)

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20 pages, 2328 KiB

Open AccessArticle

Parallel In Vitro and In Silico Studies of the Anti-Inflammatory Activity of Bioactive Compounds Found in Different Ethanolic Extracts of Bracts from B. x buttiana (var. Rose): A Comparative Analysis

by Gabriela Castañeda-Corral, Mayra Cedillo-Cortezano and Vera L. Petricevich

Pharmaceuticals 2025, 18(6), 821; https://doi.org/10.3390/ph18060821 - 30 May 2025

Abstract

Background/Objectives:Bougainvillea x buttiana is used in traditional Mexican medicine to treat various diseases. Previous studies have demonstrated its anti-inflammatory properties, which are associated with its chemical composition. This study evaluated the effect of ethanol concentration on the yield and anti-inflammatory activity of [...] Read more.

Background/Objectives:Bougainvillea x buttiana is used in traditional Mexican medicine to treat various diseases. Previous studies have demonstrated its anti-inflammatory properties, which are associated with its chemical composition. This study evaluated the effect of ethanol concentration on the yield and anti-inflammatory activity of its extracts. Additionally, an in silico analysis of the plant’s previously identified phytochemicals was conducted. Methods: Four extracts of B. x buttiana (var. Rose) (labeled as BxbREE) were prepared with increasing concentrations of ethanol (0%, 50%, 80%, and 100%). Their anti-inflammatory activity was assessed using different in vitro assays. The in silico prediction, performed with SwissADME, included the physicochemical, pharmacokinetic, and drug-like properties of the compounds. Results: The findings indicated that varying the ethanol concentration in the preparations of BxbREE-0%, BxbREE-50%, BxbREE-80%, and BxbREE-100% significantly impacted the extraction yield, with BxbREE-0% and BxbREE-50% exhibiting the highest recovery. All four extracts demonstrated significant anti-inflammatory activity, with BxbREE-50% and BxbREE-80% showing the most important effects on the denaturation of bovine serum albumin (BSA) and trypsin, inhibition of pro-inflammatory enzymes (cyclooxygenase and phospholipase A2), and increased stability of the erythrocyte membrane. The in silico analysis revealed that most phytochemicals identified in the extracts had good drug-likeness and bioavailability for oral administration and an adequate ADME profile. Conclusions: These findings reaffirm the anti-inflammatory potential of B. x buttiana (var. Rose) ethanolic extracts and the favorable pharmacokinetic and pharmacodynamic properties of its phytochemicals. Further structural exploration of the interactions of these bioactive compounds could contribute to the design of new drugs. Full article

(This article belongs to the Special Issue Medicinal Plants: A Natural Approach to Inflammatory Diseases and Conditions Related to Oxidative Stress)

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29 pages, 2759 KiB

Open AccessReview

A Review on Biomedical Applications of Plant Extract-Mediated Metallic Ag, Au, and ZnO Nanoparticles and Future Prospects for Their Combination with Graphitic Carbon Nitride

by Priyanka Panchal, Protima Rauwel, Satya Pal Nehra, Priyanka Singh, Mamta Karla, Glemarie Hermosa and Erwan Rauwel

Pharmaceuticals 2025, 18(6), 820; https://doi.org/10.3390/ph18060820 - 29 May 2025

Abstract

Since the publication of the 12 principles of green chemistry in 1998 by Paul Anastas and John Warner, the green synthesis of metal and metal oxide nanoparticles has emerged as an eco-friendly and sustainable alternative to conventional chemical methods. Plant-based synthesis utilizes natural [...] Read more.

Since the publication of the 12 principles of green chemistry in 1998 by Paul Anastas and John Warner, the green synthesis of metal and metal oxide nanoparticles has emerged as an eco-friendly and sustainable alternative to conventional chemical methods. Plant-based synthesis utilizes natural extracts as reducing and stabilizing agents, minimizing harmful chemicals and toxic by-products. Ag nanoparticles (Ag-NPs) exhibit strong antibacterial activity; Au nanoparticles (Au-NPs) are seen as a promising carrier for drug delivery and diagnostics because of their easy functionalization and biocompatibility; and ZnO nanoparticles (ZnO-NPs), on the other hand, produce reactive oxygen species (ROS) that kill microorganisms effectively. These nanoparticles also demonstrate antioxidant properties by scavenging free radicals, reducing oxidative stress, and preventing degenerative diseases. Green syntheses based on plant extracts enhance biocompatibility and therapeutic efficacy, making them suitable for antimicrobial, anticancer, and antioxidant applications. Applying a similar “green synthesis” for advanced nanostructures like graphitic carbon nitride (GCN) is an environmentally friendly alternative to the traditional ways of doing things. GCN exhibits exceptional photocatalytic activity, pollutant degradation efficiency, and electronic properties, with applications in environmental remediation, energy storage, and biomedicine. This review highlights the potential of green-synthesized hybrid nanocomposites combining nanoparticles and GCN as sustainable solutions for biomedical and environmental challenges. The review also highlights the need for the creation of a database using a machine learning process that will enable providing a clear vision of all the progress accomplished till now and identify the most promising plant extracts that should be used for targeted applications. Full article

(This article belongs to the Special Issue Metal Nanoparticles’ Biological Activity and Pharmaceutical Applications)

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20 pages, 4221 KiB

Open AccessArticle

Preparation and Evaluation of an Oral Administration System of Albendazole-Metal-Organic Framework Based on Dual Response to pH and Enzymes

by Weiqi Liu, Zhimei Guo, Yong Zhang, Yufei Guo, Ting Wang, Dahuan Liu and Chunhui Hu

Pharmaceuticals 2025, 18(6), 819; https://doi.org/10.3390/ph18060819 - 29 May 2025

Abstract

Objective: This study aims to develop a metal–organic framework (ABZ-MOFs)-based oral drug delivery system for albendazole (ABZ) to enhance its dissolution rate and oral bioavailability. Methods: ABZ@MOF-802, ABZ@UiO-66-NH₂, and ABZ@MIL-125-NH₂ were synthesized using a solvothermal method, and their physicochemical properties [...] Read more.

Objective: This study aims to develop a metal–organic framework (ABZ-MOFs)-based oral drug delivery system for albendazole (ABZ) to enhance its dissolution rate and oral bioavailability. Methods: ABZ@MOF-802, ABZ@UiO-66-NH₂, and ABZ@MIL-125-NH₂ were synthesized using a solvothermal method, and their physicochemical properties were characterized. The in vitro drug release was investigated under pH- and enzyme-responsive conditions, followed by transmembrane transport studies in Caco-2 cells. Finally, the oral bioavailability of ABZ@MOFs was evaluated in rats. Results: The particle sizes of ABZ@MOF-802, ABZ@UiO-66-NH₂, and ABZ@MIL-125-NH₂ were (1062.6 ± 94.8), (228.3 ± 12.3), and (502.3 ± 16.2) nm, with drug loading efficiencies of (1.71 ± 0.08%), (12.13 ± 0.04%), and (26.17 ± 0.10%), respectively. The ABZ@MOFs demonstrated structural stability in acidic environments and released ABZ under weakly acidic and neutral conditions, exhibiting distinct release profiles in the presence of different enzymes. Cellular experiments confirmed that ABZ@MOFs significantly improved transmembrane drug absorption. Pharmacokinetic analysis revealed that the bioavailability of ABZ@UiO-66-NH₂ and ABZ@MIL-125-NH₂ was 10.3-fold and 1.8-fold higher, respectively, compared to ABZ. Conclusions: The ABZ@MOFs systems effectively improved ABZ dissolution and oral bioavailability, with ABZ@UiO-66-NH₂ showing a dual response mechanism to pH and enzymes. Full article

(This article belongs to the Section Biopharmaceuticals)

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8 pages, 945 KiB

Open AccessCase Report

Triple Non-Statin Therapy with Ezetimibe, Inclisiran, and Bempedoic Acid in Patients with Genetically Confirmed Statin-Induced Rhabdomyolysis: A Dual Case Report

by Jozef Dodulík, Jiří Plášek, Ivana Kacířová, Romana Uřinovská, Jiří Vrtal and Jan Václavík

Pharmaceuticals 2025, 18(6), 818; https://doi.org/10.3390/ph18060818 - 29 May 2025

Abstract

Background: Statin intolerance is a serious therapeutic dilemma in secondary cardiovascular prevention (e.g., ESC/EAS Guidelines 2023). This is especially true when confirmed by genetic predisposition and complicated by rhabdomyolysis. Although several non-statin agents have become available in recent years, evidence regarding their combined [...] Read more.

Background: Statin intolerance is a serious therapeutic dilemma in secondary cardiovascular prevention (e.g., ESC/EAS Guidelines 2023). This is especially true when confirmed by genetic predisposition and complicated by rhabdomyolysis. Although several non-statin agents have become available in recent years, evidence regarding their combined use in high-risk statin-intolerant patients remains limited. Furthermore, the pharmacokinetics of statins in toxic concentrations are poorly characterized in clinical settings. Case Presentation: We present two cases of genetically confirmed statin-induced rhabdomyolysis, both accompanied by severe acute kidney injury requiring renal replacement therapy. In both patients, serial measurements of rosuvastatin plasma concentrations revealed markedly delayed elimination, with detectable levels persisting for several weeks despite ongoing dialysis. Estimated half-lives exceeded 7 days in both cases, far beyond the known therapeutic range. Genetic testing identified SLCO1B1, ABCB1, and CYP2C9 polymorphisms linked to reduced hepatic uptake and impaired drug clearance. Following biochemical recovery, both patients were initiated on a triple non-statin lipid-lowering regimen consisting of ezetimibe, bempedoic acid, and inclisiran. The combination was well tolerated, with no recurrence of muscle-related symptoms or biochemical toxicity. LDL-C levels were reduced from 3.05 to 1.59 mmol/L and from 4.99 to 1.52 mmol/L, respectively, with sustained response over 12 and 40 weeks. Full lipid profiles demonstrated favorable changes across all parameters. Conclusions: These two cases suggest that the combination of ezetimibe, inclisiran, and bempedoic acid may serve as a safe and effective therapeutic option in patients with severe statin intolerance. Pharmacogenetic testing and serial pharmacokinetic assessment may guide personalized lipid-lowering strategies and improve outcomes in this challenging patient population. Full article

(This article belongs to the Topic Research in Pharmacological Therapies, 2nd Edition)

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21 pages, 2118 KiB

Open AccessArticle

Metabolites from the Dendrobium Endophyte Pseudomonas protegens CM-YJ44 Alleviate Insulin Resistance in HepG2 Cells via the IRS1/PI3K/Akt/GSK3β/GLUT4 Pathway

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

Pharmaceuticals 2025, 18(6), 817; https://doi.org/10.3390/ph18060817 - 29 May 2025

Abstract

Background/Objectives: Endophytes can produce bioactive metabolites similar to their host plants. CM-YJ44 (Pseudomonas protegens CHA0, 99.24% similarity), an endophyte from Dendrobium officinale, has not yet validated hypoglycemic potential. This study aimed to evaluate its anti-insulin resistance (IR) activity and metabolite profile. [...] Read more.

Background/Objectives: Endophytes can produce bioactive metabolites similar to their host plants. CM-YJ44 (Pseudomonas protegens CHA0, 99.24% similarity), an endophyte from Dendrobium officinale, has not yet validated hypoglycemic potential. This study aimed to evaluate its anti-insulin resistance (IR) activity and metabolite profile. Methods: The fermentation broth of CM-YJ44 was separated into three fractions (CM-YJ44-1, -2, and -3) using semi-preparative high-performance liquid chromatography (pre-HPLC). An IR HepG2 cell model was constructed to evaluate their glucose uptake capacity. CM-YJ44-3 was further tested for oxidative stress, inflammatory, and insulin signaling pathway activation. Metabolites in CM-YJ44-3 were preliminarily identified using the Q Exactive Focus LC-MS system (QE), and the dendrobine content was quantified by ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS). Molecular docking was performed to predict the binding affinities between dendrobine and target proteins. Results: Among the three fractions, CM-YJ44-3 significantly reduced nitric oxide (NO) and reactive oxygen species (ROS) levels in IR cells, enhanced glycogen synthesis, upregulated the activities of pyruvate kinase (PK) and hexokinase (HK), and suppressed the expression of inflammatory factors. Its mechanism of action was mainly through activation of the IRS1/PI3K/Akt/GSK3β/GLUT4 signaling pathway. QE analysis preliminarily identified 24 metabolites in CM-YJ44-3. Quantitative analysis by UPLC-MS/MS showed that the dendrobine content was 78.73 ± 4.29 ng/mL. Molecular docking results indicated that dendrobine exhibited binding energies below −5 kcal/mol with multiple target proteins involved in this signaling pathway, suggesting it may be a key bioactive component responsible for the anti-IR effect. Conclusions: This study provides the first evidence of hypoglycemic bioactive metabolite production by strain CM-YJ44, indicating its potential as a novel microbial candidate for alleviating IR. Full article

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

17 pages, 3241 KiB

Open AccessArticle

Withaferin A Rescues Brain Network Dysfunction and Cognitive Deficits in a Mouse Model of Alzheimer’s Disease

by Linhan Yang, Yang Zou, Jihua Fan, Pu Yin, Han Qin, Zhen Li, Fengjuan Wu, Xingyi Li, Huaijin Teng, Yun Zhang, Xiaowei Chen and Sunny C. Li

Pharmaceuticals 2025, 18(6), 816; https://doi.org/10.3390/ph18060816 - 29 May 2025

Abstract

Background: Alzheimer’s disease (AD) is the most common dementia, characterized by significant cognitive impairments and neural network dysfunction. Currently, multiple therapeutic strategies are being developed to design effective anti-AD drugs. Among them, Withaferin A (WA), a natural steroidal lactone extracted from Withania somnifera [...] Read more.

Background: Alzheimer’s disease (AD) is the most common dementia, characterized by significant cognitive impairments and neural network dysfunction. Currently, multiple therapeutic strategies are being developed to design effective anti-AD drugs. Among them, Withaferin A (WA), a natural steroidal lactone extracted from Withania somnifera leaves, has been shown to reduce amyloid-β (Aβ) peptide levels in vitro. However, its potential to improve cognitive function in AD remains unclear. Methods: In this study, 5xFAD mice were administered WA (2 mg/kg intraperitoneally every 2 days) for 14 days, and its neuroprotective effects were evaluated through behavioral tests, wide-field imaging, immunohistochemistry, and ELISA. Results: WA significantly improved short-term memory, as evidenced by enhanced performance in the Novel Object Recognition Test (NORT) (p < 0.001, n = 10), Novel Location Recognition Test (NLRT) (p < 0.01, n = 14), and Three-Chamber Social Test (TCST) (p < 0.001, n = 8). WA also ameliorated long-term memory deficits in the Morris Water Maze Test (MWMT) (p < 0.05, n = 7). Furthermore, cortical wide-field Ca²⁺ imaging revealed that WA treatment rescued slow-wave impairments by enhancing long-range coherence (0.8363 ± 0.0185, p < 0.01, n = 8) and reducing the frequency of slow-wave activity (0.6578 ± 0.0512 Hz, p < 0.01, n = 8). Additionally, WA treatment significantly reduced Aβ plaque deposition in both cortical and hippocampal regions. Conclusions: These findings suggest that WA may be a promising therapeutic agent for AD, exerting neuroprotective effects. Full article

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2 pages, 1861 KiB

Open AccessCorrection

Correction: Lin et al. Huafengdan Inhibits Glioblastoma Cell Growth and Mobility by Acting on PLAU and CAV1 Targets. Pharmaceuticals 2025, 18, 428

by Dengxiao Lin, Wenfeng Yu, Jia Yu, Sha Cheng, Yu Song, Xiaoqing Wan, Yingjiang Xu, Heng Luo and Baofei Sun

Pharmaceuticals 2025, 18(6), 815; https://doi.org/10.3390/ph18060815 - 29 May 2025

Abstract

In the original publication [...] Full article

19 pages, 1401 KiB

Open AccessArticle

Design and Synthesis of Pyridine-Based Pyrrolo[2,3-d]pyrimidine Analogs as CSF1R Inhibitors: Molecular Hybridization and Scaffold Hopping Approach

by Srinivasulu Cherukupalli, Carsten Degenhart, Peter Habenberger, Anke Unger, Jan Eickhoff, Bård Helge Hoff and Eirik Sundby

Pharmaceuticals 2025, 18(6), 814; https://doi.org/10.3390/ph18060814 - 28 May 2025

Abstract

Background/Objectives: Colony stimulating factor 1 receptor kinase (CSF1R) is a well-validated molecular target in drug discovery for various reasons. Based on the structure of an early lead molecule identified in our lab and the marketed drug Pexidartinib (PLX3397), we merged fragments of [...] Read more.

Background/Objectives: Colony stimulating factor 1 receptor kinase (CSF1R) is a well-validated molecular target in drug discovery for various reasons. Based on the structure of an early lead molecule identified in our lab and the marketed drug Pexidartinib (PLX3397), we merged fragments of Pexidartinib with our pyrrolo[2,3-d]pyrimidine nucleus, and the idea was supported by initial molecular docking studies. Thus, several new compounds were synthesized with Pexidartinib fragments on C4, C5, and C6 on the pyrrolopyrimidine scaffold using molecular hybridization. Methods: Nine final products were synthesized using a combination of Buchwald-Hartwig and Suzuki-Miyaura cross-coupling reactions in three to four steps and in good yields. The analogues were subsequently profiled as CSF1R inhibitors in enzymatic and cellular assays, and ADME properties were evaluated for some derivatives. Results: N-Methyl-N-(3-methylbenzyl)-6-(6-((pyridin-3-ylmethyl)amino)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (12b) emerged as the most potent CSF1R inhibitor, showing low-nanomolar enzymatic activity, cellular efficacy, and favorable ADME properties, highlighting its promise as a lead compound for further development. Conclusions: These findings suggest that combining structural elements from previously reported CSF1R inhibitors such as Pexidartinib could guide the development of improved drug candidates targeting this kinase. Full article

(This article belongs to the Special Issue Design and Synthesis of Small Molecule Kinase Inhibitors)

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24 pages, 2839 KiB

Open AccessReview

Warburg-like Metabolic Reprogramming in Endometriosis: From Molecular Mechanisms to Therapeutic Approaches

by Bo-Sung Kim, Bosung Kim, Seyeong Yoon, Wonyoung Park, Sung-Jin Bae, Jongkil Joo, Wonnam Kim and Ki-Tae Ha

Pharmaceuticals 2025, 18(6), 813; https://doi.org/10.3390/ph18060813 - 28 May 2025

Abstract

Endometriosis is a chronic gynecological disorder characterized by the presence of endometrial-like tissue outside the uterus, leading to inflammation, pain, and infertility. Emerging evidence indicates that endometriotic lesions exhibit cancer-like properties, including metabolic reprogramming marked by increased glucose uptake, enhanced Warburg’s effect, and [...] Read more.

Endometriosis is a chronic gynecological disorder characterized by the presence of endometrial-like tissue outside the uterus, leading to inflammation, pain, and infertility. Emerging evidence indicates that endometriotic lesions exhibit cancer-like properties, including metabolic reprogramming marked by increased glucose uptake, enhanced Warburg’s effect, and altered mitochondrial function. These metabolic adaptations support cell survival under hypoxic conditions and contribute to immune evasion and sustained proliferation. This review summarizes current findings on the molecular mechanisms driving metabolic reprogramming in endometriosis, including the roles of mitochondrial dysfunction, hypoxia-inducible factor (HIF) signaling, the PI3K/AKT/mTOR pathway, inflammatory cytokines, and genetic and epigenetic regulators. In addition, we discuss therapeutic strategies targeting glycolytic pathways using both synthetic inhibitors and natural compounds, which represent promising non-hormonal options. Finally, we highlight the need for further preclinical and clinical studies to validate metabolic interventions and improve outcomes for patients with endometriosis. Full article

(This article belongs to the Special Issue Pharmacotherapy of Endometriosis)

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24 pages, 1926 KiB

Open AccessReview

Epithelial Cell Dysfunction in Pulmonary Fibrosis: Mechanisms, Interactions, and Emerging Therapeutic Targets

by Jing Wang and Jie Chao

Pharmaceuticals 2025, 18(6), 812; https://doi.org/10.3390/ph18060812 - 28 May 2025

Abstract

Pulmonary fibrosis (PF) is a progressive and fatal interstitial lung disease characterized by chronic epithelial injury and excessive deposition of extracellular matrix (ECM) driven by dysregulated repair. Increasing evidence has shown that epithelial cell dysfunction plays a key role in PF, involving epithelial–mesenchymal [...] Read more.

Pulmonary fibrosis (PF) is a progressive and fatal interstitial lung disease characterized by chronic epithelial injury and excessive deposition of extracellular matrix (ECM) driven by dysregulated repair. Increasing evidence has shown that epithelial cell dysfunction plays a key role in PF, involving epithelial–mesenchymal transition (EMT), chronic oxidative stress, disruption of epithelial–immune interactions, and promoting pathological remodeling. Single-cell analyses have identified functionally distinct subpopulations of type 2 alveolar (AT2) cells with pro-fibrotic potential. Epithelial cells exhibit metabolic and epigenetic alterations during PF, which provide new approaches for therapeutic targets. This review summarizes the molecular mechanisms driving epithelial dysfunction in fibrosis progression, with a focus on key regulatory pathways, including transforming growth factor-beta (TGF-β), Wnt, and Notch signaling pathways, as well as miRNA-mediated networks. We also explored emerging epithelial-targeted therapies, ranging from FDA-approved agents (pirfenidone, nintedanib) to experimental inhibitors targeting Galectin-3 and Wnt/β-catenin, providing insights into precision anti-fibrosis strategies for clinical translation. Full article

(This article belongs to the Section Biopharmaceuticals)

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18 pages, 339 KiB

Open AccessReview

Chemoprevention of Colorectal Cancer—With Emphasis on Low-Dose Aspirin and Anticoagulants

by Arnar Snaer Agustsson and Einar Stefan Bjornsson

Pharmaceuticals 2025, 18(6), 811; https://doi.org/10.3390/ph18060811 - 28 May 2025

Abstract

Background and Aims: Colorectal cancer (CRC) remains the third most common cancer worldwide and a leading cause of cancer-related death. Chemoprevention through widely used pharmaceutical agents has garnered increasing interest due to its potential cost-effectiveness and accessibility. This review summarizes current evidence from [...] Read more.

Background and Aims: Colorectal cancer (CRC) remains the third most common cancer worldwide and a leading cause of cancer-related death. Chemoprevention through widely used pharmaceutical agents has garnered increasing interest due to its potential cost-effectiveness and accessibility. This review summarizes current evidence from observational studies, randomized controlled trials, and meta-analyses on the association between commonly prescribed medications and CRC incidence and survival, with particular emphasis on low-dose aspirin and oral anticoagulants (OACs). Scope: Aspirin is the most extensively studied agent, with substantial evidence supporting its protective effect on CRC-specific survival, particularly in long-term users, those with COX-2 overexpression, or PIK3CA mutations. OACs have recently gained attention due to their association with increased gastrointestinal bleeding, which may facilitate earlier CRC detection. While emerging evidence suggests a possible survival benefit through this mechanism, data remain heterogeneous and affected by methodological challenges such as lead-time bias. Metformin is associated with improved CRC outcomes, primarily in patients with type 2 diabetes, though its direct anti-tumor potential remains under investigation. Corticosteroids, statins, and beta-blockers have both limited and inconclusive evidence. Finally, recent studies on vitamin D, calcium, and folic acid suggest inconsistent associations, often confounded by lifestyle factors or underlying comorbidities. Conclusions: While promising, chemoprevention strategies require further validation in well-designed, mechanistically informed studies that account for confounding variables, treatment duration, and tumor biology. Personalized prevention—guided by genetic, molecular, and clinical risk factors—represents a promising path forward. Full article

(This article belongs to the Section Medicinal Chemistry)

17 pages, 3142 KiB

Open AccessArticle

Evaluation of the In Vitro Permeation Parameters of Topical Diclofenac Sodium from Transdermal Pentravan^® Products and Hydrogel Celugel Through Human Skin

by Urszula Adamiak-Giera, Michał Gackowski, Joanna Szostak, Tomasz Osmałek, Damian Malinowski, Anna Nowak, Anna Machoy-Mokrzyńska, Maciej Miernik, Mirosław Halczak, Maciej Romanowski, Anna Czerkawska and Monika Białecka

Pharmaceuticals 2025, 18(6), 810; https://doi.org/10.3390/ph18060810 - 28 May 2025

Abstract

Background: Diclofenac is a phenylacetic acid derivative classified as a non-selective COX inhibitor. Similar to other NSAIDs, it is characterized by anti-inflammatory, antipyretic, and analgesic effects. Long-term therapy with diclofenac might also lead to severe gastrointestinal, renal, or cardiovascular systems disorders. Aim of [...] Read more.

Background: Diclofenac is a phenylacetic acid derivative classified as a non-selective COX inhibitor. Similar to other NSAIDs, it is characterized by anti-inflammatory, antipyretic, and analgesic effects. Long-term therapy with diclofenac might also lead to severe gastrointestinal, renal, or cardiovascular systems disorders. Aim of the study was to compare own formulation prepared from pharmaceutical raw materials with ready-to-use diclofenac product. Methods: In the in vitro permeation experiments, human skin was excised from the abdomen of living patients as a result of plastic surgery. The transdermal semi-solid formulations were compounded using Pentravan^®, a ready-to-use transdermal base and hydrophilic gel base (Celugel). In vitro Penetration Studies, HPLC analysis, optical microscopy imaging, and a spreadability test were conducted. Rheological analysis provided insights into flow behavior, structure, and thixotropy. Results: Combination of Celugel with diclofenac sodium and the addition of substances acting as absorption enhancers, e.g., menthol, may provide an interesting alternative for enteral drugs, especially in patients with multimorbidity and polypharmacy. Conclusions: Topical diclofenac sodium with of addition of permeation enhancers like menthol might provide higher drug concentrations in the surrounding tissues and better analgesic and anti-inflammatory effects in compare to commercially available product and may provide optimum effectiveness with minimal risk of adverse effects, particularly in elderly and polymedicated patients. Full article

(This article belongs to the Section Pharmaceutical Technology)

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19 pages, 3012 KiB

Open AccessArticle

A Novel Brain-Targeting Nanoparticle Loaded with Biatractylolide and Its Protective Effect on Alzheimer’s Disease

by Qianmei Hu, Candi Liu, Jiawang Tan, Jixiang Wang, Hao Yang, Yi Liu, Haochu Mao, Zixuan Jiang, Xing Feng and Xiaojun Tao

Pharmaceuticals 2025, 18(6), 809; https://doi.org/10.3390/ph18060809 - 28 May 2025

Abstract

Background: To enhance the bioavailability and neuroprotective efficacy of biatractylolide against Alzheimer’s disease by developing a novel Tween-80-modified pullulan–chenodeoxycholic acid nanoparticle as a delivery vehicle. Methods: Chenodeoxycholic acid (CDCA) was chemically conjugated to pullulan to yield hydrophobically modified pullulan (PUC), onto which [...] Read more.

Background: To enhance the bioavailability and neuroprotective efficacy of biatractylolide against Alzheimer’s disease by developing a novel Tween-80-modified pullulan–chenodeoxycholic acid nanoparticle as a delivery vehicle. Methods: Chenodeoxycholic acid (CDCA) was chemically conjugated to pullulan to yield hydrophobically modified pullulan (PUC), onto which polysorbate 80 (Tween-80) was subsequently adsorbed. The PUC polymers with CDCA substitution levels were analyzed by ¹H NMR spectroscopy. Nanoparticles were fabricated via the dialysis method and characterized by transmission electron microscopy and dynamic light scattering for morphology, size, and surface charge. In vitro neuroprotection was assessed by exposing SH-SY5Y and PC12 cells to 20 µM Aβ_25-35 to induce cytotoxicity, followed by pretreatment with biatractylolide-loaded PUC (BD-PUC) nanoparticle solutions at various biatractylolide concentrations. The in vivo brain-targeting capability of both empty PUC and BD-PUC particles was evaluated using a live imaging system. Results: The ¹H NMR analysis confirmed three distinct CDCA substitution degrees (8.97%, 10.66%, 13.92%). Transmission electron microscopy revealed uniformly dispersed, spherical nanoparticles. Dynamic light scattering measurements showed a hydrodynamic diameter of ~200 nm and a negative zeta potential. Exposure to 20 µM Aβ_25-35 significantly reduced SH-SY5Y and PC12 cell viability; pretreatment with BD-PUC nanoparticles markedly enhanced cell survival rates and preserved cellular morphology compared to cells treated with free biatractylolide. Notably, the cytoprotective effect of BD-PUC exceeded that of the free drug. In vivo imaging demonstrated that both empty PUC and Tween-80-adsorbed BD-PUC nanoparticles effectively accumulated in the brain. Conclusions: The protective effect of BD-PUC on SH-SY5Y and PC12 cells induced by Aβ_25-35 was higher than free biatractylolide solution, and the BD-PUC nanosolution modified with Tween-80 showed a brain-targeting effect. Full article

(This article belongs to the Special Issue Natural Products for Therapeutic Potential)

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14 pages, 2228 KiB

Open AccessArticle

Protective Effects of Xanthorrhizol-Rich Extracts Against PM-Induced Skin Damage in Human Keratinocytes and 3D-Reconstructed Skin Models

by Haneul Kang, Eun-Ji Ko, Dahye Lee, Junhui Kang, Jae-Kwan Hwang and Eunsoo Kim

Pharmaceuticals 2025, 18(6), 808; https://doi.org/10.3390/ph18060808 - 28 May 2025

Abstract

Background: Particulate matter (PM) is a major environmental pollutant that induces oxidative stress, inflammation, and extracellular matrix (ECM) degradation, leading to skin damage and accelerated aging. Xanthorrhizol (XAN), a bioactive compound derived from Curcuma xanthorrhiza Roxb., exhibits anti-inflammatory and antioxidative properties, making it [...] Read more.

Background: Particulate matter (PM) is a major environmental pollutant that induces oxidative stress, inflammation, and extracellular matrix (ECM) degradation, leading to skin damage and accelerated aging. Xanthorrhizol (XAN), a bioactive compound derived from Curcuma xanthorrhiza Roxb., exhibits anti-inflammatory and antioxidative properties, making it a promising candidate for protecting against PM-induced skin damage. This study investigated the protective effects of XAN and C. xanthorrhiza supercritical extract (CXSE) on PM-exposed skin cells. Methods: A 3D-reconstructed skin model and HaCaT human keratinocytes were exposed to PM (100 µg/mL) with or without CXSE or XAN. Histological analysis, enzyme-linked immunosorbent assay (ELISA), Western blot, reverse transcription-polymerase chain reaction (RT-PCR), and reporter gene assays were performed to assess the ECM integrity, inflammatory cytokine production, aryl hydrocarbon receptor (AhR) activation, and oxidative stress responses. Results: PM exposure activates AhR and mitogen-activated protein kinases (MAPK) signaling, increases reactive oxygen species (ROS) levels, and upregulates matrix metalloproteinases (MMPs) and inflammatory cytokines. CXSE and XAN suppresses AhR-mediated transcriptional activity and downregulates the expression of AhR target genes. Additionally, CXSE and XAN reduces ROS production by upregulating antioxidant enzyme-related genes. Conclusions: CXSE and XAN protect against PM-induced skin damage by inhibiting oxidative stress, inflammation, and ECM degradation, highlighting their potential as natural anti-pollution skincare ingredients. Full article

(This article belongs to the Section Natural Products)

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