Pharmaceuticals

25 pages, 4246 KB

Open AccessArticle

Drug Delivery Device Design and Compatibility with Nitrogen Dioxide Gas Sterilization

by Noelle Ray, Julia Diane Schexnayder, Aiysha Ashfaq, Nusrat Sarwahrdy, Delaney Lisco, Minufar Abdollahi Khabisi, Trevor Bateman, Tom Sadler, David Opie and Mohamad Al-Sheikhly

Pharmaceuticals 2025, 18(12), 1869; https://doi.org/10.3390/ph18121869 - 8 Dec 2025

Abstract

Polymeric materials have become important components in prefilled syringes, drug delivery systems, and advanced medical devices. Background/Objectives: Nitrogen dioxide gas is used for the terminal sterilization of drug delivery systems. For the implementation of sterilization methods, compatibility with materials must be demonstrated [...] Read more.

Polymeric materials have become important components in prefilled syringes, drug delivery systems, and advanced medical devices. Background/Objectives: Nitrogen dioxide gas is used for the terminal sterilization of drug delivery systems. For the implementation of sterilization methods, compatibility with materials must be demonstrated such that the materials maintain product requirements and specifications after sterilization and at the time of use (i.e., product shelf life). Methods: Commonly used polymers were selected based on their chemical structures to provide insight into the nature of reactions that occur at the temperature and NO₂ concentration levels used in the sterilization process. After exposure to the NO₂ process, materials were evaluated for chemical, mechanical, and biocompatibility properties. Results: In this paper, we demonstrated the compatibility of polymers comprising carbonyl, unsaturated ester, and ketone groups which have been used in medical devices sterilized with NO₂. No significant chemical or physical changes were observed upon the treatment of Amorphous Polyester, Polysulfone (PSU), Polycarbonate (PC), PolyEtherEtherKetone (PEEK), PolyArylEtherKetone (PAEK), and Polypropylene (PP) with NO₂ at a sterilization temperature of 20 °C. At this relatively low sterilization temperature, the reactions of NO₂ with the polymer do not typically occur because the activation energies of these reactions require much higher temperatures. Conclusions: Not all materials will be compatible with NO₂ sterilization, and even with the established data, many devices will need to have their polymers evaluated for compatibility before moving to NO₂ sterilization. These results will provide guidance to device designers selecting materials for new drug delivery devices and to regulators that review the safety and efficacy of these devices. Full article

(This article belongs to the Section Pharmaceutical Technology)

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20 pages, 3005 KB

Open AccessArticle

Biological Activities of Stachys rupestris, Development of S. rupestris Extract-Loaded Alginate Films as Wound Dressing

by Erkan Rayaman, Turgut Taşkın, Elif Çalışkan Salihi, Shalaleh Hasan Niari Niar, Duygu Taşkın, Ceyda Ekentok Atıcı, Ömer Kılıç, Pervin Rayaman, Pelin Özçelik and Hatice Kübra Elçioğlu

Pharmaceuticals 2025, 18(12), 1868; https://doi.org/10.3390/ph18121868 - 8 Dec 2025

Abstract

Background/Objectives: Regardless of the underlying cause, wound infections are among the most common complications associated with wound formation. The increasing prevalence of antibiotic resistance poses significant challenges in wound management. Due to their favorable therapeutic properties, alginate films have recently emerged as [...] Read more.

Background/Objectives: Regardless of the underlying cause, wound infections are among the most common complications associated with wound formation. The increasing prevalence of antibiotic resistance poses significant challenges in wound management. Due to their favorable therapeutic properties, alginate films have recently emerged as promising biomaterials for wound treatment. Methods: The petroleum ether, chloroform, and methanol extracts of the endemic plant Stachys rupestris were prepared using the maceration technique. The antimicrobial activity of the extracts and the extract-loaded alginate film was evaluated by agar well diffusion and microdilution assays, while their antibiofilm activity was assessed by crystal violet staining in microplates. The anti-infective potential was investigated using the Caenorhabditis elegans infection model, the phytochemical composition was analyzed by HPLC-DAD, and cytotoxicity was determined by the MTT assay. The alginate film was prepared by the solvent casting method and characterized using FTIR spectroscopy and light microscopy. Results: All extracts demonstrated antimicrobial activity, with the methanol extract exhibiting the most potent antimicrobial and antibiofilm effects. Quinic acid was identified as the major constituent. Both the methanol extract and the film displayed no cytotoxic effects and showed significant antimicrobial and antibiofilm activities. Conclusions: The S. rupestris methanol extract-loaded film exhibited strong antimicrobial and antibiofilm properties, indicating its potential as a valuable therapeutic agent in supporting wound healing. Full article

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15 pages, 2970 KB

Open AccessArticle

Synthesis and Evaluation of AS1411-Lenalidomide-Targeted Degradation Chimera in Antitumor Therapy

by Xueling Ma, Shuangshuang Liu, Xiao Dong, Xiuhua Li, Feiyan Wang, Jiawei Zhang, Zhenfang Xu, Weiguo Shi, Aiping Zheng, Aiping Zhang, Xuesong Feng and Liang Xu

Pharmaceuticals 2025, 18(12), 1867; https://doi.org/10.3390/ph18121867 - 7 Dec 2025

Abstract

Background: High expression of nucleolin (NCL) on the surface of tumor cells is closely associated with disease progression and poor prognosis. The aptamer–PROTAC conjugate (APC) technology provides a novel molecular design strategy for the targeted degradation of NCL. Methods: Based on [...] Read more.

Background: High expression of nucleolin (NCL) on the surface of tumor cells is closely associated with disease progression and poor prognosis. The aptamer–PROTAC conjugate (APC) technology provides a novel molecular design strategy for the targeted degradation of NCL. Methods: Based on the principles of PROTAC technology and chemical modification techniques, in this study, a series of AS1411-lenalidomide chimeras featuring different linker structures were designed and synthesized for the specific purpose of targeted degradation of NCL. Four AS1411-PROTACs (C1–C4) were successfully constructed via a click chemistry strategy, and their structures were validated. Results: In vitro experimental results showed that C4 exhibited the most optimal activity, significantly downregulating NCL expression and inhibiting the proliferation of breast cancer cells (MCF-7). Notably, the activity of C4 remained unaltered regardless of the annealing process. Mechanistic studies demonstrated that C4 induced NCL degradation through the ubiquitin–proteasome pathway while also promoting apoptosis and cell cycle arrest. In a nude mouse tumor model, C4 displayed potent antitumor efficacy, with no discernible signs of obvious systemic toxicity. Conclusions: This study provides compelling evidence demonstrating that C4 is a highly promising anticancer compound. It also provides important evidence for the development of novel nucleic acid aptamer–PROTAC conjugate drugs for more clinical applications. Full article

(This article belongs to the Special Issue Advances in Enzyme Inhibitors and Protein Degraders as Anticancer Agents)

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22 pages, 4228 KB

Open AccessArticle

Integrated Transcriptomic, Proteomic, and Network Pharmacology Analyses Unravel Key Therapeutic Mechanisms of Xuebijing Injection for Severe Acute Pancreatitis

by Linbo Yao, Xinmin Yang, Mei Yuan, Shiyu Liu, Qiqi Wang, Yongzi Wu, Wenjuan Luo, Xueying Wu, Wenhao Cai, Lan Li, Ziqi Lin, Juqin Yang, Tingting Liu, Robert Sutton, Peter Szatmary, Tao Jin, Qing Xia and Wei Huang

Pharmaceuticals 2025, 18(12), 1866; https://doi.org/10.3390/ph18121866 - 7 Dec 2025

Abstract

Background: Xuebijing Injection (XBJ), a plant-derived traditional Chinese medicine administered as an injection, is widely used in clinical practice to treat various acute critical illnesses including severe acute pancreatitis (SAP). The mechanisms by which XBJ alleviates SAP remain elusive. Methods: Active components of [...] Read more.

Background: Xuebijing Injection (XBJ), a plant-derived traditional Chinese medicine administered as an injection, is widely used in clinical practice to treat various acute critical illnesses including severe acute pancreatitis (SAP). The mechanisms by which XBJ alleviates SAP remain elusive. Methods: Active components of XBJ were identified using UPLC-QTOF/MS. A mouse SAP model was established by intraperitoneal injections of cerulein (50 μg/kg/h × 7) followed by lipopolysaccharide (10 mg/kg). XBJ of 2.5, 5, and 10 mL/kg was co-administered twice after induction of SAP. The protective effects of XBJ on pancreatic acinar cells were further investigated in vitro. An integrated analysis of transcriptomic data from human and mouse blood, as well as mouse lung, combined with network pharmacology were employed to delineate the therapeutic mechanisms of XBJ on SAP, followed by pancreatic immunoblotting and proteomics validation. Results: Component analysis revealed 9 active ingredients of XBJ. XBJ at 10 mL/kg had the best effect and consistently decreased pancreatic, lung, and circulatory pro-inflammatory indices. XBJ dose-dependently reduced necrotic cell death activation. Transcriptomics, proteomics and network pharmacology analyses identified 14 key targets, with IL-17-related signaling pathways being the most significant. Experimental validation further confirmed that XBJ significantly reduced serum levels of key IL-17-related inflammatory cytokines (such as IL-17, IL-1β, IL-6, and TNF-α) and downregulated the mRNA expression of related inflammatory factors in pancreatic tissue. Virtual docking and surface plasmon resonance demonstrate that hydroxysafflor yellow A had the highest binding affinity with MMP-9, MAPK14, and LCN2. Crucially, subsequent pancreatic immunoblotting and proteomics analyses did not confirm significant direct modulation of these targets at the protein level within pancreatic tissue. Conclusions: XBJ attenuates SAP severity by quelling pro-inflammatory mediators, an effect chiefly attributed to modulating systemic IL-17–related signaling rather than direct pancreatic intervention. Full article

(This article belongs to the Special Issue New and Emerging Treatment Strategies for Gastrointestinal Diseases)

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15 pages, 10321 KB

Open AccessArticle

Structure-Based Virtual Screening for KHK-A Inhibitors with Anti-Hepatocellular Carcinoma Activity

by Jiang-Yi Zhu, Xiao-Yang Han, Zi-Ying Zhou, Yue-Yue Guo, Hao-Tian Duan, Jia-Jia Shen and Si-Tu Xue

Pharmaceuticals 2025, 18(12), 1865; https://doi.org/10.3390/ph18121865 - 6 Dec 2025

Abstract

Background: Hepatocellular carcinoma (HCC) is the sixth most common malignant tumor worldwide and is associated with a poor prognosis. Oxidative stress is a key factor in the occurrence and progression of HCC. KHK-A, a key protein in the oxidative stress pathway, plays an [...] Read more.

Background: Hepatocellular carcinoma (HCC) is the sixth most common malignant tumor worldwide and is associated with a poor prognosis. Oxidative stress is a key factor in the occurrence and progression of HCC. KHK-A, a key protein in the oxidative stress pathway, plays an important role in various cancers. This study aimed to discover small-molecule inhibitors targeting KHK-A through structure-based virtual screening, evaluate their therapeutic effects on HCC, and explore the potential of KHK-A as a therapeutic target for HCC. Methods: Based on the crystal structure of KHK-A, potential small-molecule inhibitors (HK1 to HK-24) were screened from the SPECS database using the Discovery Studio (DS) 2019 software. The effects of these compounds were evaluated through molecular docking and cellular experiments. Results: The screened compound HK-4 significantly inhibited HCC cell proliferation, migration, and invasion ex vivo. The half-maximal inhibitory concentrations (IC₅₀) of HK-4 in HepG2, PLC/PRF/5, and HuH7 cells were 22.54 µM, 23.91 µM, and 23.38 µM, respectively. HK-4 induced G1 phase arrest and apoptosis, and reduced the protein levels of p-AKT and p-mTOR in the PI3K-AKT signaling pathway. Conclusion: Through structure-based virtual screening, this study identified HK-4, a small-molecule inhibitor of KHK-A with anti-HCC activity. Its mechanism of action is closely related to the regulation of the PI3K-AKT signaling pathway. This finding provides experimental evidence supporting KHK-A as a therapeutic target for HCC and offers a new direction for the development of novel anti-HCC drugs. Full article

(This article belongs to the Special Issue Heterocyclic Compounds in Medicinal Chemistry, 2nd Edition)

29 pages, 6397 KB

Open AccessArticle

Pine-Extracted Phytosterol β-Sitosterol (APOPROSTAT^® Forte) Inhibits Both Human Prostate Smooth Muscle Contraction and Prostate Stromal Cell Growth, Without Cytotoxic Effects: A Mechanistic Link to Clinical Efficacy in LUTS/BPH

by Alexander Tamalunas, Felix Schierholz, Henrik Poth, Victor Vigodski, Michael Brandstetter, Anna Ciotkowska, Beata Rutz, Sheng Hu, Leo Federico Stadelmeier, Heiko Schulz, Stephan Ledderose, Nina Rogenhofer, Thomas Kolben, Christian Georg Stief and Martin Hennenberg

Pharmaceuticals 2025, 18(12), 1864; https://doi.org/10.3390/ph18121864 - 6 Dec 2025

Abstract

Introduction: Medical treatment of lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH) targets prostate smooth muscle tone for rapid relieve of symptoms and prostate size to prevent disease progression. Recently, EAU guidelines introduced phytomedicines for treatment of LUTS/BPH. Phytosterols [...] Read more.

Introduction: Medical treatment of lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH) targets prostate smooth muscle tone for rapid relieve of symptoms and prostate size to prevent disease progression. Recently, EAU guidelines introduced phytomedicines for treatment of LUTS/BPH. Phytosterols may reduce the risk of prostate diseases and seem to be the smallest common denominator between different phytotherapeutic preparations. Thus, we investigated the effects of the highly concentrated phytosterol β-sitosterol on human prostate smooth muscle contraction and cellular functions, including contraction and growth of prostate stromal cells. Materials and Methods: APOPROSTAT^® forte capsules (>70% β-sitosterol, ethanol extract of Pinus pinaster) were dissolved in ethanol. Contractions were induced in human prostate tissues (n = 100) obtained from radical prostatectomy and assessed in organ bath setups. Cytoskeletal organization, proliferation, viability, cytotoxicity, and contraction in stromal cells (WPMY-1) were assessed using phalloidin staining, EdU, colony formation, CCK-8, flow cytometry, and matrix collagen assays. Results: APOPROSTAT^® forte (0.1–30 µg/mL) inhibited adrenergic, non-adrenergic, and neurogenic contractions of human prostate tissues by up to 71%, 69%, and 63%, respectively, in a dose-dependent manner. In WPMY-1 cells, it reduced proliferation and actin organization by up to 67% and 75% after 72 h, without affecting viability or inducing cytotoxicity. Colony formation decreased by up to 60% after 168 h, and contraction in collagen matrix assays was reduced by 57% in a concentration- and time-dependent manner. Conclusions: The natural phytosterol β-sitosterol effectively inhibits both prostate contraction and growth with a favorable safety profile, supporting its beneficial role in LUTS management through phytotherapy. Full article

(This article belongs to the Section Pharmacology)

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38 pages, 8927 KB

Open AccessArticle

An Ongoing Search for Multitarget Ligands as Potential Agents for Diabetes Mellitus and Its Long-Term Complications: New Insights into (5-Arylidene-4-oxothiazolidin-3-yl)alkanoic Acid Derivatives

by Rosanna Maccari, Rosaria Ottanà, Valerij Talagayev, Roberta Moschini, Francesco Balestri, Francesca Felice, Francesca Iannuccilli, Gemma Sardelli, Rebecca Sodano, Gerhard Wolber, Paolo Paoli and Antonella Del Corso

Pharmaceuticals 2025, 18(12), 1863; https://doi.org/10.3390/ph18121863 - 5 Dec 2025

Abstract

Background: Diabetes mellitus is a multifactorial disease characterized by complex metabolic dysfunctions and chronic complications induced by hyperglycaemia. The design of multitarget ligands, capable of simultaneously controlling different pathogenic processes, was proposed as a promising approach to identify novel antidiabetic drugs endowed [...] Read more.

Background: Diabetes mellitus is a multifactorial disease characterized by complex metabolic dysfunctions and chronic complications induced by hyperglycaemia. The design of multitarget ligands, capable of simultaneously controlling different pathogenic processes, was proposed as a promising approach to identify novel antidiabetic drugs endowed with improved efficacy. Methods: (5-Arylidene-4-oxothiazolidin-3-yl)alkanoic acid derivatives 1a–g and 2a–g were synthesized as potential multitarget antidiabetic agents. They were tested in vitro as inhibitors of both human recombinant AKR1B1 and PTP1B, and kinetic studies and molecular docking simulations for both enzymes were performed. Their effects on cellular glucose uptake, insulin signalling, and mitochondrial potential were assayed in cultures of murine C2C12 myocytes. A lipid accumulation assay was performed in HepG2 liver cells. The effects on high glucose-induced sorbitol accumulation were evaluated in lens HLE and retinal MIO-M1 cells. Results: All compounds displayed excellent AKR1B1 inhibitory activity (IC₅₀ 0.03–0.46 μM 1a–g; IC₅₀ 0.48–6.30 μM 2a–g); 1g and 2e–g also appreciably inhibited PTP1B at micromolar concentrations. Propanoic derivatives 2e–g significantly stimulated glucose uptake in C2C12 myocytes, in an insulin-independent way, reduced lipid accumulation in HepG2 liver cells, and caused hyperpolarization of C2C12 mitochondria at 10 μM concentration. Derivative 2e significantly reduced sorbitol accumulation in both HLE and MIO-M1 cells at a 5 μM concentration. Conclusions: The results reported here provided new insights into the mechanisms of action and structure/activity relationships of 4-thiazolidinone derivatives, underscoring the capability of compounds 2e–g of eliciting insulin-mimetic effects independent of hormone signalling. Among them, compound 2e also proved to inhibit AKR1B1-dependent sorbitol accumulation and, thus, emerged as a promising multitarget agent that can be considered for further investigations. Full article

(This article belongs to the Special Issue Antidiabetic Agents: New Drug Discovery Insights and Prospects)

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42 pages, 6181 KB

Open AccessArticle

1-Azinyl-1′-Alkenylferrocenes with Anticholinesterase, Antioxidant, and Antiaggregating Activities as Multifunctional Agents for Potential Treatment of Alzheimer’s Disease

by Galina F. Makhaeva, Irina A. Utepova, Elena V. Rudakova, Nadezhda V. Kovaleva, Natalia P. Boltneva, Elena Yu. Zyryanova, Alexandra A. Musikhina, Vladimir F. Lazarev, Snezhana A. Vladimirova, Irina V. Guzhova, Ilya N. Ganebnykh, Tatiana Y. Astakhova, Elena N. Timokhina, Oleg N. Chupakhin, Valery N. Charushin and Rudy J. Richardson

Pharmaceuticals 2025, 18(12), 1862; https://doi.org/10.3390/ph18121862 - 5 Dec 2025

Abstract

Background/Objectives: This study focused on synthesizing novel alkenyl derivatives of azinylferrocenes and evaluating their potential as Alzheimer’s disease (AD) therapeutics. Methods: 1-Azinyl-1′-acetylferrocenes were obtained by regioselective acetylation of azinylferrocenes, followed by the Wittig reaction or reduction of 1-azinyl-1′-acetylferrocenes and subsequent dehydration [...] Read more.

Background/Objectives: This study focused on synthesizing novel alkenyl derivatives of azinylferrocenes and evaluating their potential as Alzheimer’s disease (AD) therapeutics. Methods: 1-Azinyl-1′-acetylferrocenes were obtained by regioselective acetylation of azinylferrocenes, followed by the Wittig reaction or reduction of 1-azinyl-1′-acetylferrocenes and subsequent dehydration of the resulting alcohols. The synthesized compounds underwent the following biological activity testing relevant to AD: inhibition of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and off-target carboxylesterase (CES); antioxidant capacity (ABTS and FRAP assays); inhibition of Aβ₄₂ self-aggregation (thioflavin method); blocking AChE-induced β-amyloid aggregation (propidium displacement); and cytotoxicity in SH-SY5Y and MSC-Neu cells (MTT assay). Results: Quinoline and bipyridine derivatives demonstrated effective cholinesterase inhibition, especially quinoline 7b (AChE IC₅₀ 3.32 μM; BChE IC₅₀ 3.68 μM), while acridine derivatives were poor inhibitors. Quantum chemical (QC) calculations predicted that acridine derivatives were especially prone to form stable dimers. Molecular docking into protein targets generated by an AlphaFold3 reproduction code showed that these dimers were too bulky to access enzyme active sites, yet they could bind to protein surfaces to inhibit Aβ₄₂ self-aggregation and displace propidium from the AChE peripheral anionic site. All compounds showed high antioxidant activity in ABTS and FRAP assays, with quinoline derivatives being 2–4 times more potent than Trolox. QC calculations supported these findings. Quinoline and bipyridine derivatives also exhibited low cytotoxicity and scant CES inhibition. Conclusions: Overall, the synthesized ferrocenes, particularly the quinoline and bipyridine derivatives, appear promising for further research as multifunctional therapeutic agents targeting AD due to their anticholinesterase, antiaggregating, and antioxidant activities combined with low toxicity. Full article

(This article belongs to the Special Issue Current Advances, Applications and Future Development of Transition Metal Complexes, 2nd Edition)

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16 pages, 715 KB

Open AccessArticle

Awareness of Risk Minimization Measures for Valproate and Pregnancy Prevention Program Compliance Among Pharmacists: A Cross-Sectional Survey in Romania

by Madalina Huruba, Daniel Leucuta, Andreea Farcas and Cristina Mogosan

Pharmaceuticals 2025, 18(12), 1861; https://doi.org/10.3390/ph18121861 - 5 Dec 2025

Abstract

Background/Objectives: Risk minimization measures, including a pregnancy prevention program (PPP), have been established by the European Medicine Agency to strengthen the restrictions on valproate (VPA) use in pregnant women/women with childbearing potential. We aimed to assess pharmacists’ awareness of the new measures and [...] Read more.

Background/Objectives: Risk minimization measures, including a pregnancy prevention program (PPP), have been established by the European Medicine Agency to strengthen the restrictions on valproate (VPA) use in pregnant women/women with childbearing potential. We aimed to assess pharmacists’ awareness of the new measures and behavior in terms of compliance to PPP recommendations. Methods: We performed a cross-sectional, national, non-interventional survey among pharmacists between December 2024 and February 2025. No sample size calculations were performed. Inclusion criteria were pharmacists active in community pharmacies in Romania. Results: In total, 267 pharmacists were included, balanced in terms of age groups, with a slight predominance for 31–40 year olds (33.7%) and mostly female (93.3%). More than half (60.7%) did not recall receiving any type of PPP information (direct healthcare professional communication [DHPC] or educational materials [EMs]). Participants generally read the DHPC, fully (64.1%) or partially (21.4%); all reportedly read the EMs, generally fully (73.0%). Half (145, 54.2%) dispensed VPA at least once during the last 12 months. Among this subgroup, 15.2% used the EMs, 38.6% counseled the patient regarding the VPA teratogenic risk, and 32.4% counseled on the importance of effective contraceptive measures at every VPA dispensing. Neither awareness nor behavior met the pre-established success criteria; therefore, the overall PPP compliance was not demonstrated. Conclusions: Despite notable proportions of pharmacists offering counseling when dispensing, overall PPP compliance and EM use could be enhanced. More research is needed to identify why some measures are not properly adhered to, in order to increase the overall risk mitigation efficacy. Full article

(This article belongs to the Special Issue Drug Safety and Risk Management in Clinical Practice)

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19 pages, 4052 KB

Open AccessArticle

Rosuvastatin Versus Atorvastatin for Cardiovascular Disease Risk in Patients with Type 2 Diabetes: A Korean Cohort Study

by Chaeyoon Kim, Junhyuk Chang, Sujin Gan, Sohyeon Park, Kalynn Park, Hong-Ah Kim, Rae Woong Park and Sandy Jeong Rhie

Pharmaceuticals 2025, 18(12), 1860; https://doi.org/10.3390/ph18121860 - 5 Dec 2025

Abstract

Background: Rosuvastatin and atorvastatin are indicated for cardiovascular protection in patients with type 2 diabetes (T2D) but may differ in clinical effectiveness and safety. This study compared real-world cardiovascular and safety outcomes associated with rosuvastatin versus atorvastatin in patients with T2D, with [...] Read more.

Background: Rosuvastatin and atorvastatin are indicated for cardiovascular protection in patients with type 2 diabetes (T2D) but may differ in clinical effectiveness and safety. This study compared real-world cardiovascular and safety outcomes associated with rosuvastatin versus atorvastatin in patients with T2D, with an emphasis on older adults. Methods: This retrospective cohort study used electronic health records from 10 Korean hospitals standardized to the Common Data Model. Adults (≥18 years) with T2D who were newly prescribed rosuvastatin or atorvastatin were included. After propensity score matching, primary outcomes (myocardial infarction [MI], heart failure, stroke, cardiac arrest, and in-hospital death), secondary outcomes (peripheral arterial disease [PAD] and glaucoma), and safety outcomes (acute kidney injury, cataract, and myalgia) were compared. Subgroup and sensitivity analyses were conducted among patients aged ≥65 years. Results: Among 49,034 patients (rosuvastatin, 16,123; atorvastatin, 32,911), baseline characteristics were well balanced. Across all participating hospitals, the comparative analyses showed no meaningful differences in cardiovascular or safety outcomes between the two statins. However, among patients aged ≥65 years, rosuvastatin was associated with a higher risk of PAD (hazard ratio [HR] 1.19; 95% confidence interval [CI] 1.03–1.38), and this finding was consistent in sensitivity analysis (HR 1.31; 95% CI 1.01–1.70). Conclusions: Rosuvastatin and atorvastatin demonstrated comparable cardiovascular effectiveness and safety. Although rosuvastatin was associated with a modestly higher incidence of PAD in older adults, the difference was small. From a clinical perspective, these findings underscore the importance of individualized statin therapy tailored to patient-specific factors such as age, comorbidity, and vascular health. Overall, both statins provide overall therapeutic equivalence for cardiovascular prevention. Full article

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38 pages, 1411 KB

Open AccessReview

Sirtuins in Women’s Health

by Rasajna Madhusudhana, Abu Hamza, Emily Boyle, Shannon Pollock and Yana Cen

Pharmaceuticals 2025, 18(12), 1859; https://doi.org/10.3390/ph18121859 - 5 Dec 2025

Abstract

The human sirtuins (SIRT1–SIRT7) are NAD⁺-dependent protein deacylases that orchestrate key cellular events such as metabolism, stress response, DNA repair, and aging. Accumulating evidence highlights their central role in women’s health. This review integrates recent insights into the roles of sirtuins [...] Read more.

The human sirtuins (SIRT1–SIRT7) are NAD⁺-dependent protein deacylases that orchestrate key cellular events such as metabolism, stress response, DNA repair, and aging. Accumulating evidence highlights their central role in women’s health. This review integrates recent insights into the roles of sirtuins across the female lifespan and their involvement in reproductive, metabolic, oncologic, and age-related disorders. Sirtuins regulate reproductive function, pregnancy outcomes, and hormone-dependent cancers. Their decline with aging contributes to menopausal and metabolic complications. Pharmacological interventions that enhance sirtuin activity, such as NAD⁺ precursors and SIRT1 activators, show promise in mitigating these conditions. Collectively, understanding the isoform- and tissue-specific roles of sirtuins provides a foundation for developing therapeutics to improve the lifespan and healthspan of women. Full article

(This article belongs to the Special Issue Sirtuins as Novel Biological Targets for Pharmacological Intervention in Physiology and Pathology—2nd Edition)

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27 pages, 11077 KB

Open AccessReview

Research Progress of Functionalized Drug Delivery Nanosystems in Regulating Depression

by Leying Qiang and Yongquan Huo

Pharmaceuticals 2025, 18(12), 1858; https://doi.org/10.3390/ph18121858 - 5 Dec 2025

Abstract

Depression, as a highly prevalent psychiatric disorder, has emerged as a global public health challenge. Its pathological mechanisms involve the cross-regulation of multiple pathways, including neurotransmitter imbalance, neuroinflammation, and oxidative stress. Conventional oral antidepressants are limited in clinical application due to low blood–brain [...] Read more.

Depression, as a highly prevalent psychiatric disorder, has emerged as a global public health challenge. Its pathological mechanisms involve the cross-regulation of multiple pathways, including neurotransmitter imbalance, neuroinflammation, and oxidative stress. Conventional oral antidepressants are limited in clinical application due to low blood–brain barrier penetration, significant side effects, and restricted therapeutic response rates. In recent years, drug delivery nanosystems (DDNs) have achieved precise regulation and repair of the pathological processes underlying depression through various functional modification strategies, such as targeted conjugation, stimuli responsiveness, and biomimetic simulation. Future efforts should focus on promoting their clinical translation via multi-functional integration, optimization of intelligent response mechanisms, and interdisciplinary collaboration. This review systematically summarizes the major pathogenic pathways of depression, as well as the mechanisms of action and research progress of functionalized DDNs in alleviating depression by targeting and remodeling key pathogenic pathways. It provides theoretical and technical references for the precise treatment of depression and the development of precision medicine for psychiatric disorders. Full article

(This article belongs to the Section Pharmaceutical Technology)

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21 pages, 2780 KB

Open AccessArticle

Repurposing of FDA-Approved Antiviral Drugs Against Monkeypox Virus: Comparative In Vitro Screening and Structure Based In Silico Studies

by Yassmin Moatasim, Omnia Kutkat, Mokhtar Gomaa, Yaseen A. M. M. Elshaier, Mina Nabil, Ahmed A. El-Rashedy, Wael H. Roshdy, Ghazi Kayali, Mohamed Ahmed Ali and Rabeh El-Shesheny

Pharmaceuticals 2025, 18(12), 1857; https://doi.org/10.3390/ph18121857 - 5 Dec 2025

Abstract

Background/Objectives: Monkeypox is endemic to the African continent and has recently garnered global attention due to reported outbreaks in non-endemic nations. No approved drug is available for non-severe cases, and some isolates gained resistance to approved antivirals. In this study, we employed [...] Read more.

Background/Objectives: Monkeypox is endemic to the African continent and has recently garnered global attention due to reported outbreaks in non-endemic nations. No approved drug is available for non-severe cases, and some isolates gained resistance to approved antivirals. In this study, we employed a drug repositioning strategy to evaluate the efficacy of existing FDA-approved antiviral drugs if repurposed for use against emerging Monkeypox, representing a cost-effective method for identifying novel therapeutic interventions. Methods: Methodology including Egyptian virus strain isolation, propagation and titration followed by in vitro studies, molecular docking and molecular dynamics simulations combined with binding free energy were carried out. Twenty-three FDA-approved drugs, including Abacavir, Acyclovir, Amantadine, Chloroquine, Daclatasvir, Dolutegravir, Entecavir, Favipiravir, Hydroxychloroquine, Lamivudine, Molnupiravir, Nevirapine, Oseltamivir, Penciclovir, Remdesivir, Ribavirin, Sofosbuvir, Tenofovir, Valaciclovir, Valganciclovir, Velpatasvir, Zanamivir, and Zidovudine, were screened for potential anti-monkeypox activity in vitro. In silico studies were carried out against three monkeypox proteins, Thymidylate Kinase, A42R Profilin-Like Protein, and VACV D13, to identify their potential targets. Results: In vitro testing showed that two antiviral drugs are positive. The employed computational methods indicate that remdesivir demonstrated superior binding patterns with elevated scores and stable complexes throughout the simulation. Conclusions: Our findings showed that Remdesivir therapeutic compound is potent against the tested strain of MPXV, and exhibited a robust binding affinity for Thymidylate Kinase, A42R Profilin-Like Protein, and VACV D13 enzymes, and thus may potentially be utilized as antiviral for the treatment of monkeypox virus. Full article

(This article belongs to the Section Medicinal Chemistry)

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15 pages, 272 KB

Open AccessArticle

Pharmacological Evaluation of Ticagrelor and Aspirin Versus Clopidogrel and Aspirin Pretreatment on Infarct Artery Flow in Patients with Acute STEMI

by Miljan Opancina, Valentina Opancina, Miloš N. Milosavljević, Ana V. Pejčić, Milos Stepovic and Zoran Jovic

Pharmaceuticals 2025, 18(12), 1856; https://doi.org/10.3390/ph18121856 - 5 Dec 2025

Abstract

Background and Objectives: Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor is standard in ST-segment elevation myocardial infarction (STEMI). Guidelines favor ticagrelor over clopidogrel, but their effect on infarct artery flow prior to percutaneous coronary intervention (PCI) remains debated. Objective [...] Read more.

Background and Objectives: Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor is standard in ST-segment elevation myocardial infarction (STEMI). Guidelines favor ticagrelor over clopidogrel, but their effect on infarct artery flow prior to percutaneous coronary intervention (PCI) remains debated. Objective was to compare the effects of aspirin + clopidogrel versus aspirin + ticagrelor pretreatment on infarct artery Thrombolysis in Myocardial Infarction (TIMI) flow in STEMI patients. Materials and Methods: This retrospective cohort study included first-time STEMI patients ≥ 18 years admitted to the Military Medical Academy, Belgrade (January 2016–January 2022), who received pretreatment with aspirin + clopidogrel or aspirin + ticagrelor and underwent PCI. TIMI flow was graded before and after PCI. Primary outcomes were pre- and post-PCI TIMI flow; secondary outcome was in-hospital mortality. Results: Of 299 STEMI patients, 174 received aspirin + ticagrelor and 125 received aspirin + clopidogrel. Pre-PCI TIMI flow was significantly higher in the ticagrelor group (p < 0.001), while post-PCI TIMI flow (p = 0.056) and in-hospital mortality (p = 0.083) did not significantly differ between groups. After exclusion of patients receiving glycoprotein IIb/IIIa inhibitors, the difference in PCI TIMI flow grade after PCI became statistically significant (p = 0.007), favoring the aspirin + ticagrelor group. In multivariate analysis, male gender, drug-eluting stent implantation, and glycoprotein IIb/IIIa inhibitor use were independently associated with reduced in-hospital mortality. Conclusions: In STEMI patients, ticagrelor-based DAPT was associated with better initial coronary flow compared to clopidogrel. However, this advantage was not evident after PCI. Male gender, drug-eluting stent implantation, and glycoprotein IIb/IIIa inhibitor use were associated with improved survival. Full article

(This article belongs to the Section Pharmacology)

11 pages, 958 KB

Open AccessArticle

VEGF Signaling Pathway Germline Polymorphisms as Prognostic Pharmacogenetic Biomarkers in Localized High-Grade Osteosarcoma Patients from the GEIS-33 Protocol

by Juliana Salazar, María J. Arranz, Javier Martin-Broto, Massimo Serra, Emanuela Palmerini, Jeronimo Martínez-García, Antonio Juan-Ribelles, Maitane Andion, Javier Martinez-Trufero, Guiomar Gutiérrez, Aizpea Echebarria-Barona, Maria A. Vaz-Salgado, Alexandra Regueiro, Rosa Alvarez, Claudia Valverde, Pablo Luna, Pilar Blay and Ana Sebio

Pharmaceuticals 2025, 18(12), 1855; https://doi.org/10.3390/ph18121855 - 5 Dec 2025

Abstract

Background/Objective: The vascular endothelial growth factor (VEGF) signaling pathway induces angiogenesis, which impacts tumor progression and clinical outcomes in patients with localized osteosarcoma. This study evaluates whether genetic polymorphisms in the VEGF signaling pathway are associated with survival outcomes in these patients. Methods: [...] Read more.

Background/Objective: The vascular endothelial growth factor (VEGF) signaling pathway induces angiogenesis, which impacts tumor progression and clinical outcomes in patients with localized osteosarcoma. This study evaluates whether genetic polymorphisms in the VEGF signaling pathway are associated with survival outcomes in these patients. Methods: Sixty-nine patients with localized high-grade osteosarcoma enrolled in the GEIS-33 protocol and treated with MAP (methotrexate, doxorubicin, cisplatin) chemotherapy, surgery, and subsequent adjuvant treatment were included. Nine variants of interest in the VEGFA (rs1570360, rs2010963 and rs699947), FLT1 (VEGFR1; rs7993418, rs9513070 and rs9582036), and KDR (VEGFR2; rs1551641 and rs1870377 and rs2071559) genes were genotyped from peripheral blood samples using TaqMan Assay technology. Genetic data were correlated with relapse-free survival (RFS) and overall survival (OS) considering clinical variables as covariates. Results: The analyses showed nominally significant associations between the FLT1 variants rs7993418 and rs9582036 and survival. Patients carrying the rs7993418(C) allele had worse RFS (p = 0.01) and OS (p = 0.01). Carriers of the minor rs9582036(C) allele also had worse RFS (p = 0.02) and OS (p = 0.03). Additionally, patients harboring the TT genotype of the KDR rs1551641 variant had significantly worse RFS (p = 0.002). These polymorphisms remained statistically significant in the multivariate Cox regression analyses that included surgical margins and pathological response as covariates. Conclusions: Pharmacogenetics may contribute to precision medicine in oncology. Germline polymorphisms in the VEGF pathway may be useful as predictors of survival in high-grade localized osteosarcoma patients treated with chemotherapy, following validation in a large cohort of patients. Current treatment strategies aimed at improving outcomes for osteosarcoma patients may benefit from the identification of new biomarkers, such as these FLT1 rs7993418 and rs9582036 variants. Full article

(This article belongs to the Special Issue Osteosarcomas: Treatment Strategies, 2nd Edition)

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30 pages, 7533 KB

Open AccessArticle

Structure-Guided Design of Novel Diarylpyrimidine-Based NNRTIs Through a Comprehensive In Silico Approach: 3D-QSAR, ADMET Evaluation, Molecular Docking, and Molecular Dynamics

by Mouna Baassi, Mohamed Moussaoui, Sanchaita Rajkhowa, Hatim Soufi, Rachid Daoud and Said Belaaouad

Pharmaceuticals 2025, 18(12), 1854; https://doi.org/10.3390/ph18121854 - 5 Dec 2025

Abstract

Background/Objectives: The emergence of drug-resistant HIV-1 strains challenges the long-term efficacy of current antiretroviral therapies. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are critical in HIV-1 treatment; however, the need for new candidates with improved resistance profiles and pharmacokinetics remains. This study aims to design [...] Read more.

Background/Objectives: The emergence of drug-resistant HIV-1 strains challenges the long-term efficacy of current antiretroviral therapies. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are critical in HIV-1 treatment; however, the need for new candidates with improved resistance profiles and pharmacokinetics remains. This study aims to design and evaluate novel NNRTIs targeting both wild-type (WT) and mutant-type (MT) HIV-1 reverse transcriptase (RT) using integrated computational strategies. Methods: We conducted a 3D-QSAR study on 33 naphthyl-diarylpyrimidine derivatives using CoMFA and CoMSIA models. We designed thirty-five novel molecules based on contour map insights. We applied ADMET and drug-likeness filters to prioritize ten candidates. Molecular docking was performed on WT (PDB: 3HVT) and MT (PDB: 4PUO) RT structures. The top candidates underwent 100 ns molecular dynamics (MD) simulations. We analyzed structural stability via RMSD, RMSF, and Rg, while we used SASA and MolSA to assess solvent exposure and surface compactness. Results: The CoMFA and CoMSIA models demonstrated robust predictivity (R² = 0.979/0.920, Q² = 0.643/0.546, R²_test = 0.747/0.603). P14 and P43 showed higher binding affinities than nevirapine and favorable ADMET profiles. MD simulations confirmed stable binding in WT-RT and adaptive flexibility in MT-RT. SASA and MolSA analysis revealed favorable conformational compaction. Drug-likeness profiles indicated optimal log P, strong hydrogen bonding, and acceptable bioavailability. Conclusions: P14 and P43 demonstrate strong potential as NNRTI leads, combining binding affinity, structural stability, and favorable pharmacokinetics, supporting further experimental development. Full article

(This article belongs to the Special Issue Application of 2D and 3D-QSAR Models in Drug Design)

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10 pages, 459 KB

Open AccessArticle

SAR Modeling to Predict Ames Mutagenicity Across Different Salmonella typhimurium Strains

by Alexander V. Dmitriev, Alexey A. Lagunin, Anastasia V. Rudik, Polina I. Savosina, Dmitry S. Druzhilovskiy, Dmitry A. Filimonov and Vladimir V. Poroikov

Pharmaceuticals 2025, 18(12), 1853; https://doi.org/10.3390/ph18121853 - 4 Dec 2025

Abstract

Background: The Ames test, a biological assay employing various strains of Salmonella typhimurium, serves as a cornerstone in genetic toxicology for evaluating the mutagenic and potentially carcinogenic properties of chemical compounds. However, experimental testing is resource-intensive and time-consuming for screening the vast [...] Read more.

Background: The Ames test, a biological assay employing various strains of Salmonella typhimurium, serves as a cornerstone in genetic toxicology for evaluating the mutagenic and potentially carcinogenic properties of chemical compounds. However, experimental testing is resource-intensive and time-consuming for screening the vast chemical space of existing and novel drug candidates in pharmaceutical development. Methods: To address this limitation, we have developed the Ames Mutagenicity Predictor web application, which predicts mutagenic activity in the Ames test for given structural formulas across a comprehensive panel of different bacterial strains. The application utilizes advanced structure–activity relationship (SAR) models generated by PASS (Prediction of Activity Spectra for Substances) v2024 software. The training set comprised 3250 compounds with experimentally determined mutagenicity across 69 different strains, compiled from peer-reviewed literature and established databases, and 4285 non-mutagenic compounds from the WWAD as negative examples. Results: Leave-one-out cross-validation (LOOCV) of the 69 strain-specific models yielded an average Invariant Accuracy of Prediction (IAP) of about 0.944, and for the unspecified mutagenicity, a value of 0.962 was obtained. Conclusions: These validated models have been integrated into a freely accessible web application Ames Mutagenicity Predictor that enables users to input compound structures through multiple formats: a built-in chemical editor, SMILES notation, or compound name search. The application generates comprehensive reports detailing the predicted probability of positive Ames test results for each individual strain, providing researchers with detailed mutagenicity profiles. Full article

(This article belongs to the Special Issue QSAR and Chemoinformatics in Drug Design and Discovery)

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21 pages, 4146 KB

Open AccessArticle

Network Pharmacology Analysis and Experimental Study of Yinchen Against Neuroinflammation in Ischemic Stroke

by Minmin Guo, Yijie Ma, Linlin Wang, Ruipeng Ge, You Wang, Gefei Ma, Guanhua Du and Li Li

Pharmaceuticals 2025, 18(12), 1852; https://doi.org/10.3390/ph18121852 - 4 Dec 2025

Abstract

Objective: Ischemic stroke (IS) is an acute neurologic injury in which inflammatory responses play a key role. Yinchen, a common medicinal plant used in Traditional Chinese Medicine (TCM), has been proven to possess strong anti-inflammatory effects. However, its efficacy in treating IS remains [...] Read more.

Objective: Ischemic stroke (IS) is an acute neurologic injury in which inflammatory responses play a key role. Yinchen, a common medicinal plant used in Traditional Chinese Medicine (TCM), has been proven to possess strong anti-inflammatory effects. However, its efficacy in treating IS remains unclear. In this study, we aimed to investigate the therapeutic potential of Yinchen for IS and the material basis of this potential. Methods: The main active components in Artemisia scoparia extract (ASE, the extract of Yinchen), were identified by HPLC and MS. The targets of Yinchen and IS were obtained from public databases. Network pharmacology, molecular docking, and experimental investigation were further applied to acquire the core constituents in Yinchen that work against the neuroinflammation that occuring during IS. The neurological outcomes were evaluated in a transient Middle Cerebral Artery Occlusion (tMCAO) rat model. Additionally, the changes in the inflammatory responses in both the ischemic brain and in lipopolysaccharide (LPS)-treated microglial cells were examined using real-time qPCR. Results: Four active compounds of ASE, including isochlorogenic acid C (ICGA-C), isochlorogenic acid B (ICGA-B), isochlorogenic acid A (ICGA-A), and chlorogenic acid (CGA), were identified by HPLC and MS. Network pharmacology predicted that 103 compounds of Yinchen had 198 intersection targets with IS. The top five of these targets were TNF, STAT3, IL1B, AKT1, and SRC. Molecular docking results demonstrated that the abovementioned four compounds detected in ASE showed good interaction with all of the above five core targets. Moreover, both the four compounds and ASE were observed to attenuate NO release and suppress the release of various inflammatory factors (TNF-α, IL-1β, IL-6, and MCP-1) in a dose-dependent manner in LPS-induced BV2 microglial cells. ASE was further found to exert neuroprotective effects against ischemia–reperfusion (I/R) injury and inhibit the production of inflammatory factors in tMCAO rats. Conclusions: Yinchen exerts an anti-neuroinflammatory effect on IS, and its constituents with high scores binding to five core targets contribute to this effect. This supports its potential as an anti-inflammatory agent for the treatment of IS. Full article

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

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20 pages, 4100 KB

Open AccessArticle

Therapeutic Potential of Gynostemma pentaphyllum (Thunb.) Makino Against COVID-19 Identified Through Network Pharmacology

by Min Ho Kim, Jin Ah Won, Jun Sang Yu, Su Min Kim, Dong Keun Lee, Xiang-Lan Piao and Hye Hyun Yoo

Pharmaceuticals 2025, 18(12), 1851; https://doi.org/10.3390/ph18121851 - 4 Dec 2025

Abstract

Background/Objectives: The ongoing challenges posed by COVID-19 have highlighted the need for multi-target therapeutic strategies addressing both acute immune responses and systemic complications. Gynostemma pentaphyllum (Thunb.) Makino, a traditional herbal medicine rich in flavonoids and saponins, exhibits diverse pharmacological activities, including immunomodulatory and [...] Read more.

Background/Objectives: The ongoing challenges posed by COVID-19 have highlighted the need for multi-target therapeutic strategies addressing both acute immune responses and systemic complications. Gynostemma pentaphyllum (Thunb.) Makino, a traditional herbal medicine rich in flavonoids and saponins, exhibits diverse pharmacological activities, including immunomodulatory and cardiovascular effects. In this study, we investigated the potential of G. pentaphyllum as a complementary treatment for COVID-19 using a network pharmacology approach combined with molecular docking analysis. Methods: To delve into the therapeutic mechanisms of G. pentaphyllum, we identified 59 active compounds and predicted 408 protein targets, of which 19 overlapped with COVID-19-associated genes, including IL1B, IL6, TNF, ACE, and REN. GO and KEGG enrichment analyses were conducted to determine relevant biological processes and pathways, focusing on cytokine signaling, inflammatory responses, and the renin–angiotensin system. Network analyses evaluated interactions of flavonoids and triterpenoid saponins with immunological, inflammatory, renin–angiotensin system, and host entry pathways. Molecular docking was performed to validate the binding affinities of key compounds to their predicted targets. Results: The compound–target–pathway network revealed class-specific patterns: flavonoids primarily mapped to immuno-inflammatory nodes, whereas triterpenoid saponins were enriched for renin–angiotensin system/host-entry–related targets. Docking energies spanned −6.1 to −11.9 kcal/mol, with six compound–target pairs ≤ −10.0 kcal/mol. Notably, NOS2–rutin (−11.9 kcal/mol), NOS2–gypenoside LI (−11.6 kcal/mol), and ACE–gypenoside LI (−11.3 kcal/mol) showed the strongest affinities. Conclusions: These findings provide evidence that G. pentaphyllum exerts therapeutic effects through the complementary actions of flavonoid and saponin components, each modulating distinct molecular pathways. This dual mechanistic potential underscores the value of G. pentaphyllum as a versatile therapeutic for COVID-19 therapy. Full article

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

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