Pharmaceuticals

14 pages, 2020 KiB

Open AccessArticle

Impact of Age and Menopausal Status on T-DM1 (Ado-Trastuzumab Emtansine) Treatment Outcomes in HER2-Positive Breast Cancer

by Heves Surmeli, Deniz Isik, Oguzcan Kinikoglu, Yunus Emre Altintas, Ugur Ozkerim, Sıla Oksuz, Tugba Basoglu, Hatice Odabas and Nedim Turan

Pharmaceuticals 2025, 18(6), 931; https://doi.org/10.3390/ph18060931 - 19 Jun 2025

Viewed by 495

Abstract

Background/Objectives: HER2-positive breast cancer is an aggressive subtype with an established responsiveness to HER2-targeted therapies like ado-trastuzumab emtansine (T-DM1). However, inter-patient variability in treatment response and toxicity remains a challenge. Hormonal status, particularly menopausal state, may influence breast cancer behavior, therapeutic tolerance, [...] Read more.

Background/Objectives: HER2-positive breast cancer is an aggressive subtype with an established responsiveness to HER2-targeted therapies like ado-trastuzumab emtansine (T-DM1). However, inter-patient variability in treatment response and toxicity remains a challenge. Hormonal status, particularly menopausal state, may influence breast cancer behavior, therapeutic tolerance, and outcomes, yet data on its effect in patients treated with T-DM1 are scarce. This study aimed to evaluate whether menopausal status independently affects treatment response, side effects, and survival outcomes in HER2-positive breast cancer patients receiving T-DM1, accounting for the confounding role of age. Methods: This retrospective cohort study included 98 female patients with HER2-positive breast cancer treated with T-DM1: 53 premenopausal and 45 postmenopausal. The clinical characteristics, metastatic patterns, treatment history, T-DM1 outcomes, and toxicities were recorded. The statistical analysis included chi-square, t-tests, Mann–Whitney U tests, and Spearman’s correlations. Partial correlation analyses were conducted to isolate the effect of menopausal status by controlling for age. Results: The postmenopausal patients showed higher rates of lung metastasis (42.2% vs. 20.8%) and mortality (60.0% vs. 39.6%) than premenopausal patients. However, no significant differences were found in the T-DM1 response or toxicity profiles. After adjusting for age, menopausal status had no independent association with the treatment outcomes or side effects. Age was the dominant factor influencing performance status, metastatic burden, and mortality risk. Conclusions: Menopausal status affects disease presentation but not T-DM1 efficacy or toxicity when age is accounted for. Treatment decisions should consider age and clinical profile rather than menopausal classification alone when managing HER2-positive breast cancer with T-DM1. Full article

(This article belongs to the Section Biopharmaceuticals)

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5 pages, 164 KiB

Open AccessEditorial

Pharmacotherapy of Neuropathic Pain

by Sergio Marques Borghi

Pharmaceuticals 2025, 18(6), 930; https://doi.org/10.3390/ph18060930 - 19 Jun 2025

Viewed by 400

Abstract

Despite advances in recent decades, the management of neuropathic pain remains one of the greatest challenges in modern clinical medicine [...] Full article

(This article belongs to the Special Issue Pharmacotherapy of Neuropathic Pain)

16 pages, 815 KiB

Open AccessReview

Nerve Growth Factor in Pediatric Brain Injury: From Bench to Bedside

by Lorenzo Di Sarno, Serena Ferretti, Lavinia Capossela, Antonio Gatto, Valeria Pansini, Anya Caroselli, Luigi Manni, Marzia Soligo and Antonio Chiaretti

Pharmaceuticals 2025, 18(6), 929; https://doi.org/10.3390/ph18060929 - 19 Jun 2025

Viewed by 380

Abstract

Background: Traumatic brain injury (TBI) and hypoxic–ischemic encephalopathy (HIE) are major causes of long-term neurological disability in children, with limited options for effective neuronal recovery. Recent research has highlighted the therapeutic potential of nerve growth factor (NGF) in promoting neural repair through mechanisms [...] Read more.

Background: Traumatic brain injury (TBI) and hypoxic–ischemic encephalopathy (HIE) are major causes of long-term neurological disability in children, with limited options for effective neuronal recovery. Recent research has highlighted the therapeutic potential of nerve growth factor (NGF) in promoting neural repair through mechanisms such as neuroprotection, neurogenesis, and the modulation of neuroinflammation. This review evaluates the current evidence on NGF as a treatment strategy for pediatric brain injury, emphasizing its mechanisms of action and translational clinical applications. Methods: A comprehensive review was conducted using the PubMed, Scopus, and Cochrane CENTRAL databases to identify studies published between 1 January 1978 and 1 March 2025, investigating NGF in the context of brain injury. The inclusion criteria comprised studies assessing neurological outcomes through clinical scales, biochemical markers, neuroimaging, or electrophysiological examinations. Results: Seventeen studies met the inclusion criteria, encompassing both preclinical and clinical research. Preclinical models consistently demonstrated that NGF administration reduces neuroinflammation, enhances neurogenesis, and supports neuronal survival following TBI and HIE. Clinical studies, including case reports of pediatric patients treated with intranasal NGF, reported improvements in motor and cognitive function, neuroimaging findings, and electrophysiological parameters, with no significant adverse effects observed. Conclusions: NGF demonstrates significant promise as a neuroprotective and neuroregenerative agent in pediatric brain injury, with both experimental and early clinical evidence supporting its safety and efficacy. Large-scale controlled clinical trials are warranted to validate these preliminary findings and to determine the optimal dosage regimens and administration schedules for NGF in the treatment of TBI and HIE. Full article

(This article belongs to the Special Issue Applications of Nerve Growth Factor in Pharmaceuticals)

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48 pages, 3898 KiB

Open AccessReview

Stable Gastric Pentadecapeptide BPC 157 as a Therapy and Safety Key: A Special Beneficial Pleiotropic Effect Controlling and Modulating Angiogenesis and the NO-System

by Predrag Sikiric, Sven Seiwerth, Anita Skrtic, Mario Staresinic, Sanja Strbe, Antonia Vuksic, Suncana Sikiric, Dinko Bekic, Dragan Soldo, Boris Grizelj, Luka Novosel, Lidija Beketic Oreskovic, Ivana Oreskovic, Mirjana Stupnisek, Alenka Boban Blagaic and Ivan Dobric

Pharmaceuticals 2025, 18(6), 928; https://doi.org/10.3390/ph18060928 - 19 Jun 2025

Viewed by 1912

Abstract

Although approached through many concepts, the pleiotropic healing issue, specifically, maintaining/reestablishing tissue integrity, remains a central challenge in pharmacology, particularly when the process is misdirected or not properly controlled. Robert and Szabo’s concept of cytoprotection holds that innate cell (epithelial (Robert), endothelial (Szabo)) [...] Read more.

Although approached through many concepts, the pleiotropic healing issue, specifically, maintaining/reestablishing tissue integrity, remains a central challenge in pharmacology, particularly when the process is misdirected or not properly controlled. Robert and Szabo’s concept of cytoprotection holds that innate cell (epithelial (Robert), endothelial (Szabo)) integrity and protection/maintenance/reestablishment in the stomach is translated to other organ therapy (cytoprotection → organoprotection) via the cytoprotection agent’s effect. Therefore, we defend stable gastric pentadecapeptide BPC 157 therapy’s efficacy and pleiotropic beneficial effects, along with its high safety (LD1 not achieved), against speculation of its negative impact, speculation of angiogenesis toward tumorigenesis, increased NO and eNOS, damaging free radical formation, and neurodegenerative diseases (Parkinson’s disease and Alzheimer’s disease). Contrarily, in wound healing and general healing capabilities, as reviewed, as a cytoprotective agent and native cytoprotection mediator, BPC 157 controls angiogenesis and the NO-system’s healing functions and counteracts the pathological presentation of neurodegenerative diseases in acknowledged animal models (i.e., Parkinson’s disease and Alzheimer’s disease), and it presents prominent anti-tumor potential in vivo and in vitro. BPC 157 resolved cornea transparency maintenance, cornea healing “angiogenic privilege” (vs. angiogenesis/neovascularization/tumorigenesis), and it does not produce corneal neovascularization but rather opposes it. Per Folkman’s concept, it demonstrates an anti-tumor effect in vivo and in vitro. BPC 157 exhibits a distinctive effect on the NO-level (increase vs. decrease), always combined with the counteraction of free radical formation, and, in mice and rats, BPC 157 therapy counteracts Parkinson’s disease-like and Alzheimer’s disease-like disturbances. Thus, BPC 157 therapy means targeting angiogenesis and NO’s cytotoxic and damaging actions but maintaining, promoting, or recovering their essential protective functions. Full article

(This article belongs to the Special Issue Application of Gastrointestinal Peptides in Medicine)

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22 pages, 3876 KiB

Open AccessArticle

In Vivo PK-PD and Drug–Drug Interaction Study of Dorzagliatin for the Management of PI3Kα Inhibitor-Induced Hyperglycemia

by Guanqin Jin, Kewei Zheng, Shihuang Liu, Huan Yi, Wei Wei, Congjian Xu, Xiaoqiang Xiang and Yu Kang

Pharmaceuticals 2025, 18(6), 927; https://doi.org/10.3390/ph18060927 - 19 Jun 2025

Viewed by 420

Abstract

Objectives: The anticancer effects of PI3Kα inhibitors (PI3Ki) are constrained by their hyperglycemic side effects, while the efficacy of conventional hypoglycemic agents, such as insulin, metformin, and SGLT-2 inhibitors, in mitigating PI3Ki-induced hyperglycemia remains suboptimal. Dorzagliatin, a novel glucokinase activator, has been approved [...] Read more.

Objectives: The anticancer effects of PI3Kα inhibitors (PI3Ki) are constrained by their hyperglycemic side effects, while the efficacy of conventional hypoglycemic agents, such as insulin, metformin, and SGLT-2 inhibitors, in mitigating PI3Ki-induced hyperglycemia remains suboptimal. Dorzagliatin, a novel glucokinase activator, has been approved in China for the management of hyperglycemia, offering a promising alternative. This study aims to investigate the pharmacokinetic properties and potential mechanisms of drug interactions of dorzagliatin in the regulation of PI3K-induced hyperglycemia. Methods: Plasma concentrations of WX390, BYL719, and Dorz in mice were measured using high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. Pharmacokinetic (PK) parameters and PK/PD models were derived by using Phoenix WinNonlin 8.3.5 software. Blood glucose levels at various time points and tumor volume changes over a four-week period were assessed to explore the interactions when PI3Ki were combined with dorzagliatin. Results: The results indicated that, compared to the Dorz group, the combination groups (Dorz + BYL719, Dorz + WX390) exhibited increases in

{A U C}_{0 \to t}

of dorzagliatin by 41.65% and 20.25%, and in C_max by 33.48% and 13.32%, respectively. In contrast, co-administration of these PI3Ki with dorzagliatin resulted in minimal increase in their plasma exposure. The combination therapy group (Dorz+BYL719) exhibited superior antitumor efficacy compared to the BYL719 group. Conclusions: Our findings indicate that the drug–drug interactions (DDIs) between dorzagliatin and multiple PI3Ki (including WX390 and BYL719) may partially account for the enhanced antitumor efficacy observed in the combination therapy group compared to PI3Ki monotherapy. This interaction may be explained by the inhibition of P-glycoprotein (P-gp) and the pharmacological mechanism of dorzagliatin regarding the activation of insulin regulation. Full article

(This article belongs to the Special Issue Mathematical Modeling in Drug Metabolism and Pharmacokinetics)

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19 pages, 2030 KiB

Open AccessArticle

From Ethnopharmacology to Active Compound: Effects of Traditional Plant Extracts on Varicose Vein-Related Enzymes and Isolation of Active Flavonoids from Helichrysum plicatum DC. subsp. plicatum

by Tugsen Buyukyildirim, F. Sezer Senol Deniz, Merve Yuzbasioglu Baran, Ece Salihoglu, Mustafa Abdullah Yilmaz and Osman Tugay

Pharmaceuticals 2025, 18(6), 926; https://doi.org/10.3390/ph18060926 - 19 Jun 2025

Viewed by 481

Abstract

Background: Varicose veins and chronic venous insufficiency are chronic venous disorders involving abnormalities in the venous system. Inflammation, an increase in proteolytic enzymes, and free radicals are important factors that play a role in the varicose vein pathology. Methods: In this study, the [...] Read more.

Background: Varicose veins and chronic venous insufficiency are chronic venous disorders involving abnormalities in the venous system. Inflammation, an increase in proteolytic enzymes, and free radicals are important factors that play a role in the varicose vein pathology. Methods: In this study, the antioxidant properties and inhibitor activities of 17 plant extracts used to treat varicose veins in traditional medicine were evaluated against varicose veins-related enzymes (hyaluronidase, elastase, collagenase, lipooxygenase, prolylendopeptidase, and xanthine oxidase). The most effective compounds responsible for the activity of the Helichrysum plicatum subsp. plicatum extract were isolated by open column chromatography techniques. The active compounds were determined to be naringenin, apigenin, and luteolin by spectroscopic methods. In the activity-guided isolation study, the xanthine oxidase enzyme inhibition method was used. Results: The fractions containing naringenin and apigenin (IC₅₀ = 0.269 ± 0.009 µg/mL) and apigenin and luteolin (IC₅₀ = 0.285 ± 0.019 µg/mL) compounds showed synergistic and strong effects against xanthine oxidase and were found to be as active as the positive control allopurinol (IC₅₀ = 0.250 ± 0.006 µg/mL). In the LC-MS/MS analysis of the Helichrysum plicatum extract, quinic acid (22.649 mg compound/g extract), chlorogenic acid (14.573 mg/g extract), isoquercitrin (14.371 mg/g extract), cosmosin (9.885 mg/g extract), and astragalin (11.506 mg/g extract) were detected as the major components. Naringenin, apigenin, and luteolin were detected at concentrations of 1.457, 2.518, and 1.368 mg/g in the extract, respectively. Conclusions: In conclusion, it is predicted that the combination of naringenin, apigenin, and luteolin has a promising use as a conservative treatment option for diseases associated with varicose veins due to their synergistic effects with each other. Full article

(This article belongs to the Section Natural Products)

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27 pages, 4059 KiB

Open AccessArticle

3D-QSAR Design of New Bcr-Abl Inhibitors Based on Purine Scaffold and Cytotoxicity Studies on CML Cell Lines Sensitive and Resistant to Imatinib

by David Cabezas, Thalía Delgado, Guisselle Sepúlveda, Petra Krňávková, Veronika Vojáčková, Vladimír Kryštof, Miroslav Strnad, Nicolás Ignacio Silva, Javier Echeverría, Christian Espinosa-Bustos, Guido Mellado, Jiao Luo, Jaime Mella and Cristian O. Salas

Pharmaceuticals 2025, 18(6), 925; https://doi.org/10.3390/ph18060925 - 19 Jun 2025

Viewed by 527

Abstract

Background/Objectives: Bcr-Abl inhibitors such as imatinib have been used to treat chronic myeloid leukemia (CML). However, the efficacy of these drugs has diminished due to mutations in the kinase domain, notably the T315I mutation. Therefore, in this study, new purine derivatives were designed [...] Read more.

Background/Objectives: Bcr-Abl inhibitors such as imatinib have been used to treat chronic myeloid leukemia (CML). However, the efficacy of these drugs has diminished due to mutations in the kinase domain, notably the T315I mutation. Therefore, in this study, new purine derivatives were designed as Bcr-Abl inhibitors based on 3D-QSAR studies. Methods: A database of 58 purines that inhibit Bcr-Abl was used to construct 3D-QSAR models. Using chemical information from these models, a small group of new purines was designed, synthesized, and evaluated in Bcr-Abl. Viability assays were conducted on imatinib-sensitive CML cells (K562 and KCL22) and imatinib-resistant cells (KCL22-B8). In silico analyses were performed to confirm the results. Results: Seven purines were easily synthesized (7a–g). Compounds 7a and 7c demonstrated the highest inhibition activity on Bcr-Abl (IC₅₀ = 0.13 and 0.19 μM), surpassing the potency of imatinib (IC₅₀ = 0.33 μM). 7c exhibited the highest potency, with GI₅₀ = 0.30 μM on K562 cells and 1.54 μM on KCL22 cells. The GI₅₀ values obtained for non-neoplastic HEK293T cells indicated that 7c was less toxic than imatinib. Interestingly, KCL22-B8 cells (expressing Bcr-Abl^T315I) showed greater sensitivity to 7e and 7f than to imatinib (GI₅₀ = 13.80 and 15.43 vs. >20 μM, respectively). In silico analyses, including docking and molecular dynamics studies of Bcr-Abl^T315I, were conducted to elucidate the enhanced potency of 7e and 7f. Thus, this study provides in silico models to identify novel inhibitors that target a kinase of significance in CML. Full article

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

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12 pages, 1713 KiB

Open AccessArticle

Influence of Tariquidar, an ABC Transporter Inhibitor, on the Ca²⁺-Dependent Mitochondrial Permeability Transition Pore

by Tatiana A. Fedotcheva, Alexey G. Kruglov and Nadezhda I. Fedotcheva

Pharmaceuticals 2025, 18(6), 924; https://doi.org/10.3390/ph18060924 - 19 Jun 2025

Viewed by 343

Abstract

Background: Tariquidar (Tq) is an inhibitor of the multidrug resistance (MDR) proteins relevant to ATP-binding cassette transporters (ABC transporters), which suppresses the ATP-dependent efflux of a variety of hydrophilic and amphipathic compounds, including anticancer drugs. Tq is a representative of a new [...] Read more.

Background: Tariquidar (Tq) is an inhibitor of the multidrug resistance (MDR) proteins relevant to ATP-binding cassette transporters (ABC transporters), which suppresses the ATP-dependent efflux of a variety of hydrophilic and amphipathic compounds, including anticancer drugs. Tq is a representative of a new generation of MDR inhibitors with high affinity to ABC proteins. However, there are still no data on the possible effect of Tq on mitochondria as an important target in the regulation of cell death or survival. Methods: We investigated the influence of Tq on the Ca²⁺-dependent mitochondrial permeability transition pore (mPTP). The effect of Tq was assessed using several parameters, including the calcium load, membrane potential, and mitochondrial swelling. To evaluate the specific targets of Tq, selective inhibitors of components of the mitochondrial pore were used, including adenine nucleotides, carboxyatractylozide (Catr) and bongkrekic acid (BA), oligomycin, and cyclosporine A. Results: Tq decreased the calcium retention capacity, activated mitochondrial swelling, and lowered the influence of ADP and ATP, the inhibitors of the Ca²⁺-induced pore opening, at their low concentrations. These effects of Tq were observed in both calcium-load and swelling assays, thus mimicking the effect of Catr, a selective inhibitor of adenine nucleotide translocase (ANT). Tq also decreased the protective effect of BA, an inhibitor of ANT and mPTP, on the calcium retention capacity of mitochondria. Further, Tq dose-dependently decreased the inhibitory effect of a low ATP concentration but not of high concentrations, at which the effect of Tq was activated by oligomycin, an inhibitor of F-ATP synthase. Conclusions: The influence of Tq extends to mitochondria, specifically to the regulation of membrane permeability, promoting the activation of pore opening, probably through an interaction with ANT, a component of the pore-forming complex. The effect of Tq on the opening of mPTP is strongly dependent on the concentrations of adenine nucleotides and, consequently, on the functional state of mitochondria. The direct influence of Tq on mitochondria can be considered as a new activity that promotes the sensitization of cells to various treatments and stimuli. Full article

(This article belongs to the Section Biopharmaceuticals)

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17 pages, 3077 KiB

Open AccessArticle

Development of Mannitol-Based Microparticles for Dry Powder Inhalers: Enhancing Pulmonary Delivery of NSAIDs

by Petra Party, Zsófia Ilona Piszman and Rita Ambrus

Pharmaceuticals 2025, 18(6), 923; https://doi.org/10.3390/ph18060923 - 19 Jun 2025

Viewed by 483

Abstract

Background/Objectives: Chronic lung diseases are among the leading causes of death worldwide. In the treatment of these diseases, non-steroidal anti-inflammatory drugs can be effective. We have previously developed an excipient formulation alongside a modern manufacturing protocol, which we aim to further investigate. We [...] Read more.

Background/Objectives: Chronic lung diseases are among the leading causes of death worldwide. In the treatment of these diseases, non-steroidal anti-inflammatory drugs can be effective. We have previously developed an excipient formulation alongside a modern manufacturing protocol, which we aim to further investigate. We have chosen two new model drugs, meloxicam (MX) and its water-soluble salt, meloxicam-potassium (MXP). The particles in dry powder inhaler (DPI) formulation were expected to have a spherical shape, fast drug release, and good aerodynamic properties. Methods: The excipients were poloxamer-188, mannitol, and leucine. The samples were prepared by spray drying, preceded by solution preparation and wet grinding. Particle size was determined by laser diffraction, shape by scanning electron microscopy (SEM), crystallinity by powder X-ray diffraction (PXRD), interactions by Fourier-transform infrared spectroscopy (FT-IR), in vitro drug dissolution by paddle apparatus, and in vitro aerodynamic properties by Andersen cascade impactor and Spraytec^® device. Results: We achieved the proper particle size (<5 μm) and spherical shape according to laser diffraction and SEM. The XRPD showed partial amorphization. FT-IR revealed no interaction between the materials. During the in vitro dissolution tests, more than 90% of MX and MXP were released within the first 5 min. The best products exhibited an aerodynamic diameter of around 4 µm, a fine particle fraction around 50%, and an emitted fraction over 95%. The analysis by Spraytec^® supported the suitability for lung targeting. Conclusions: The developed preparation process and excipient system can be applied in the development of different drugs containing DPIs. Full article

(This article belongs to the Special Issue Recent Advances in Inhalation Therapy)

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18 pages, 1994 KiB

Open AccessArticle

Prognostic Modeling of Deleterious IDUA Mutations L238Q and P385R in Hurler Syndrome Through Molecular Dynamics Simulations

by Madhana Priya Nanda Kumar, Esakki Dharsini Selvamani, Archana Pai Panemangalore, Sidharth Kumar Nanda Kumar, Vasundra Vasudevan and Magesh Ramasamy

Pharmaceuticals 2025, 18(6), 922; https://doi.org/10.3390/ph18060922 - 19 Jun 2025

Viewed by 536

Abstract

MPS I (Mucopolysaccharidosis type I) is a rare lysosomal storage disease originating from the deficiency of the enzyme alpha-L-iduronidase, encoded by the IDUA gene, which impairs the degradation of glycosaminoglycans (GAGs) and diminishes biological functioning across several organs. Background: Out of the eleven [...] Read more.

MPS I (Mucopolysaccharidosis type I) is a rare lysosomal storage disease originating from the deficiency of the enzyme alpha-L-iduronidase, encoded by the IDUA gene, which impairs the degradation of glycosaminoglycans (GAGs) and diminishes biological functioning across several organs. Background: Out of the eleven MPS disorders, MPS I includes three syndromes, of which the first, named Hurler syndrome, affects the most. Methods: Several in silico tools were used, such as ConSurf (73 variants), Mutation Assessor (69 variants), PredictSNP, MAPP, PhDSNP, Polyphen-1, Polyphen-2, SIFT, SNAP, PANTHER, MetaSNP (24 variants); Missense 3D-DB (11 variants) and AlignGVGD (eight variants) for physicochemical properties; and I-Mutant, Mupro, CUPSAT, and INPS for stability predictions (four variants). Results: A molecular docking study was performed for the two variants: L238Q and P385R scored −7.22 and −7.05 kcal/mol, respectively, and the native scored −7.14 kcal/mol with IDR as the ligand. Molecular dynamics anticipated how these molecules fluctuate over a period of 100 nanoseconds. Conclusions: Alpha-L-iduronidase enzyme has a critical role in the lysosomal degradation of glycosaminoglycans. According to the comparative analysis of the three structures by MDS, P385R had the least stability in all aspects of the plots. Our study demonstrates that the mutation significantly alters protein stability and binding efficiency with the ligands. Full article

(This article belongs to the Special Issue Computational Predictions of Molecules with Potential Therapeutic Effects)

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35 pages, 2933 KiB

Open AccessReview

NEU1-Mediated Extracellular Vesicle Glycosylation in Alzheimer’s Disease: Mechanistic Insights into Intercellular Communication and Therapeutic Targeting

by Mohd Adnan, Arif Jamal Siddiqui, Fevzi Bardakci, Malvi Surti, Riadh Badraoui and Mitesh Patel

Pharmaceuticals 2025, 18(6), 921; https://doi.org/10.3390/ph18060921 - 19 Jun 2025

Viewed by 588

Abstract

Alzheimer’s disease (AD), a progressive neurodegenerative disorder, is marked by the pathological accumulation of amyloid-β plaques and tau neurofibrillary tangles, both of which disrupt neuronal communication and function. Emerging evidence highlights the role of extracellular vesicles (EVs) as key mediators of intercellular communication, [...] Read more.

Alzheimer’s disease (AD), a progressive neurodegenerative disorder, is marked by the pathological accumulation of amyloid-β plaques and tau neurofibrillary tangles, both of which disrupt neuronal communication and function. Emerging evidence highlights the role of extracellular vesicles (EVs) as key mediators of intercellular communication, particularly in the propagation of pathological proteins in AD. Among the regulatory factors influencing EV composition and function, neuraminidase 1 (NEU1), a lysosomal sialidase responsible for desialylating glycoproteins has gained attention for its involvement in EV glycosylation. This review explores the role of NEU1 in modulating EV glycosylation, with particular emphasis on its influence on immune modulation and intracellular trafficking pathways and the subsequent impact on intercellular signaling and neurodegenerative progression. Altered NEU1 activity has been associated with abnormal glycan profiles on EVs, which may facilitate the enhanced spread of amyloid-β and tau proteins across neural networks. By regulating glycosylation, NEU1 influences EV stability, targeting and uptake by recipient cells, primarily through the desialylation of surface glycoproteins and glycolipids, which alters the EV charge, recognition and receptor-mediated interactions. Targeting NEU1 offers a promising therapeutic avenue to restore EV homeostasis and reduces pathological protein dissemination. However, challenges persist in developing selective NEU1 inhibitors and effective delivery methods to the brain. Furthermore, altered EV glycosylation patterns may serve as potential biomarkers for early AD diagnosis and monitoring. Overall, this review highlights the importance of NEU1 in AD pathogenesis and advocates for deeper investigation into its regulatory functions, with the aim of advancing therapeutic strategies and biomarker development for AD and related neurological disabilities. Full article

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

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17 pages, 3664 KiB

Open AccessArticle

Neuroprotective Effect of Methylene Blue in a Rat Model of Traumatic Optic Neuropathy

by Nicolás S. Ciranna, Ronan Nakamura, Rafael Peláez, Álvaro Pérez-Sala, Patricia Sarrión, Juan C. Fernández, Alejandra Paganelli, Agustín P. Aranalde, Ulises P. Ruiz, Juan J. López-Costa, César F. Loidl, Alfredo Martínez and Manuel Rey-Funes

Pharmaceuticals 2025, 18(6), 920; https://doi.org/10.3390/ph18060920 - 19 Jun 2025

Viewed by 604

Abstract

Background: Traumatic optic neuropathy (TON) represents a major cause of vision loss worldwide, and treatment options are limited. Here, we study whether methylene blue (MB), a free radical scavenger, is able to prevent morphological and electrophysiological hallmarks of neuropathy in an animal [...] Read more.

Background: Traumatic optic neuropathy (TON) represents a major cause of vision loss worldwide, and treatment options are limited. Here, we study whether methylene blue (MB), a free radical scavenger, is able to prevent morphological and electrophysiological hallmarks of neuropathy in an animal model of TON. Methods: The left eyes of Wistar rats were subjected to intraorbital nerve crush (IONC) while the right ones were sham operated. The group of rats treated with MB (n = 16) received five intraperitoneal injections with 2.0 mg/kg MB in the 24 h following IONC while the control group (n = 16) received just vehicle (PBS) as a control. Twenty-one days after surgery, scotopic full field (scERG), scotopic oscillatory potentials (OP), photopic full field (phERG) and pattern (PERG) electroretinography were performed for retinal function assessment. Furthermore, the number of cell nuclei in the ganglion cell layer (GCL) was recorded in post mortem histological sections. Results: IONC induced very significant reductions in electrophysiological parameters including scotopic a- and b-wave, OPs, photopic b-wave, PhNR amplitude and N2 amplitude. In addition, it also generated a significant prolongation of the N2 implicit time, indicating a profound impact on retinal function. This was further corroborated by a very significant reduction in the number of neuronal nuclei in the GCL, suggesting an intense loss and functional impairment of retinal ganglion cells. MB treatment was able to prevent, partially or completely, all those parameters, indicating the efficiency of such approach. Conclusions: Since MB is already approved for clinical use and presents a high safety profile, it could be repurposed as a neuroprotective drug for ophthalmological applications once proper phase 2 clinical trials are accomplished. Full article

(This article belongs to the Special Issue Innovations in Therapeutic Strategies for Retinal and Neurodegenerative Diseases)

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63 pages, 3732 KiB

Open AccessReview

TrypPROTACs Unlocking New Therapeutic Strategies for Chagas Disease

by Ana Luísa Rodriguez Gini, Pamela Souza Tada da Cunha, Emílio Emílio João, Chung Man Chin, Jean Leandro dos Santos, Esteban Carlos Serra and Cauê Benito Scarim

Pharmaceuticals 2025, 18(6), 919; https://doi.org/10.3390/ph18060919 - 19 Jun 2025

Viewed by 1221

Abstract

Chagas disease, caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), continues to pose significant public health challenges due to the toxicity, poor tolerability, and limited efficacy of current treatments. Targeted protein degradation (TPD) using proteolysis-targeting chimeras (PROTACs) represents a novel [...] Read more.

Chagas disease, caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), continues to pose significant public health challenges due to the toxicity, poor tolerability, and limited efficacy of current treatments. Targeted protein degradation (TPD) using proteolysis-targeting chimeras (PROTACs) represents a novel therapeutic avenue by leveraging the ubiquitin–proteasome system to selectively degrade essential parasite proteins. This review introduces the conceptual framework of “TrypPROTACs” as a prospective strategy for T. cruzi, integrating a comprehensive analysis of druggable targets across critical biological pathways, including ergosterol biosynthesis, redox metabolism, glycolysis, nucleotide synthesis, protein kinases, molecular chaperones such as heat shock protein 90 (Hsp90), and epigenetic regulators such as T. cruzi bromodomain factor 3 (TcBDF3). It is important to note that no TrypPROTAC compound has yet been synthesized or experimentally validated in T. cruzi; the approach discussed herein remains theoretical and forward-looking. Representative inhibitors for each target class are compiled, highlighting potency, selectivity, and structural features relevant to ligand design. We also examine the parasite’s ubiquitination machinery and compare it to the human system to identify putative E3 ubiquitin ligases. Key aspects of linker engineering and ternary complex stabilization are discussed, alongside potential validation techniques such as the cellular thermal shift assay (CETSA) and bioluminescence resonance energy transfer (NanoBRET). Collectively, these insights outline a roadmap for the rational design of TrypPROTACs and support the feasibility of expanding targeted protein degradation strategies to neglected tropical diseases. Full article

(This article belongs to the Special Issue A Commemorative Special Issue in Honor of Professor Carlos Alberto Manssour Fraga: Medicinal Chemistry’s Efforts to Discover Novel Bioactive Molecules for Complex Diseases)

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12 pages, 1265 KiB

Open AccessArticle

Pharmacodynamic Evaluation of Adjuvant Targets: Low Molecular Weight PBP7/8 Effects on β-Lactam Activity Against Carbapenem-Resistant Acinetobacter Baumannii

by Brian M. Ho, Jingxiu Jin, Jacob T. Sanborn, Thomas D. Nguyen, Navaldeep Singh, Christina Cheng, Nader N. Nasief, Ulrike Carlino-MacDonald, Brian T. Tsuji, Yanan Zhao, Liang Chen, Bartolome Moya, Thomas A. Russo and Nicholas M. Smith

Pharmaceuticals 2025, 18(6), 918; https://doi.org/10.3390/ph18060918 - 18 Jun 2025

Viewed by 460

Abstract

Background/Objectives: The increasing occurrence of carbapenem resistance A. baumannii (CRAB) has forced clinicians to seek out alternative options with activity against CRAB. CRAB with inactivated PBP7/8 has been shown to result in an increased outer membrane permeability and could serve as a potential [...] Read more.

Background/Objectives: The increasing occurrence of carbapenem resistance A. baumannii (CRAB) has forced clinicians to seek out alternative options with activity against CRAB. CRAB with inactivated PBP7/8 has been shown to result in an increased outer membrane permeability and could serve as a potential new adjuvant target. Methods: Two isogenic clinical isolates of A. baumannii HUMC1 were utilized (WT and HUMC1 ΔPBP7/8). Static concentration time-kill assays were performed against both isolates with escalating exposures to antibiotics. The resulting data were modeled using the Monolix software suite to capture parameters related to bacterial killing and PBP7/8 synergism. The model results were used to prospectively simulate clinically relevant antibiotic dosing of three antibiotics under physiological conditions and were validated using a hollow-fiber infection model (HFIM). Results: Treatment with monotherapy or combination therapy resulted in concentration-dependent killing for both isolates. Bacterial killing was greater with HUMC1 ΔPBP7/8 for all tested antibiotic concentrations. The mean bacterial population reduction was 4.38 log₁₀ CFU/mL for HUMC1 and 5.38 log₁₀ CFU/mL for HUMC1ΔPBP7/8 knockout isolate. The final mechanism-based model demonstrated improved antibacterial activity with PBP7/8 inhibition through a decline in KC₅₀ values of 59.7% across the beta-lactams in the PBP7/8 knockout. HFIM observations that were retrospectively compared to the simulated model-predicted bacterial concentration time course showed our final model was able to appropriately capture changes in bacterial population within a dynamic HFIM scenario. Conclusions: The quantification of KC₅₀ decline and increase in effectiveness of previously sidelined antimicrobial therapies with PBP7/8 inhibition suggests PBP7/8 is a promising potential target for an antibacterial adjuvant. This lends further support to advance to next-stage studies for identifying compounds that specifically inhibit PBP7/8 activity. Full article

(This article belongs to the Special Issue Next-Generation Antibiotic Strategies Against Drug-Resistant Bacteria)

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10 pages, 215 KiB

Open AccessArticle

Spontaneous Adverse Drug Reaction Reporting of Congenital Malformations: A Danish National Register Study

by Ulrik Lausten-Thomsen, Rasmus Huan Olsen, Michael Christiansen, Paula L. Hedley, Ida Marie Heerfordt, Jon Trærup Andersen and Christina Gade

Pharmaceuticals 2025, 18(6), 917; https://doi.org/10.3390/ph18060917 - 18 Jun 2025

Viewed by 402

Abstract

Background/Objectives: Maternal use of medication during pregnancy may have teratogenic effects, as seen with drugs like thalidomide, valproate, and phenytoin. Despite rigorous testing, both new and established drugs still pose a risk of teratogenesis, particularly if the teratogenic effects are probabilistic and [...] Read more.

Background/Objectives: Maternal use of medication during pregnancy may have teratogenic effects, as seen with drugs like thalidomide, valproate, and phenytoin. Despite rigorous testing, both new and established drugs still pose a risk of teratogenesis, particularly if the teratogenic effects are probabilistic and not deterministic. Public health organizations maintain registers to centralize and evaluate adverse drug reactions (ADR). However, underreporting in these registries can obscure the signals of drug-related congenital malformations. This study aims to evaluate potential ADR-associated congenital malformations in Denmark over the past decade; Methods: An observational cross-sectional study was conducted using data from the national Danish Medicines Agency’s pharmacovigilance database, which includes all spontaneous ADR reports submitted to the Danish Medicines Agency from 1 July 2013 to 30 June 2023. Maternal antenatal drug use was identified, and reported ADRs were assessed for congenital malformations; Results: We identified reports of potential ADR-related congenital malformations in 75 children, with 92 diagnoses as classified by ICD-10. Eighty-five different drugs from 58 ATC codes were implicated. Only three diagnoses were reported in five or more children. The reports were generally sporadic, with no new signals detected; Conclusions: Public awareness is crucial when novel threats arise from medications, infections, or technologies, as these may pose risks to unborn children. Ongoing monitoring of potential ADR-related congenital malformations remains a critical component of public health. Given the potential underreporting, we encourage a low threshold for reporting ADRs based on suspicion alone, with final causality assessments made by health authorities. Full article

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

22 pages, 5391 KiB

Open AccessArticle

Combined Network Pharmacology, Transcriptomics and Metabolomics Strategies Reveal the Mechanism of Action of Lang Chuang Wan to Ameliorate Lupus Nephritis in MRL/lpr Mice

by Cuicui Li, Guoxin Ji, Xinru Zhang, Hang Yu, Zhimeng Li, Bo Yang, Zhuangzhuang Yao, Shilei Wang, Tongwei Jiang and Shumin Wang

Pharmaceuticals 2025, 18(6), 916; https://doi.org/10.3390/ph18060916 - 18 Jun 2025

Viewed by 422

Abstract

Background: Lupus nephritis (LN) is a serious complication of systemic lupus erythematosus (SLE) and is difficult to cure. Lang Chuang Wan (LCW) has been widely used in clinical practice as a treatment for SLE and LN, but its active ingredients and mechanism [...] Read more.

Background: Lupus nephritis (LN) is a serious complication of systemic lupus erythematosus (SLE) and is difficult to cure. Lang Chuang Wan (LCW) has been widely used in clinical practice as a treatment for SLE and LN, but its active ingredients and mechanism of action have not been elucidated. To address this, we aim to analyze LCW’s chemical components and clarify its mechanisms in treating LN. Methods: We utilized ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS) to analyze the components of LCW and assessed its effects on MRL/lpr mice through ELISA, H&E staining, Masson’s trichrome staining, and IgG immunofluorescence. Then, we further explored the mechanisms of action through network pharmacology, transcriptomics, and metabolomics, and validated with Western blot. Results: LCW contained 1303 chemical components, primarily flavonoids and terpenoids. It significantly improved kidney pathology and normalized levels of serum ANA, anti-dsDNA, anti-Sm, C3, C4, Cr, BUN, IL-6, IL-10, IL-17, TNF-α, and urinary protein (UP) in MRL/lpr mice. Network pharmacology, transcriptomics, and metabolomics indicated that LCW’s therapeutic effect on LN involved the PI3K/AKT pathway, confirmed by Western blot showing LCW’s suppression of the PI3K/AKT/mTOR pathway. Conclusions: LCW alleviates pathological symptoms in MRL/lpr mice by inhibiting the PI3K/AKT/mTOR signaling pathway, providing insights into its therapeutic mechanisms for lupus nephritis. Full article

(This article belongs to the Section Pharmacology)

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20 pages, 715 KiB

Open AccessReview

Microenvironment and Tumor Heterogeneity as Pharmacological Targets in Precision Oncology

by Stelvio Tonello, Roberta Rolla, Paolo Amedeo Tillio, Pier Paolo Sainaghi and Donato Colangelo

Pharmaceuticals 2025, 18(6), 915; https://doi.org/10.3390/ph18060915 - 18 Jun 2025

Viewed by 555

Abstract

Tumor diseases are characterized by high interindividual and intratumoral heterogeneity (ITH). The development and progression of neoplasms outline complex networks of extracellular and cellular signals that have yet to be fully elucidated. This narrative review provides a comprehensive overview of the literature related [...] Read more.

Tumor diseases are characterized by high interindividual and intratumoral heterogeneity (ITH). The development and progression of neoplasms outline complex networks of extracellular and cellular signals that have yet to be fully elucidated. This narrative review provides a comprehensive overview of the literature related to the cellular and molecular mechanisms underlying the heterogeneity of the tumor mass. Furthermore, it examines the possible role of the tumor microenvironment in the development and support of the neoplasm, in order to highlight its potential in the construction of a diagnostic–therapeutic approach to precision medicine. Many authors underline the importance of the tumor microenvironment (TME) as it actively takes part in the growth of the neoplastic mass and in the formation of metastases and in the acquisition of resistance to anticancer drugs. In specific body districts, the ideal conditions occur for the TME establishment, particularly the inflammatory state, the recruitment of cell types, the release of specific cytokines and growth factors, hypoxic conditions. These components actively intervene by enabling tumor progression and construction of physical barriers shaped by the extracellular matrix that contribute to forming peripheral tolerance by intervention of myeloid precursors and the polarization of M2 macrophages. In recent years, ITH and the TME have assumed an important position in cancer research and pharmacology as they enable understanding the dense network of communication existing between the neoplasm and the surrounding environment, and to monitor and deepen the effects of drugs with a view to develop increasingly precise and effective therapies. In the last decade, knowledge of TME has been exploited to produce targeted molecular agents (inhibitory small molecules, monoclonal antibodies, gene therapy). Nonetheless, the bibliography shows the need to study ITH through new prognostic and predictive biomarkers (e.g., ctDNA and CTCs) and to increase its basic biology knowledge. Precision medicine is a new opportunity in the treatment of oncological diseases that is transforming the development of new drug approaches and their clinical use. Biology and biotechnologies are providing the bases for this revolution. Full article

(This article belongs to the Section Pharmacology)

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15 pages, 2552 KiB

Open AccessArticle

Curcumin-like Compound Inhibits Proliferation of Adenocarcinoma Cells by Inducing Cell Cycle Arrest and Senescence

by Rafael Fonseca, Yasmin dos Santos Louzano, Cindy Juliet Cristancho Ortiz, Matheus de Freitas Silva, Maria Luiza Vieira Felix, Guilherme Álvaro Ferreira-Silva, Ester Siqueira Caixeta, Bruno Zavan, Claudio Viegas, Jr. and Marisa Ionta

Pharmaceuticals 2025, 18(6), 914; https://doi.org/10.3390/ph18060914 - 18 Jun 2025

Viewed by 1366

Abstract

Background: Lung cancer is the leading cause of cancer-related death in the male sex worldwide. Non-small cell lung cancer (NSCLC) is the most prevalent type, accounting for 80–85% of cases, and lung adenocarcinoma is the most common and lethal NSCLC subtype, being responsible [...] Read more.

Background: Lung cancer is the leading cause of cancer-related death in the male sex worldwide. Non-small cell lung cancer (NSCLC) is the most prevalent type, accounting for 80–85% of cases, and lung adenocarcinoma is the most common and lethal NSCLC subtype, being responsible for ca. 50% of deaths. Despite new therapeutic strategies, lung cancer mortality rates remain high, highlighting the need for the development of new drugs. Objectives: We investigated the pharmacological potential of a series of curcumin-like compounds using two lung adenocarcinoma cell lines as models. Methods and Results: Cell viability assay led to the identification of PQM-214 as the hit compound, and other methodologies were employed to investigate the mechanisms underlying its antitumor potential, including cell cycle analysis, mitotic index determination, assessment of clonogenic capacity, senescence-associated β-galactosidase and annexin V assays, quantitative PCR, and Western blot analyses. The mechanism of action of PQM-214 was investigated in A549 cells, revealing that it effectively inhibits cell proliferation by inducing cell cycle arrest, apoptosis, or senescence. Cell cycle key regulators were significantly modulated by PQM-214, with cyclin E2, MYC, and FOXM1 being downregulated, while senescence markers such as cyclin D1, CDKN1A (p21), IL-8, TIMP1, and TIMP2 were upregulated. Moreover, Western blot results revealed upregulation of cyclin D1 and p21 in PQM-214-treated samples, with a downregulation of cyclin B. Conclusions: PQM-214 seems to act on different molecular targets in lung adenocarcinoma cells, inhibiting cell proliferation and inducing apoptosis. Further studies will be conducted to explore whether PQM-214 can also act as a senolytic agent, which would reinforce its anticancer potential. Full article

(This article belongs to the Special Issue A Commemorative Special Issue in Honor of Professor Eliezer J. Barreiro: Early Drug Discovery: From Target Identification and Validation to Lead Optimization)

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28 pages, 1754 KiB

Open AccessArticle

Effects of Periploca chevalieri Browicz on Postprandial Glycemia and Carbohydrate-Hydrolyzing Enzymes

by Katelene Lima, Maryam Malmir, Shabnam Sabiha, Rui Pinto, Isabel Moreira da Silva, Maria Eduardo Figueira, João Rocha, Maria Paula Duarte and Olga Silva

Pharmaceuticals 2025, 18(6), 913; https://doi.org/10.3390/ph18060913 - 18 Jun 2025

Viewed by 403

Abstract

Background/Objectives: Periploca chevalieri Browicz (Apocynaceae), an endemic species of the Cabo Verde archipelago, is commonly used in traditional medicine for the treatment of diabetes. The aim of this study was to characterize the chemical profiles of the aqueous and hydroethanolic [...] Read more.

Background/Objectives: Periploca chevalieri Browicz (Apocynaceae), an endemic species of the Cabo Verde archipelago, is commonly used in traditional medicine for the treatment of diabetes. The aim of this study was to characterize the chemical profiles of the aqueous and hydroethanolic (70%) extracts of the P. chevalieri dried aerial parts (PcAE and PcEE) and evaluate their potential to modulate postprandial glycemia and inhibit key carbohydrate-hydrolyzing enzymes. Methods: The chemical characterization was performed by LC/UV-DAD-ESI/MS/MS. An in vivo evaluation of postprandial glycemia modulation was conducted on healthy CD1 mice submitted to an oral sucrose tolerance test. In vitro enzymatic inhibition was performed for the α-amylase, α-glucosidase, and DPP4 enzymes. Additionally, antioxidant and antiglycation activities were also assessed. Results: Phenolic acid derivatives, flavanols, proanthocyanidins, and flavonols were the major classes of secondary metabolites identified. PcEE at 170 mg/kg of body weight significantly (p < 0.05) reduced the postprandial glycemia peak in CD1 mice submitted to sucrose overload. Regarding the enzymatic inhibition, both extracts showed concentration-dependent inhibitory potential against the α-amylase, α-glucosidase, and DPP4 enzymes. Both extracts inhibited α-glucosidase more effectively than acarbose. Conclusions: The obtained results supports the traditional use of P. chevalieri and suggest the potential for further pharmacological investigation. 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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23 pages, 1148 KiB

Open AccessReview

Ferulic Acid as an Anti-Inflammatory Agent: Insights into Molecular Mechanisms, Pharmacokinetics and Applications

by Jiaying Liu, Yu Guan, Le Yang, Heng Fang, Hui Sun, Ye Sun, Guangli Yan, Ling Kong and Xijun Wang

Pharmaceuticals 2025, 18(6), 912; https://doi.org/10.3390/ph18060912 - 18 Jun 2025

Viewed by 785

Abstract

Ferulic acid (FA), a hydroxycinnamic acid derivative, is a key bioactive component in traditional medicinal plants including Angelica sinensis and Asafoetida. Accumulating evidence supports its therapeutic efficacy in inflammatory disorders, such as rheumatoid arthritis (RA) and ulcerative colitis (UC). FA exerts anti-inflammatory [...] Read more.

Ferulic acid (FA), a hydroxycinnamic acid derivative, is a key bioactive component in traditional medicinal plants including Angelica sinensis and Asafoetida. Accumulating evidence supports its therapeutic efficacy in inflammatory disorders, such as rheumatoid arthritis (RA) and ulcerative colitis (UC). FA exerts anti-inflammatory effects through (1) the regulation of inflammatory cytokine levels; (2) modulation of signaling pathways such as nuclear factor kappa B (NF-κB), mitogen-activated protein kinase (MAPK), and janus kinase/signal transducer and activator of transcription (JAK/STAT); (3) amelioration of oxidative stress; and (4) regulation of immune cell homeostasis. At the pharmacokinetic level, studies show that FA is rapidly absorbed but exhibits low bioavailability, mainly due to the influence of metabolic pathways and food matrix characteristics. This review systematically summarizes the literature on the anti-inflammatory effects of FA, covering molecular mechanisms, pharmacokinetic characteristics, and application scenarios. Preclinical studies show that FA has low toxicity and good safety, demonstrating potential for development as a novel anti-inflammatory drug. However, its clinical translation is hindered by bottlenecks such as low bioavailability and insufficient human clinical data. Future research should prioritize developing novel drug delivery systems and conducting large-scale clinical trials to facilitate its clinical translation. Full article

(This article belongs to the Special Issue Antioxidant and Anti-Inflammatory Effects of Natural Product Extracts)

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13 pages, 566 KiB

Open AccessArticle

Evaluation of Statins Use in Hemodialysis Patients: A Retrospective Analysis of Clinical and Safety Outcomes

by Abdulmalik S. Alotaibi, Mohamed A. Albekery, Ahmed A. Alanazi, Ibrahim S. Alhomoud, Khalid A. Alamer, Mohammad Shawaqfeh, Reem H. Alshammari, Fayez Alhejaili, Muthana Al Sahlawi, Ibrahim Aldossary, Hajar Adel Aljuayl, Mohammad Alkathiri, Shmeylan Alharbi, Abdulkareem Albekairy and Abdulmalik Alkatheri

Pharmaceuticals 2025, 18(6), 911; https://doi.org/10.3390/ph18060911 - 18 Jun 2025

Viewed by 597

Abstract

Background: Lipid metabolism disturbances are common in end-stage renal disease (ESRD) patients on hemodialysis (HD), leading to dyslipidemia, which is characterized by abnormal plasma lipids and lipoproteins. Although large randomized controlled trials have generally not demonstrated a survival benefit associated with statin therapy [...] Read more.

Background: Lipid metabolism disturbances are common in end-stage renal disease (ESRD) patients on hemodialysis (HD), leading to dyslipidemia, which is characterized by abnormal plasma lipids and lipoproteins. Although large randomized controlled trials have generally not demonstrated a survival benefit associated with statin therapy among patients receiving hemodialysis, limited observational studies have reported potential associations with improved clinical outcomes in this population. Methods: This retrospective cohort study investigated the clinical and safety outcomes of statin use in ESRD patients on HD with documented dyslipidemia over a two-year period from 1 January 2018 to 30 December 2019. The primary endpoints evaluated the clinical outcomes of statins by assessing changes in specific lipid parameters, including low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), total cholesterol (TC), and high-density lipoprotein cholesterol (HDL-C). The secondary endpoints assessed safety by monitoring liver enzymes and creatine kinase (CK) levels. Results: Among 179 participants, diabetes mellitus was present in 134 patients (74.9%), while 168 patients (93.9%) had hypertension. Cardiovascular events occurred in 95 patients (53.1%). Statin therapy was administered to 146 patients (82.0%), with atorvastatin being the most frequently prescribed statin (69.3%). Modest reductions in LDL-C levels were observed in the rosuvastatin and atorvastatin groups, whereas slight increases were noted in the simvastatin and non-statin groups. None of these within-group changes were statistically significant. In the atorvastatin group, LDL-C decreased slightly from 2.058 to 2.003 mmol/L. The rosuvastatin group experienced a more pronounced LDL-C reduction from 2.607 to 2.113 mmol/L. Conversely, the simvastatin group showed an LDL-C increase from 1.550 to 1.901 mmol/L. Among the non-statin group, LDL-C increased from 2.678 to 2.820 mmol/L. Liver enzyme and CK levels fluctuated slightly but remained within normal ranges. Conclusions: This study evaluated statin therapy in hemodialysis patients with dyslipidemia. Although modest reductions in LDL-C levels were observed in the atorvastatin and rosuvastatin groups, statin therapy did not reduce the incidence of atherosclerotic events in hemodialysis patients with dyslipidemia. Additionally, statin use was not associated with any clinically or statistically significant effects. Full article

(This article belongs to the Special Issue New Development in Pharmacotherapy of Kidney Diseases)

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17 pages, 1412 KiB

Open AccessArticle

Effect of Acoustic Pressure on Temozolomide-Loaded Oleic Acid-Based Liposomes and Its Safety to Brain Tissue

by Vasilisa D. Dalinina, Vera S. Shashkovskaya, Iman M. Khaskhanova, Daria Yu. Travnikova, Nelly S. Chmelyuk, Dmitry A. Korzhenevskiy, Vsevolod V. Belousov and Tatiana O. Abakumova

Pharmaceuticals 2025, 18(6), 910; https://doi.org/10.3390/ph18060910 - 18 Jun 2025

Viewed by 440

Abstract

Background: Glioblastoma (GBM) is a highly aggressive primary brain tumor with limited therapeutic options, particularly due to the limited blood–brain barrier (BBB) permeability. Nanoparticle-based drug delivery systems, such as liposomes, can prolong drugs’ circulation time and enhance their accumulation within brain tumors, thereby [...] Read more.

Background: Glioblastoma (GBM) is a highly aggressive primary brain tumor with limited therapeutic options, particularly due to the limited blood–brain barrier (BBB) permeability. Nanoparticle-based drug delivery systems, such as liposomes, can prolong drugs’ circulation time and enhance their accumulation within brain tumors, thereby improving therapeutic outcomes. Controlled drug release further contributes to high local drug concentrations while minimizing systemic toxicity. Oleic acid (OA), a monounsaturated fatty acid, is commonly used to enhance drug loading and increase lipid membrane fluidity. In this study, we developed liposomal formulations with optimized temozolomide (TMZ)’s loading and analyze its response to focused ultrasound (FUS). Methods: We synthetized OA-based liposomes with different lipid composition, performed physicochemical characterization (DLS, TEM) and analyzed the TMZ loading efficiency. Different FUS parameters were tested for effective OA-based liposomes destruction. Safety of selected parameters was evaluated in vivo by MRI, histological staining and RT-PCR of pro-inflammatory cytokines. Results: All the formulations exhibited comparable hydrodynamic diameters; however, OA-containing liposomes demonstrated a significantly higher TMZ encapsulation efficiency and enhanced cytotoxicity in U87 glioma cells. Moreover, it was shown that OA-liposomes were disrupted at lower acoustic pressures (5 MPa), while conventional liposomes required higher thresholds (>8 MPa). A safety analysis of FUS parameters indicated that pressures exceeding 11 MPa induced brain edema, necrotic lesions and elevated cytokine levels within 72 h post-treatment. Conclusions: These results suggest that OA-based liposomes possess favorable characteristics, with an increased sonosensitivity for the site-specific delivery of TMZ, offering a promising strategy for glioma treatment. Full article

(This article belongs to the Special Issue Recent Advances in the Research of Drug Delivery System: Materials, Preparation Methods, and Mechanisms)

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16 pages, 2264 KiB

Open AccessArticle

Ethanolic Extract of Ganoderma mexicanum Pat. Mycelium: A Source of Bioactive Compounds with Antiproliferative Activity and Potential PPAR-γ Natural Ligands

by Lucia T. Angulo-Sanchez, Max Vidal-Gutiérrez, Heriberto Torres-Moreno, Martín Esqueda, Aldo Gutiérrez, Georgina Vargas, Juan Luis Monribot-Villanueva, José A. Guerrero-Analco, César Muñoz-Bacasehua and Ramón Enrique Robles-Zepeda

Pharmaceuticals 2025, 18(6), 909; https://doi.org/10.3390/ph18060909 - 18 Jun 2025

Viewed by 642

Abstract

Background/Objective: Ganoderma spp. have long been studied for their bioactive pharmacological properties, and their biomass and extracts have been obtained from various sources. This study adopts a novel approach: enriching a liquid culture of Ganoderma mexicanum with a vineyard pruning waste extract [...] Read more.

Background/Objective: Ganoderma spp. have long been studied for their bioactive pharmacological properties, and their biomass and extracts have been obtained from various sources. This study adopts a novel approach: enriching a liquid culture of Ganoderma mexicanum with a vineyard pruning waste extract to identify bioactive compounds with antiproliferative activity through enriched chromatographic fractions. Methods: The ethanolic extract from a mycelial culture was separated following a partitioning process, and the hexane fraction was subsequently separated in a chromatographic column. The fractions were evaluated for their antiproliferative properties against cancer cell lines. The interactions of the molecules identified with peroxisome proliferator-activated receptor gamma (PPAR-γ) were analyzed via molecular docking. Results: Three chromatographic fractions (FH11–FH13) exhibited antiproliferative activity which was significantly more effective against non-small lung cancer cells (A549). The cells treated with the crude extract and fractions presented a balloon-like morphology. A chemical analysis of the active fractions allowed us to identify four compounds: one fatty acid (9-Hydroxy-10E,12Z-octadecadienoic acid) and three triterpenes (ganoderic acids DM, TQ, and X). These compounds showed interactions with the PPAR-γ receptor through molecular docking. Conclusions: Ganoderma mexicanum is a promising source of compounds with antiproliferative activity that could serve as natural ligands for PPAR-γ and has possible applications in lung cancer therapy. Full article

(This article belongs to the Special Issue The 20th Anniversary of Pharmaceuticals—Ethnopharmacology in Latin America)

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60 pages, 981 KiB

Open AccessReview

Innovative Formulation Strategies for Biosimilars: Trends Focused on Buffer-Free Systems, Safety, Regulatory Alignment, and Intellectual Property Challenges

by Tomas Gabriel Bas

Pharmaceuticals 2025, 18(6), 908; https://doi.org/10.3390/ph18060908 - 17 Jun 2025

Viewed by 974

Abstract

The formulation of biosimilar products critically determines their stability, safety, immunogenicity, and market accessibility. This article presents a novel integrative framework for biosimilar formulation that balances scientific, regulatory, and intellectual property dimensions, offering a holistic perspective rarely unified in the literature. It highlights [...] Read more.

The formulation of biosimilar products critically determines their stability, safety, immunogenicity, and market accessibility. This article presents a novel integrative framework for biosimilar formulation that balances scientific, regulatory, and intellectual property dimensions, offering a holistic perspective rarely unified in the literature. It highlights the growing trend toward buffer-free, high-concentration systems that leverage protein self-buffering to improve patient comfort and formulation stability. The article also addresses regulatory flexibility from the FDA and EMA, which allows scientifically justified deviations from reference formulations to ensure pharmaceutical equivalence and minimize immunogenicity. A novelty of this article is its comprehensive analysis of how digital innovations, such as Quality-by-Design, Process-Analytical-Technology, and AI-based in silico simulations, are transforming formulation design and bioprocess optimization to reduce immunogenic risks and enhance bioequivalence. Two important key takeaways emerge: (1) strategic innovation in formulation, especially using buffer-free and high concentration systems, improve product stability and patient tolerability while complying with regulatory standards; and (2) intellectual property challenges, including patent thickets, strongly influence formulation decisions, making early legal-strategic alignment essential for market entry. The article confirms that practical recommendations for the selection of recombinant therapeutic protein formulations can effectively guide developers and regulators toward safer, more efficient, and commercially viable biosimilar products. Full article

(This article belongs to the Special Issue Biosimilars Development Strategies)

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24 pages, 13737 KiB

Open AccessArticle

Cold Atmospheric Plasma Improves the Therapeutic Success of Photodynamic Therapy on UV-B-Induced Squamous Cell Carcinoma in Hairless Mice

by Stephanie Arndt, Petra Unger, Irina Ivanova, Wolfgang Bäumler, Konstantin Drexler, Mark Berneburg and Sigrid Karrer

Pharmaceuticals 2025, 18(6), 907; https://doi.org/10.3390/ph18060907 - 17 Jun 2025

Viewed by 487

Abstract

Background/Objectives: Actinic keratosis (AK) occurs on sun-damaged skin and is considered a precursor to squamous cell carcinoma (SCC). Photodynamic therapy (PDT), using 5-aminolevulinic acid (ALA) and red light, is a common treatment for AK. However, its clinical efficacy for invasive tumors such as [...] Read more.

Background/Objectives: Actinic keratosis (AK) occurs on sun-damaged skin and is considered a precursor to squamous cell carcinoma (SCC). Photodynamic therapy (PDT), using 5-aminolevulinic acid (ALA) and red light, is a common treatment for AK. However, its clinical efficacy for invasive tumors such as SCC is limited by the poor penetration and distribution of the photosensitizer. Cold atmospheric plasma (CAP), a partially ionized gas, increases skin permeability and exhibits anti-cancer properties through the generation of reactive oxygen species (ROS). In a previous study, CAP showed promising synergistic effects when combined with ALA-PDT for the treatment of SCC cells in vitro. The present study investigated the effects of combining CAP with ALA-PDT on cutaneous AK and SCC induced by ultraviolet B (UV-B) irradiation in SKH1 hairless mice. Methods: We compared various application sequences (CAP-ALA–red light, ALA–red light–CAP, and ALA-CAP–red light) against conventional ALA-PDT using visual, histological, and molecular assessments of the affected skin. Results: The results demonstrated that combined treatments strongly inhibited the growth of UV-B-induced skin lesions. TUNEL staining revealed increased apoptosis following both single and combined therapies, while Ki-67 staining indicated reduced keratinocyte proliferation and diminished DNA damage in treated areas. mRNA expression analysis showed the upregulation of apoptosis-related genes (p16^INK4a, p21^CIP1) alongside enhanced anti-tumor immune responses (IL-6, IL-8) in the affected tissue samples. Notably, the combined treatment enhances the therapeutic effect, whereas the sequence of application does not seem to be relevant for therapeutic efficacy in vivo. Conclusions: Overall, these results suggest that CAP may enhance the anti-tumor effect of conventional ALA-PDT, supporting previous findings on SCC cells. Full article

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30 pages, 1334 KiB

Open AccessEditor’s ChoiceReview

Revolutionizing Prostate Cancer Detection: The Role of Approved PSMA-PET Imaging Agents

by Ute Hennrich, Laurène Wagner, Harun Taş, Luciana Kovacs and Martina Benešová-Schäfer

Pharmaceuticals 2025, 18(6), 906; https://doi.org/10.3390/ph18060906 - 17 Jun 2025

Viewed by 1022

Abstract

Locametz^®/Illuccix^®/Gozellix^TM (Novartis AG (Basel, Switzerland) and Telix Pharmaceuticals, Ltd. (Melbourne, Australia), all three [⁶⁸Ga]Ga-PSMA-11), Pylarify^®/Pylclari^® (Progenics Pharmaceuticals, Inc. (New York, USA) and Curium PET France SA (Paris, France), both [¹⁸F]DCFPyL), Radelumin [...] Read more.

Locametz^®/Illuccix^®/Gozellix^TM (Novartis AG (Basel, Switzerland) and Telix Pharmaceuticals, Ltd. (Melbourne, Australia), all three [⁶⁸Ga]Ga-PSMA-11), Pylarify^®/Pylclari^® (Progenics Pharmaceuticals, Inc. (New York, USA) and Curium PET France SA (Paris, France), both [¹⁸F]DCFPyL), Radelumin^® (ABX GmbH (Radeberg, Germany), [¹⁸F]PSMA-1007), and Posluma^® (Blue Earth Diagnostics, Ltd. (Oxford, UK), [¹⁸F]rhPSMA-7.3) are four approved PSMA-PET imaging agents that have significantly advanced the diagnosis and management of prostate cancer. These agents offer a new level of precision and accuracy, enabling clinicians to detect prostate cancer with enhanced sensitivity. As a result, they play a critical role in improving detection, staging, and management, ultimately enhancing clinical outcomes for patients. Their use in routine clinical practice is expected to increase diagnostic precision and provide clearer pathways for personalized therapy. This review offers a comprehensive chemical, pharmaceutical, and medicinal overview, discusses comparative studies, and highlights additional highly relevant candidates for prostate cancer detection. Full article

(This article belongs to the Special Issue Past, Present and Future Radiotracer Techniques: Radiopharmaceuticals in Cancer Theranostics)

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17 pages, 6308 KiB

Open AccessArticle

PARP Inhibition in Colorectal Cancer—A Comparison of Potential Predictive Biomarkers for Therapy

by Abdulaziz Alfahed

Pharmaceuticals 2025, 18(6), 905; https://doi.org/10.3390/ph18060905 - 17 Jun 2025

Viewed by 446

Abstract

Background/Objectives: PARP inhibitors (PARPis) currently play frontline roles in the management of prostate, pancreatic, ovarian and breast cancers, but their roles in colorectal cancer (CRC) management have yet to be clarified. Importantly, the specific predictive biomarkers for PARPis in CRC are still [...] Read more.

Background/Objectives: PARP inhibitors (PARPis) currently play frontline roles in the management of prostate, pancreatic, ovarian and breast cancers, but their roles in colorectal cancer (CRC) management have yet to be clarified. Importantly, the specific predictive biomarkers for PARPis in CRC are still matters of investigations. The aim of this study is to identify the potential predictive biomarkers of PARP inhibition in CRC. Methods: Gene set enrichment analyses (GSEAs) and drug ontology enrichment analyses (DOEAs) of PARPi response gene sets were applied as the surrogates of PARPi response to two CRC cohorts in order to compare the predictive capacities of TP53 mutation status, MSI status, as well as PARP1 and PARP2 expression for PARP inhibition to those of a homologous repair deficiency surrogate, and large-scale state transition (LST). Differential enrichment score (ES) and ontology enrichment (OE) analyses were used to interrogate the differential correlation of the predictive biomarkers with PARPi response, relative to LST. Results: The results demonstrated that LST-low, rather than LST-high, CRC subsets exhibited an enrichment of the PARPi response, in contrast to what has been established for other cancers. Furthermore, CRC subsets with wild-type TP53, positive MSI, as well as high PARP1 and PARP2 expression exhibited an enrichment of the PARPi response gene sets. Moreover, there was no differential enrichment of the PARPi response between LST and each of the MSI statuses, PARP1 expression and PARP2 expression. Furthermore, the preliminary differential enrichment observed between the LST-based and TP53 mutation status-based PARPi responses could not be validated with further testing. Conclusions: MSI status, TP53 mutation status as well as PARP1 and PARP2 expression may be substitutes for low LST as predictive biomarkers of PARPi response in CRC. Full article

(This article belongs to the Special Issue Precision Oncology: Targeting Molecular Subtypes in Cancer Therapy)

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11 pages, 231 KiB

Open AccessArticle

Adverse Drug Reactions to SGLT2i Reported by Type 2 Diabetes New Users: An Active Surveillance Study

by Camelia Bucșa, Ioana Frenț, Ramona Stefan, Adriana Fodor, Georgeta Inceu, Andreea Farcaș, Adriana Rusu, Monica Negovan and Cristina Mogoșan

Pharmaceuticals 2025, 18(6), 904; https://doi.org/10.3390/ph18060904 - 16 Jun 2025

Viewed by 453

Abstract

Background/Objectives: Patients’ perspectives on adverse drug reactions (ADRs) may be used to update the safety profile of a drug. We aimed to prospectively follow-up on type 2 diabetes (T2D) patients who were new users of sodium-glucose co-transporter 2 inhibitors (SGLT2i) and to [...] Read more.

Background/Objectives: Patients’ perspectives on adverse drug reactions (ADRs) may be used to update the safety profile of a drug. We aimed to prospectively follow-up on type 2 diabetes (T2D) patients who were new users of sodium-glucose co-transporter 2 inhibitors (SGLT2i) and to characterize the patient-reported ADRs within routine practice in Romania. Methods: T2D patients from ambulatory settings were interviewed over the phone based on standardized forms, at four time-points across 12 months. We captured the patients’ history and auto-medication, as well as any ADR that implied causality to SGLT2i, based on the patient’s perspective. Results: In total, 64 patients, with genders being equally represented and with a median age of 59 years (Q1, Q3: 51, 64) were followed-up with. We identified 73 ADRs to SGLT2i that were suspected to be associated with the drug, with an average of 2.35 ADRs per patient (range 0–7 ADRs/patient). The most reported ADR was pollakiuria (7; 9.58%), followed by vulvovaginal candidiasis (6; 8.21%), dysuria (4; 5.47%), and hypoglycemia (4; 5.47%). SGLT2i treatment was interrupted for eight patients. Three (4.10%) ADRs were considered serious as important medical events (hypertensive crisis, angina pectoris, and dyspnea). A positive dechallenge was recorded for 14 ADRs, of which 9 ADRs had a positive rechallenge as well. A probable causality was assessed for 13 of the 73 patient-reported ADRs. Conclusions: Most of the identified ADRs were in line with the known safety profile of SGLT2i. Only three ADRs were serious and unexpected relative to the safety profile, but these had confounding factors that could explain the reactions. Therefore, no new safety concerns related to SGLT2i were determined in this observational study. Full article

(This article belongs to the Section Pharmacology)

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14 pages, 1690 KiB

Open AccessArticle

Investigation of the ABCB1 Gene Polymorphism and Food Effects on the Avatrombopag Pharmacokinetics in Chinese Individuals: A Population Pharmacokinetic/Pharmacodynamic Analysis

by Xin Liu, Lulu Chen, Gehang Ju, Chao Li, Bijue Liu, Yunzhou Fei, Xintong Wang, Yang Gao, Qingfeng He, Xiao Zhu and Dongsheng Ouyang

Pharmaceuticals 2025, 18(6), 903; https://doi.org/10.3390/ph18060903 - 16 Jun 2025

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Abstract

Background/Objectives: Avatrombopag (AVA), a thrombopoietin receptor agonist used to treat thrombocytopenia in patients with chronic liver disease, exhibits significant pharmacokinetic (PK) variability, particularly under fasting conditions. This study investigates the combined influence of food intake and genetic polymorphisms in CYP2C9 and ABCB1 on [...] Read more.

Background/Objectives: Avatrombopag (AVA), a thrombopoietin receptor agonist used to treat thrombocytopenia in patients with chronic liver disease, exhibits significant pharmacokinetic (PK) variability, particularly under fasting conditions. This study investigates the combined influence of food intake and genetic polymorphisms in CYP2C9 and ABCB1 on the PK and pharmacodynamics (PD) of AVA, with the goal of informing individualized dosing strategies. Methods: A pharmacogenetic analysis was conducted in 92 healthy participants, who received 20 mg of AVA under both fasting and fed conditions. A population PK/PD model was developed to evaluate the covariates effects on the PK variability. Monte Carlo simulations were used to predict AVA exposure and platelet count profiles under diverse dosing scenarios. Results: Food intake significantly reduced PK variability, with approximately 50% reductions in clearance (CL/F) and volume of distribution (Vd/F) compared to fasting conditions. Under fed conditions, CYP2C9 intermediate metabolizers showed a 1.70-fold increase in exposure compared to normal metabolizers, but this difference was not observed under fasting conditions. ABCB1 polymorphisms showed minimal impact, with the exception of ABCB1 (C1236T) heterozygotes, which exhibited 1.37-fold increased exposure. Despite the observed PK variability, simulations demonstrated a consistent platelet count response across dosing regimens. Conclusions: While food intake and genetic polymorphisms in CYP2C9 and ABCB1 influenced AVA PK, these factors may not require dose adjustments, as platelet count responses remained consistent across genotypes and dosing conditions in the Chinese participants. These findings support simplified dosing strategies without the need for pharmacogenetic testing in Chinese individuals and may contribute to more individualized thrombocytopenia management. Full article

(This article belongs to the Special Issue Mathematical Modeling in Drug Metabolism and Pharmacokinetics)

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21 pages, 4691 KiB

Open AccessArticle

Exploring Brazilian Green Propolis Phytochemicals in the Search for Potential Inhibitors of B-Raf⁶⁰⁰E Enzyme: A Theoretical Approach

by Garcia Ferreira de Souza, Airis Farias Santana, Fernanda Sanches Kuhl Antunes, Ramon Martins Cogo, Matheus Dornellas Pereira, Daniela Gonçales Galasse Rando and Carolina Passarelli Gonçalves

Pharmaceuticals 2025, 18(6), 902; https://doi.org/10.3390/ph18060902 - 16 Jun 2025

Viewed by 664

Abstract

Background/Objectives: Melanoma is one of the most aggressive forms of skin cancer and is frequently associated with the B-Raf⁶⁰⁰E mutation, which constitutively activates the MAPK signaling pathway. Although selective inhibitors such as Vemurafenib offer clinical benefits, their long-term efficacy is often [...] Read more.

Background/Objectives: Melanoma is one of the most aggressive forms of skin cancer and is frequently associated with the B-Raf⁶⁰⁰E mutation, which constitutively activates the MAPK signaling pathway. Although selective inhibitors such as Vemurafenib offer clinical benefits, their long-term efficacy is often hindered by resistance mechanisms and adverse effects. In this study, twelve phytochemicals from Brazilian green propolis were evaluated for their potential as selective B-Raf⁶⁰⁰E inhibitors using a computational approach. Methods: Physicochemical, ADME, and electronic properties were assessed, followed by molecular docking using the B-Raf⁶⁰⁰E crystal structure (PDB ID: 3OG7). Redocking validation and 500 ns molecular dynamics simulations were performed to investigate the stability of the ligand-protein complexes, and free energy calculations were then computed. Results: Among the tested compounds, Artepillin C exhibited the strongest binding affinity (−8.17 kcal/mol) in docking and maintained stable interactions with key catalytic residues throughout the simulation, also presenting free energy of binding ΔG of −20.77 kcal/mol. HOMO-LUMO and electrostatic potential analyses further supported its reactivity and selectivity. Notably, Artepillin C remained bound within the ATP-binding site, mimicking several critical interactions observed with Vemurafenib. Results: Among the tested compounds, Artepillin C exhibited the strongest binding affinity (−8.17 kcal/mol) and maintained stable interactions with key catalytic residues throughout the simulation. HOMO-LUMO and electrostatic potential analyses further supported its reactivity and selectivity. Notably, Artepillin C remained bound within the ATP-binding site, mimicking several critical interactions observed with Vemurafenib. Conclusions: These findings indicate that Artepillin C is a promising natural compound for further development as a selective B-Raf⁶⁰⁰E inhibitor and suggest its potential utility in melanoma treatment strategies. This study reinforces the value of natural products as scaffolds for targeted drug design and supports continued experimental validation. Full article

(This article belongs to the Special Issue Computational Methods in Drug Development)

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Pharmaceuticals, Volume 18, Issue 6 (June 2025) – 167 articles

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