Pharmaceuticals

29 pages, 2681 KiB

Open AccessArticle

In Silico Prediction of Tetrastatin-Derived Peptide Interactions with αvβ3 and α5β1 Integrins

by Vivien Paturel, Stéphanie Baud, Christophe Schneider and Sylvie Brassart-Pasco

Pharmaceuticals 2025, 18(7), 940; https://doi.org/10.3390/ph18070940 (registering DOI) - 21 Jun 2025

Background/Objectives: Tetrastatin, the globular non collagenous (NC1) domain of the α4 chain of collagen IV, was previously demonstrated to inhibit melanoma progression. We identified the minimal active sequence (QKISRCQVCVKYS: QS-13) that reproduced the anti-tumor effects of whole Tetrastatin and demonstrated its anti-angiogenic [...] Read more.

Background/Objectives: Tetrastatin, the globular non collagenous (NC1) domain of the α4 chain of collagen IV, was previously demonstrated to inhibit melanoma progression. We identified the minimal active sequence (QKISRCQVCVKYS: QS-13) that reproduced the anti-tumor effects of whole Tetrastatin and demonstrated its anti-angiogenic activity mediated through αvβ3 and α5β1 binding. As QS-13 peptide was not fully soluble in aqueous solution, we designed new peptides with better water solubility. The present work aimed to investigate the interactions of ten QS-13-derived peptides, exhibiting improved hydro-solubility, with αvβ3 and α5β1 integrins. Methods: Using bioinformatics tools such as GROMACS, VMD, and the Autodock4 suite, we investigated the ability of the substituted peptides to bind αvβ3 and α5β1 integrins in silico. Results: We demonstrated in silico that all substituted peptides were able to bind both integrins at the RGD-binding site and determined their theoretical binding energy. Conclusions: The new soluble peptides should be able to compete with natural integrin ligands such as fibronectin, but also FGF1, FGF2, IGF1, and IGF2. Taken together, these findings suggest that the QS-13-derived peptides are reliable anti-angiogenic and anti-tumor agents. Full article

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

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13 pages, 1534 KiB

Open AccessArticle

Osteogenic Potential of Simvastatin and Fluvastatin in an Organotypic Bone Model

by Lukas Poskevicius, Victor Martin, Guilherme Costa, Gintaras Juodžbalys and Pedro Sousa Gomes

Pharmaceuticals 2025, 18(7), 939; https://doi.org/10.3390/ph18070939 (registering DOI) - 21 Jun 2025

Abstract

Background/Objectives: Statins, widely prescribed for their lipid-lowering properties, also exert pleiotropic effects on various tissues, including bone. However, their osteogenic potential remains poorly defined due to variability in statin type, dosage, and experimental models. This study investigates the osteogenic effects of fluvastatin [...] Read more.

Background/Objectives: Statins, widely prescribed for their lipid-lowering properties, also exert pleiotropic effects on various tissues, including bone. However, their osteogenic potential remains poorly defined due to variability in statin type, dosage, and experimental models. This study investigates the osteogenic effects of fluvastatin (FV) and simvastatin (SV) on the ex vivo embryonic chick femur model. Methods: Femora were cultured with logarithmic concentrations (0.1–10 µM) of FV or SV, followed by characterization via microcomputed tomography, histological analysis, and quantitative gene expression. Results: Both statins enhanced osteogenic outcomes at low concentrations (0.1–1 µM), as evidenced by increased bone volume fraction, trabecular organization, collagen matrix maturation, and mineral deposition. Molecular analysis revealed upregulation of key osteogenic markers—RUNX2, SPP1, and COL1A2—with no significant change in chondrogenic markers (SOX9, ACAN), indicating selective activation of osteogenic pathways. In contrast, higher-dose treatment (10 µM) attenuated these effects. Conclusions: These findings underscore the dose-dependent osteoinductive potential of statins and support their application in bone repair strategies within carefully defined therapeutic windows. Full article

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11 pages, 652 KiB

Open AccessArticle

Optimized Enoxolone-Loaded Microsponges for Drug Delivery: A Design of Experiments Approach

by Juste Baranauskaite, Sedef Sefer, Augusta Zevzikoviene, Andrejus Zevzikovas and Liudas Ivanauskas

Pharmaceuticals 2025, 18(7), 938; https://doi.org/10.3390/ph18070938 (registering DOI) - 21 Jun 2025

Abstract

Enoxolon is widely recognized for its pharmacological potential, exhibiting antioxidant, anti-inflammatory, anticancer, and antiviral properties. Objectives: This study aimed to develop an enhanced formulation of enoxolone-loaded microsponges as a novel drug delivery system. A design of experiments (DoE) approach was employed for [...] Read more.

Enoxolon is widely recognized for its pharmacological potential, exhibiting antioxidant, anti-inflammatory, anticancer, and antiviral properties. Objectives: This study aimed to develop an enhanced formulation of enoxolone-loaded microsponges as a novel drug delivery system. A design of experiments (DoE) approach was employed for the optimization process. Methods: The microsponges were produced using the quasi-emulsion technique. The selected formulation was evaluated for yield, particle size, and entrapment efficiency. Furthermore, the microsponges were incorporated into a 1% MC solution matrix, and in vitro release studies were performed to assess their drug delivery performance. Results: The optimal formulation was determined through the DoE methodology, which involved varying the concentrations of methylcellulose (MC) (0.55–1.87%, w/w), polyvinyl alcohol (PVA) (0.5–1%, w/w), and Tween 80 (TW80) (1.5–2.5%, w/w). The results showed a particle size of 142.8 ± 10.02 µm and an entrapment efficiency of 80.3 ± 1.99%. When comparing the optimized microsponge formulation to pure enoxolon, a 1.29 times higher release rate was observed (p ≤ 0.05). Conclusions: Following optimizationand physicochemical characterization studies were conducted to further assess the formulation. These findings suggest that microsponge-based delivery systems hold considerable potential as an alternative platform for the topical treatment of chronic periodontitis. Full article

(This article belongs to the Section Pharmaceutical Technology)

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18 pages, 973 KiB

Open AccessArticle

Stability Assessment of Furosemide Oral Suspension in Hospital Extemporaneous Preparations

by Fai Alkathiri, Omamah Eid, Njoud Altuwaijri, Rihaf Alfaraj, Eram K. Eltahir, Hend Alsabbagh, Shamma Bin Shoia, Mashal Aljead, Haya H. Alnufaie and Ghadah AlToum

Pharmaceuticals 2025, 18(7), 937; https://doi.org/10.3390/ph18070937 - 20 Jun 2025

Abstract

Background: Furosemide is a loop diuretic used extensively to treat adult and pediatric patients. In some hospitals, furosemide oral liquids are not available in stock, thus necessitating the extemporaneous preparation of the drug. This study evaluates the stability of on-the-spot formulations of furosemide [...] Read more.

Background: Furosemide is a loop diuretic used extensively to treat adult and pediatric patients. In some hospitals, furosemide oral liquids are not available in stock, thus necessitating the extemporaneous preparation of the drug. This study evaluates the stability of on-the-spot formulations of furosemide oral suspensions from crushed tablets evaluated in various vehicles: Dextrose 50%, Dextrose 70%, Ora-Sweet, and Ora-Plus over 60 days. This examination was prompted by the frequent shortage of certain excipients in the hospital, leading to the need to switch to Dextrose 50% or Dextrose 70% when Ora-Sweet and Ora-Plus are out of stock. Methods: The extemporaneous furosemide oral suspensions were prepared following the same compounding method used in the pharmacy. The suspensions were maintained at 4 °C in the refrigerator and assessed immediately and later, on days 7, 14, 30, and 60. The assessed parameters included visual appearance, redispersion time, sedimentation volume, and pH levels for stability analysis. We also examined the drug content, dissolution of the suspension, and microbiological stability. Results: Initial examinations indicated that Dextrose 50% and Ora-Plus maintained pH levels and stable appearances, while significant changes, mainly in appearance and redispersion time, indicated the instability of Dextrose 70%. Ora-Sweet showed fluctuations but stabilized by day 30. Dissolution studies demonstrated that Ora-Plus had dissolution characteristics superior to the other formulations, while Dextrose 50% showed declining dissolution percentages over time. Overall, the Ora-Plus vehicle showed superior stability (60 days), followed by Ora-Sweet (30 days), while Dextrose 70% and Dextrose 50% showed shorter stability durations of 14 and 7 days, respectively. The microbiological test results showed no microbial growth. Conclusion: This study demonstrates that the vehicle used in extemporaneous furosemide suspensions critically affects their stability and performance. Ora-Plus emerged as the most suitable vehicle, maintaining physical, chemical, and microbiological stability over 60 days, with consistent pH, redispersion, and dissolution behavior. Ora-Sweet showed intermediate stability (30 days), while Dextrose 50% and 70% exhibited early instability—7 and 14 days, respectively—marked by sedimentation, poor redispersibility, and declining drug release. These findings underscore the importance of vehicle selection and regular stability monitoring in compounded formulations to ensure therapeutic reliability and patient safety. Full article

(This article belongs to the Section Pharmaceutical Technology)

33 pages, 3336 KiB

Open AccessArticle

Computational Insights into the Polypharmacological Landscape of BCR-ABL Inhibitors: Emphasis on Imatinib and Nilotinib

by Rima Hajjo, Dima A. Sabbah, Raghad Alhaded, Aye Alquabe'h and Sanaa K. Bardaweel

Pharmaceuticals 2025, 18(7), 936; https://doi.org/10.3390/ph18070936 - 20 Jun 2025

Abstract

Background: BCR-ABL inhibitors such as imatinib and nilotinib exhibit multi-kinase activity that extends beyond oncology, offering significant potential for drug repurposing. Objectives: This study aims to systematically evaluate and prioritize the repurposing potential of BCR-ABL inhibitors, particularly imatinib and nilotinib. Methods: An integrated [...] Read more.

Background: BCR-ABL inhibitors such as imatinib and nilotinib exhibit multi-kinase activity that extends beyond oncology, offering significant potential for drug repurposing. Objectives: This study aims to systematically evaluate and prioritize the repurposing potential of BCR-ABL inhibitors, particularly imatinib and nilotinib. Methods: An integrated pharmacoinformatics framework was applied to analyze seven BCR-ABL inhibitors. Structural clustering, cheminformatics analysis, and transcriptomic profiling using the Connectivity Map were employed to evaluate structural relationships, target profiles, and gene expression signatures associated with non-oncology indications. Results: Structurally, imatinib and nilotinib clustered closely, while HY-11007 exhibited distinct features. Nilotinib’s high selectivity correlated with strong transcriptional effects in neurodegeneration-related pathways (e.g., HSP90 and LYN), whereas imatinib’s broader kinase profile (PDGFR and c-KIT) was linked to fibrosis and metabolic regulation. Connectivity Map analysis identified more than 30 non-cancer indications, including known off-target uses (e.g., imatinib for pulmonary hypertension) and novel hypotheses (e.g., nilotinib for Alzheimer’s via HSPA5 modulation). A substantial portion of these predictions aligned with the existing literature, underscoring the translational relevance of the approach. Conclusions: These findings highlight the importance of integrating structure–activity relationships and transcriptomic signatures to guide rational repurposing. We propose prioritizing nilotinib for CNS disorders and imatinib for systemic fibrotic diseases, supporting their advancement into preclinical and clinical evaluation. More broadly, this framework offers a versatile platform for uncovering hidden therapeutic potential across other drug classes with complex polypharmacology. Full article

(This article belongs to the Special Issue Design, Synthesis, Evaluation and Biopharmaceutical Uses of Imatinib, Nilotinib and Their Analogues)

15 pages, 2522 KiB

Open AccessReview

Regulation of L-Lactate in Glutamate Excitotoxicity Under Cerebral Ischemia: Pathophysiology and Preventive Strategy

by Mao Zhang, Yanyan Wang, Zili Gong, Wen Jiang, Guodong Ge and Hong Guo

Pharmaceuticals 2025, 18(7), 935; https://doi.org/10.3390/ph18070935 - 20 Jun 2025

Abstract

Glutamate is an excitatory neurotransmitter in the central nervous system (CNS) that mediates synaptic transmission. However, glutamate homeostasis among neural cells is broken in cerebral ischemia. Excessive glutamate triggers N-methyl-d-aspartate receptors (NMDARs) in postsynaptic neurons, leading to intracellular calcium (Ca [...] Read more.

Glutamate is an excitatory neurotransmitter in the central nervous system (CNS) that mediates synaptic transmission. However, glutamate homeostasis among neural cells is broken in cerebral ischemia. Excessive glutamate triggers N-methyl-d-aspartate receptors (NMDARs) in postsynaptic neurons, leading to intracellular calcium (Ca²⁺) overload and excitoneurotoxicity. At this moment, L-lactate may affect NMDARs and play a protective role in cerebral ischemia. This work proposes that L-lactate regulates glutamate signaling among neural cells. But, dysregulation of L-lactate in glutamate signaling cascades contributes to glutamate excitotoxicity in cerebral ischemia. In detail, L-lactate regulates the glutamine(Gln)-glutamate cycle between astrocytes and presynaptic neurons, which triggers the astroglial L-lactate-sensitive receptor (LLR)-cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway, coordinating astroglial glutamate uptake and neuronal glutamate transmission. L-lactate mediates glutamate signaling and synaptic transmission among neural cells. In addition, L-lactate promotes the function of mitochondrial calcium uniporter complex (MCUC), which quickly depletes intracellular Ca²⁺ in postsynaptic neurons. In addition, L-lactate can promote the conversion of microglia from the pro-inflammatory (M1) to anti-inflammatory (M2) phenotype. Therefore, regulation of L-lactate in glutamate signaling in the CNS might become a preventive target for cerebral ischemia. Full article

(This article belongs to the Section Biopharmaceuticals)

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19 pages, 24617 KiB

Open AccessArticle

Research on Sinomenine Inhibiting the cGAS-STING Signaling Pathway to Alleviate Renal Inflammatory Injury in db/db Mice

by Xiaofei Jin, Tongtong He, Tianci Zhang, Xiaorong Wang, Xiangmei Chen, Bin Cong and Weijuan Gao

Pharmaceuticals 2025, 18(7), 934; https://doi.org/10.3390/ph18070934 - 20 Jun 2025

Abstract

Objectives: This study aims to elucidate the potential molecular mechanism of Sinomenine (SIN) in treating renal injury in Diabetic Nephropathy (DN) through network pharmacology, molecular docking, and in vivo validation. Materials and Methods: db/db mice were used as a DN model to [...] Read more.

Objectives: This study aims to elucidate the potential molecular mechanism of Sinomenine (SIN) in treating renal injury in Diabetic Nephropathy (DN) through network pharmacology, molecular docking, and in vivo validation. Materials and Methods: db/db mice were used as a DN model to evaluate the therapeutic effects of SIN on body weight, blood glucose levels, renal function, and histopathology. Network pharmacology and molecular docking were integrated to predict the potential molecular mechanisms of SIN in DN treatment. Subsequently, in vivo validation was performed on db/db mice using ELISA, Western blotting, RT-qPCR, immunofluorescence, and immunohistochemistry. Results: Firstly, we found that SIN (62.4 mg/kg) improved general conditions and renal function in db/db mice, alleviating renal pathological damage. Network pharmacology analysis identified IL-1β, IL-6, and TNF-α as key targets of SIN in DN. SIN reduced IL-1β, IL-6, and TNF-α levels by inhibiting the cGAS/STING signaling pathway and its downstream p-TBK1, p-IRF3, and NF-κB expression. Conclusions: SIN alleviates inflammatory injury in DN, potentially through the cGAS/STING pathway. Full article

(This article belongs to the Section Natural Products)

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15 pages, 2455 KiB

Open AccessArticle

Paeoniflorin Improves Stroke by Modulating the ESR1 Pathway: Data Mining and Validation Based on Network Approaches

by Zhenshan Sun, Junjie Peng, Jiangbangrui Chu, Zhengyi Wang, Kefan Hu, Zhanpeng Feng, Mingfeng Zhou, Xingqin Wang, Songtao Qi, Zhu Zhang and Ken Kin Lam Yung

Pharmaceuticals 2025, 18(7), 933; https://doi.org/10.3390/ph18070933 - 20 Jun 2025

Abstract

Aim of the study: Traditional Chinese herbs have a unique therapeutic effect on stroke and numerous successful clinical cases. However, these clinical cases are highly dispersed, creating challenges for translational research. This study employs a new paradigm to identify treatment patterns and the [...] Read more.

Aim of the study: Traditional Chinese herbs have a unique therapeutic effect on stroke and numerous successful clinical cases. However, these clinical cases are highly dispersed, creating challenges for translational research. This study employs a new paradigm to identify treatment patterns and the active compound interactions contained within these clinical cases, with experimental validation after target screening. Methods and Materials: Stroke-related targets were identified through GEO, DisGeNET, and Genecards. Active ingredients were extracted from BATMAN-TCM 2.0. All herbs and diseases were confirmed by the Pharmacopoeia of the People’s Republic of China (2020 edition) and Medical Subject Heading (MeSH). All networks in this study were constructed by Cytoscape, and data analysis was done by Python. All formulations and herbs were retrieved from the literature review. For the molecular docking process, Autodock was applied as the docking platform, and all the protein structures were downloaded from PDB. For experimental validation after target screening, HT22 cells were incubated with glucose-free DMEM and placed in an anaerobic chamber for 2 h. Subsequently, HT22 cells were reoxygenated for 24 h. Estrogen Receptor 1 (ESR1) protein levels were measured in vitro. Results: seven materials, including Angelicae Sinensis Radix, Pheretima, Chuanxiong Rhizoma, Persicae Semen, Astragali Radix, Carthami Flos, and Radix Paeoniae Rubra, were identified as the core herbs for the treatment of stroke. The targets of the stroke mechanism were screened, and the herbs-compound-target network was constructed. Among them, paeoniflorin (PF) was identified as the core active compound, and its interaction with ESR1 was verified by molecular docking as the key interaction for the treatment of stroke. In vitro experiments showed that PF inhibited cell apoptosis under hypoxia by increasing the expression of ESR1 compared with the oxygen-glucose deprivation-reperfusion (OGD/R) model group. Western showed that PF (100 μM, 200 μM) can significantly increase the decreased ESR1 protein level caused by the OGD/R model. Conclusions: seven key herbs were screened. Further bioinformatics and network pharmacology studies suggested that PF is expected to become a new active compound for the treatment of stroke. In vitro validation further demonstrated that PF enhanced neuronal survival and ESR1 expression under ischemic conditions, supporting its therapeutic candidacy. Full article

(This article belongs to the Section Pharmacology)

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32 pages, 18091 KiB

Open AccessArticle

Yinchenhao Decoction Mitigates Cholestatic Liver Injury in Mice via Gut Microbiota Regulation and Activation of FXR-FGF15 Pathway

by Weiwei Li, Doudou Huang, Zichen Luo, Ting Zhou and Ziwen Jin

Pharmaceuticals 2025, 18(7), 932; https://doi.org/10.3390/ph18070932 - 20 Jun 2025

Abstract

Objective: Yinchenhao decoction (YCHD), a classical herbal formula comprising Artemisia capillaris, Gardenia jasminoides, and Rheum palmatum, has been clinically used for over 1000 years to treat cholestasis. However, its mechanism of action remains undefined. This study aimed to elucidate YCHD’s [...] Read more.

Objective: Yinchenhao decoction (YCHD), a classical herbal formula comprising Artemisia capillaris, Gardenia jasminoides, and Rheum palmatum, has been clinically used for over 1000 years to treat cholestasis. However, its mechanism of action remains undefined. This study aimed to elucidate YCHD’s therapeutic mechanisms against cholestasis, with a focus on the gut microbiota-mediated regulation of the farnesoid X receptor (FXR)–fibroblast growth factor 15 (FGF15) pathway. Methods: An alpha-naphthyl isothiocyanate (ANIT)-induced cholestasis mouse model was established. Mice received YCHD (3/9 g/kg) for 7 days. 16S rRNA sequencing, targeted LC/MS (bile acid (BA) quantification), untargeted GC/MS (fecal metabolite detection), qPCR/Western blot (FXR pathway analysis), fecal microbiota transplantation (FMT), and antibiotic depletion were employed to dissect the gut–liver axis interactions. Results: YCHD alleviated cholestatic liver injury by reducing serum biomarkers, restoring BA homeostasis via FXR-FGF15 activation, and suppressing hepatic Cyp7a1-mediated BA synthesis. It remodeled gut microbiota, enriched FXR-activating secondary BAs (CDCA, DCA, CA), and restored the intestinal barrier integrity. Antibiotic cocktail abolished YCHD’s efficacy, while FMT from YCHD-treated mice enhanced its therapeutic effects, confirming microbiota dependency. Conclusions: YCHD mitigates cholestasis through gut microbiota-driven FXR activation and direct hepatobiliary regulation. These findings bridge traditional medicine and modern pharmacology, highlighting microbiome modulation as a therapeutic strategy for cholestatic liver diseases. Full article

(This article belongs to the Special Issue Natural Products in Gut Microbiome Modulation: From Mechanisms to Clinical Applications)

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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

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

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

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

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

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

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

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

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

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

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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