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Dapagliflozin in diabetic kidney disease patients with different filtration status
IF 4.3 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-02-15 DOI: 10.1016/j.ejps.2025.107045
Yang Yang , Manna Li , Honghong Zou , Pingping Yang , Li Wang , Gaosi Xu

Background

Few studies have discussed the effects and mechanism of dapagliflozin on diabetic kidney disease (DKD) with different glomerular filtration rate (GFR) and systolic blood pressure (SBP). This study aimed to investigate the variation in the eGFR and proteinuria after dapagliflozin treatment in DKD patients with different filtration status and SBP levels.

Methods

First, we conducted a cross-sectional study to determined hyperfiltration threshold for the DKD trial. Then, we enrolled 259 DKD patients with an eGFR greater than 70 mL/min/1.73m2 and an albumin-to-creatinine ratio (ACR) between 30 and 200 mg/g to receive treatment with dapagliflozin. Hyperfiltration was defined as the 95th percentile of eGFR above the age- and gender- specific in healthy subjects, DKD patients were divided into hyperfiltration and non-hyperfiltration groups, and SBP > 120 mmHg and ≤ 120 mmHg groups. The eGFR, ACR, and blood and urine electrolytes were measured before and after treatment.

Results

The mean eGFR change at 2 weeks in the hyperfiltration with SBP > 120 mmHg group was greater than in the non-hyperfiltration with SBP ≤ 120 mmHg group (P = 0.048). The mean ACR reduction values were greater in the non-hyperfiltration with SBP ≤ 120 mmHg group than in the hyperfiltration with SBP > 120 mmHg group at 12 weeks (P = 0.042). There was no difference in other blood or urine electrolytes before and after treatment, except for the fractional excretion of sodium (FENa), which significantly increased after 2 weeks (P < 0.001) and recovered after 8 weeks (P = 0.305).

Conclusion

DKD with non-hyperfiltration with SBP ≤ 120 mmHg had a lower mean eGFR decline and greater decrease in the ACR after treatment. The initial increase in FENa and subsequent decrease after dapagliflozin treatment may be the main mechanism behind the eGFR variation.
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引用次数: 0
CRISPR/Cas9 based knockout of lncRNA MALAT1 attenuates TGF-β1 induced Smad 2/3 mediated fibrosis during AKI-to-CKD transition 基于CRISPR/Cas9的lncRNA MALAT1基因敲除可减轻TGF-β1诱导的Smad 2/3介导的AKI向CKD转变过程中的纤维化现象
IF 4.3 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-02-15 DOI: 10.1016/j.ejps.2025.107044
Bhupendra Puri , Syamantak Majumder , Anil Bhanudas Gaikwad
Acute kidney injury (AKI) is a significant clinical issue with potential long-term consequences, as even a single episode can progress to chronic kidney disease (CKD). The AKI-to-CKD transition involves complex pathophysiology, including persistent inflammation, apoptosis, and fibrosis. Long noncoding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been recognized as a potential therapeutic target for various kidney diseases, including AKI and CKD. In our previous study, we conducted the transcriptomic analysis of lncRNAs in-vitro and animal models of AKI-to-CKD transition and found several dysregulated lncRNAs such as MALAT1, MEG3, NEAT1, MIAT, and H19 in this transition. Among these, we have selected lncRNA MALAT1 to further validate its role in AKI-to-CKD transition as a therapeutic target via a cluster regularly intercept short palindromic protein (CRISPR) associated protein 9 (Cas9)-mediated knockout approach in NRK52E cells. Guide RNAs (gRNAs) were designed to target MALAT1, and the PX459 turbo green fluorescence protein (GFP) plasmid containing MALAT1 gRNA1&2 was transfected into NRK52E cells using CRISPRMAX. Results demonstrated that MALAT1 knockout significantly reduced MALAT1 expression and attenuated Smad2/3-mediated fibrosis by decreasing pSmad2, pSmad2/3, Smad4, vimentin, fibronectin, collagen-I, and α-SMA expression levels, while increasing Smad7, Smurf2, and E-cadherin levels. These findings suggest that targeting the MALAT1/Smad2/3 pathway could be a potential therapeutic target for mitigating fibrosis to prevent AKI-to-CKD transition.
{"title":"CRISPR/Cas9 based knockout of lncRNA MALAT1 attenuates TGF-β1 induced Smad 2/3 mediated fibrosis during AKI-to-CKD transition","authors":"Bhupendra Puri ,&nbsp;Syamantak Majumder ,&nbsp;Anil Bhanudas Gaikwad","doi":"10.1016/j.ejps.2025.107044","DOIUrl":"10.1016/j.ejps.2025.107044","url":null,"abstract":"<div><div>Acute kidney injury (AKI) is a significant clinical issue with potential long-term consequences, as even a single episode can progress to chronic kidney disease (CKD). The AKI-to-CKD transition involves complex pathophysiology, including persistent inflammation, apoptosis, and fibrosis. Long noncoding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been recognized as a potential therapeutic target for various kidney diseases, including AKI and CKD. In our previous study, we conducted the transcriptomic analysis of lncRNAs <em>in-vitro</em> and animal models of AKI-to-CKD transition and found several dysregulated lncRNAs such as MALAT1, MEG3, NEAT1, MIAT, and H19 in this transition. Among these, we have selected lncRNA MALAT1 to further validate its role in AKI-to-CKD transition as a therapeutic target via a cluster regularly intercept short palindromic protein (CRISPR) associated protein 9 (Cas9)-mediated knockout approach in NRK52E cells. Guide RNAs (gRNAs) were designed to target MALAT1, and the PX459 turbo green fluorescence protein (GFP) plasmid containing MALAT1 gRNA1&amp;2 was transfected into NRK52E cells using CRISPRMAX. Results demonstrated that MALAT1 knockout significantly reduced MALAT1 expression and attenuated Smad2/3-mediated fibrosis by decreasing pSmad2, pSmad2/3, Smad4, vimentin, fibronectin, collagen-I, and α-SMA expression levels, while increasing Smad7, Smurf2, and E-cadherin levels. These findings suggest that targeting the MALAT1/Smad2/3 pathway could be a potential therapeutic target for mitigating fibrosis to prevent AKI-to-CKD transition.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"207 ","pages":"Article 107044"},"PeriodicalIF":4.3,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143428622","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Enhancement of the in vitro anti-leukemic effect of the histone deacetylase inhibitor romidepsin using Poly-(D, L-lactide-co-glycolide) nanoparticles as a drug carrier
IF 4.3 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-02-12 DOI: 10.1016/j.ejps.2025.107043
Pinyadapat Aroonthongsawat , Siriphan Manocheewa , Chatchawan Srisawat , Primana Punnakitikashem , Yaneenart Suwanwong
The goal of this work is to develop a delivery system for histone deacetylase inhibitor (HDACi) romidepsin (ROM) using Poly(D, L-lactide-co-glycolide) as a carrier and evaluate its anti-leukemic effects. Romidepsin-loaded nanoparticles (ROM NPs) required for this purpose were fabricated using a single emulsion-solvent evaporation technique. Their physical characteristics and in vitro drug release profiles were studied, alongside biocompatibility and hemocompatibility assessments. Cell viability assays and Annexin V/Propidium Iodide (PI) staining were conducted to evaluate the anti-leukemic and apoptosis induction efficiency of ROM NPs in vitro. ROM NPs displayed a spherical shape with an average hydrodynamic size of about 149.7 ± 8.4 nm, a PDI of 0.11 ± 0.03, and a zeta potential of -25.27 ± 2.12 mV. The nanoparticles demonstrated a high encapsulation efficiency of ROM (∼93 %) and these nanoparticles effectively entered acute leukemia cells, including U937 and Jurkat. ROM NPs also exhibited a prolonged biphasic release pattern, specifically, the initial burst release phase occurred within the first 24 h, followed by a slower, sustained release. Additionally, they showed no hematological or biological toxicity, indicating their potential use for the delivery of anti-cancer drugs through the circulatory system. In tests on acute leukemia cell lines, ROM NPs showed significantly stronger anti-leukemic effects and induced apoptosis to a greater extent compared to free ROM. In summary, ROM NPs represent a promising therapy option for leukemia according to their enhanced anti-leukemic effects. Further modification of this strategy could be performed to enable target specificity, hence minimizing damage to normal cells.
{"title":"Enhancement of the in vitro anti-leukemic effect of the histone deacetylase inhibitor romidepsin using Poly-(D, L-lactide-co-glycolide) nanoparticles as a drug carrier","authors":"Pinyadapat Aroonthongsawat ,&nbsp;Siriphan Manocheewa ,&nbsp;Chatchawan Srisawat ,&nbsp;Primana Punnakitikashem ,&nbsp;Yaneenart Suwanwong","doi":"10.1016/j.ejps.2025.107043","DOIUrl":"10.1016/j.ejps.2025.107043","url":null,"abstract":"<div><div>The goal of this work is to develop a delivery system for histone deacetylase inhibitor (HDACi) romidepsin (ROM) using Poly(D, L-lactide-co-glycolide) as a carrier and evaluate its anti-leukemic effects. Romidepsin-loaded nanoparticles (ROM NPs) required for this purpose were fabricated using a single emulsion-solvent evaporation technique. Their physical characteristics and <em>in vitro</em> drug release profiles were studied, alongside biocompatibility and hemocompatibility assessments. Cell viability assays and Annexin V/Propidium Iodide (PI) staining were conducted to evaluate the anti-leukemic and apoptosis induction efficiency of ROM NPs <em>in vitro</em>. ROM NPs displayed a spherical shape with an average hydrodynamic size of about 149.7 ± 8.4 nm, a PDI of 0.11 ± 0.03, and a zeta potential of -25.27 ± 2.12 mV. The nanoparticles demonstrated a high encapsulation efficiency of ROM (∼93 %) and these nanoparticles effectively entered acute leukemia cells, including U937 and Jurkat. ROM NPs also exhibited a prolonged biphasic release pattern, specifically, the initial burst release phase occurred within the first 24 h, followed by a slower, sustained release. Additionally, they showed no hematological or biological toxicity, indicating their potential use for the delivery of anti-cancer drugs through the circulatory system. In tests on acute leukemia cell lines, ROM NPs showed significantly stronger anti-leukemic effects and induced apoptosis to a greater extent compared to free ROM. In summary, ROM NPs represent a promising therapy option for leukemia according to their enhanced anti-leukemic effects. Further modification of this strategy could be performed to enable target specificity, hence minimizing damage to normal cells.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"207 ","pages":"Article 107043"},"PeriodicalIF":4.3,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Pharmaceutical quality of herbal medicinal products and dietary supplements – a case study with oral solid formulations containing Lavandula species
IF 4.3 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-02-12 DOI: 10.1016/j.ejps.2025.107042
Banaz Jalil , Michael Heinrich
The effectiveness and safety of regulated herbal medicinal products and dietary/food supplements are key areas of research. However, limited evidence exists of their pharmaceutical performance quality (including the standard in the respective pharmacopeial monographs). We evaluated the applicability of the European Pharmacopoeia general chapter protocols for disintegration testing of oral dosage forms using 73 products containing Lavandula species. Several Lavandula species, hybrids and cultivars are important medicinal plants globally in the phytopharmaceuticals and dietary/food supplement industry, including Lavandula Mill., traditionally used to treat conditions linked to nervousness and sleep disorders. We evaluate the pharmaceutical performance quality, particularly the in vitro disintegration and the phytochemical quality of 73 Lavandula oral dosage forms of single and multi–ingredients with different regulatory statuses. The phytochemical quality testing showed that 63 % of products contain less or none of the main marker compounds (e.g., linalool, linalyl acetate, and cineole). There was also considerable variability of the main marker compounds between products, with some containing ‘often/sometimes undeclared’ and significant amounts of rapeseed and sunflower oils as excipients. The pharmaceutical performance quality testing showed that 30 % of oral solid formulations always failed the disintegration testing (seven soft gels, ten hard shells, and five tablets/caplets). Pass rates for gelatine-based capsules were higher than for non-gelatine (cellulose-based) capsules. Overall, our findings highlighted problems with the pharmaceutical performance and phytochemical quality of the investigated products. These results have implications for the interpretations of the benefits and risks of phytopharmaceuticals used as compared to dietary/food supplements.
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引用次数: 0
Impact of surface energy and surface tension on vial fogging within lyophilized drug products
IF 4.3 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-02-11 DOI: 10.1016/j.ejps.2025.107040
Shuangxiu Shu , Zidan Yuan , Jitang Chen , Zhi Yang , Lingyun Zou , Yuhui Gong , Chunyuan Jia , Bingquan (Stuart) Wang , Jianjun Luo
Vial fogging is a typical cosmetic cake appearance issue in lyophilized products, mostly occurring in amphiphilic protein-like freeze-dried formulations, especially antibody drug conjugate (ADC) formulations. Although fogging is currently believed to have no directly impact on product quality, its occurrence can raise concerns about container closure integrity, leading to an increased product rejection rate in pharmaceutical production. Vial fogging is typically believed to be related to the driving force from the interfacial energy at the liquid/solid interface, which is impacted by several factors. This study delves into fogging impacting factors including vial types, depyrogenation process, and formulation with the aim of appearance enhancement. Employing a Surface Tensiometer and a Drop Shape Analyzer to ascertain surface tension, surface energy, and contact angle measurements, this study incorporated results from lyophilization processes as well and discerned that the degree of fogging is directly proportional to the increase in surface energy and inversely related to surface tension. Consequently, this research identified the critical parameters for forecasting the fogging level prior to lyophilization, offering innovative strategies for enhancing the visual quality of lyophilized pharmaceuticals in subsequent developments.
{"title":"Impact of surface energy and surface tension on vial fogging within lyophilized drug products","authors":"Shuangxiu Shu ,&nbsp;Zidan Yuan ,&nbsp;Jitang Chen ,&nbsp;Zhi Yang ,&nbsp;Lingyun Zou ,&nbsp;Yuhui Gong ,&nbsp;Chunyuan Jia ,&nbsp;Bingquan (Stuart) Wang ,&nbsp;Jianjun Luo","doi":"10.1016/j.ejps.2025.107040","DOIUrl":"10.1016/j.ejps.2025.107040","url":null,"abstract":"<div><div>Vial fogging is a typical cosmetic cake appearance issue in lyophilized products, mostly occurring in amphiphilic protein-like freeze-dried formulations, especially antibody drug conjugate (ADC) formulations. Although fogging is currently believed to have no directly impact on product quality, its occurrence can raise concerns about container closure integrity, leading to an increased product rejection rate in pharmaceutical production. Vial fogging is typically believed to be related to the driving force from the interfacial energy at the liquid/solid interface, which is impacted by several factors. This study delves into fogging impacting factors including vial types, depyrogenation process, and formulation with the aim of appearance enhancement. Employing a Surface Tensiometer and a Drop Shape Analyzer to ascertain surface tension, surface energy, and contact angle measurements, this study incorporated results from lyophilization processes as well and discerned that the degree of fogging is directly proportional to the increase in surface energy and inversely related to surface tension. Consequently, this research identified the critical parameters for forecasting the fogging level prior to lyophilization, offering innovative strategies for enhancing the visual quality of lyophilized pharmaceuticals in subsequent developments.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"207 ","pages":"Article 107040"},"PeriodicalIF":4.3,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143406486","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Extracellular fungal Hsp90 represents a promising therapeutic target for combating fungal infections
IF 4.3 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-02-11 DOI: 10.1016/j.ejps.2025.107041
Ting Fang, Hui Lu (Associate Senior Research Fellow), Yuanying Jiang (Professor)
Heat shock protein 90 (Hsp90) is a pivotal virulence factor in pathogenic fungi, playing a significant role in conferring drug resistance. However, due to the high amino acid sequence similarity between fungal and mammalian Hsp90, targeting fungal intracellular Hsp90 therapeutically is associated with marked toxic side effects, thereby limiting clinical application. Studies have demonstrated that intracellular fungal Hsp90 can be secreted as extracellular Hsp90 (eHsp90), which plays a crucial role in fungal infections. Strategies targeting fungal eHsp90 have exhibited promising therapeutic outcomes. Unlike intracellular targeting, such antifungal approaches can operate without cell penetration, thereby circumventing the toxic side effects due to Hsp90′s high conservation. This review summarizes the potential extracellular secretion pathways of fungal eHsp90, its roles in fungal pathogenesis, as well as the development of vaccines and antibodies targeting fungal eHsp90. The review underlines the significance of eHsp90 in fungal infections and suggests that eHsp90 represents a promising therapeutic target for fungal infection treatment.
{"title":"Extracellular fungal Hsp90 represents a promising therapeutic target for combating fungal infections","authors":"Ting Fang,&nbsp;Hui Lu (Associate Senior Research Fellow),&nbsp;Yuanying Jiang (Professor)","doi":"10.1016/j.ejps.2025.107041","DOIUrl":"10.1016/j.ejps.2025.107041","url":null,"abstract":"<div><div>Heat shock protein 90 (Hsp90) is a pivotal virulence factor in pathogenic fungi, playing a significant role in conferring drug resistance. However, due to the high amino acid sequence similarity between fungal and mammalian Hsp90, targeting fungal intracellular Hsp90 therapeutically is associated with marked toxic side effects, thereby limiting clinical application. Studies have demonstrated that intracellular fungal Hsp90 can be secreted as extracellular Hsp90 (eHsp90), which plays a crucial role in fungal infections. Strategies targeting fungal eHsp90 have exhibited promising therapeutic outcomes. Unlike intracellular targeting, such antifungal approaches can operate without cell penetration, thereby circumventing the toxic side effects due to Hsp90′s high conservation. This review summarizes the potential extracellular secretion pathways of fungal eHsp90, its roles in fungal pathogenesis, as well as the development of vaccines and antibodies targeting fungal eHsp90. The review underlines the significance of eHsp90 in fungal infections and suggests that eHsp90 represents a promising therapeutic target for fungal infection treatment.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"207 ","pages":"Article 107041"},"PeriodicalIF":4.3,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143403392","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A2A receptor antagonist 4-(2-((6-Amino-9-ethyl-8-(furan-2-yl)-9H-purin-2-yl)amino)ethyl)phenol, a promising adenosine derivative for glioblastoma treatment
IF 4.3 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-02-10 DOI: 10.1016/j.ejps.2025.107039
Akshaya Murugesan , Aleksei Smirnov , Anxo Vila Alonso , Michela Buccioni , Chang Cui , Diego Dal Ben , Beatrice Francucci , Catia Lambertucci , Gabriella Marucci , Rosaria Volpini , Saravanan Konda Mani , Sandhanasamy Devanesan , Mohamad S. AlSalhi , Olli Yli-Harja , Andrea Spinaci , Meenakshisundaram Kandhavelu
Adenosine, a pervasive signaling molecule mediated by its interaction with G-protein-coupled receptor subtypes, especially the A2A adenosine receptor (A2AAR), plays a crucial role in cancer treatment. Recently, A2AAR targeting adenosine analogs have been proposed as a potential therapeutic target for cancer treatment. However, the molecules targeting A2AAR and their mode of action in inhibiting glioblastoma cell progression remain unknown. We synthesized six adenosine derivatives substituted at the 9-, 2- and/or N6- and/or 8- positions, and their anti-proliferative efficacy against the GBM cell lines LN229 and SNB19 was assessed. Molecular dynamic simulation integrated with experimental analyses, including cell cycle arrest, apoptosis assay, ligand binding assay, absorption, distribution, metabolism, excretion and toxicity (ADMET) profiling, PAMPA assay, and 3D spheroid analysis, were performed to identify the interaction efficacy of the potential derivative with A2AAR and its ability to prevent GBM cell progression. The most potent A2AAR derivative (ANR), 4-(2-((6-Amino-9-ethyl-8-(furan-2-yl)-9H-purin-2-yl)amino)ethyl)phenol (ANR 672) inhibits 5′-N-Ethylcarboxamidoadenosine (NECA)-induced cAMP validating the antagonistic property with higher cytotoxicity effect against GBM cells. ANR 672 showed higher affinity toward A2AAR (Ki = 1.02 ± 0.06 nM) and exhibited significant IC50 concentrations of ∼ 60–80 µM, than FDA approved drug istredefylline. The A2AAR-ANR 672 interaction profile showed well-defined hydrogen bonds and hydrophobic contacts, indicating a typical binding mechanism inside the receptor pocket and a higher degree of conformational flexibility than the A2AAR-Istradefylline complex. The antagonist effect of ANR 672 blocked the A2AAR signaling pathway, leading to necrosis-mediated cell death and cell cycle arrest at the S-phase in both the GBM cells. ANR 672 treated 3D tumour spheroids analysis with real-time spheroid volume and cell proliferation analysis revealed the potential ability of ANR 672 against GBM cell growth. Drug-likeness assessments also showed favorable pharmacokinetic profiles for ANR 672. Further validation of blood-brain barrier crossing potential revealed that ANR 672 possesses moderate permeability. Our findings shed light on how ANR 672 exerts its GBM-suppressive effect through the interaction of A2AAR. These preclinical results suggest that A2AAR blockade could be a unique strategy for treating GBM.
{"title":"A2A receptor antagonist 4-(2-((6-Amino-9-ethyl-8-(furan-2-yl)-9H-purin-2-yl)amino)ethyl)phenol, a promising adenosine derivative for glioblastoma treatment","authors":"Akshaya Murugesan ,&nbsp;Aleksei Smirnov ,&nbsp;Anxo Vila Alonso ,&nbsp;Michela Buccioni ,&nbsp;Chang Cui ,&nbsp;Diego Dal Ben ,&nbsp;Beatrice Francucci ,&nbsp;Catia Lambertucci ,&nbsp;Gabriella Marucci ,&nbsp;Rosaria Volpini ,&nbsp;Saravanan Konda Mani ,&nbsp;Sandhanasamy Devanesan ,&nbsp;Mohamad S. AlSalhi ,&nbsp;Olli Yli-Harja ,&nbsp;Andrea Spinaci ,&nbsp;Meenakshisundaram Kandhavelu","doi":"10.1016/j.ejps.2025.107039","DOIUrl":"10.1016/j.ejps.2025.107039","url":null,"abstract":"<div><div>Adenosine, a pervasive signaling molecule mediated by its interaction with G-protein-coupled receptor subtypes, especially the A<sub>2A</sub> adenosine receptor (A<sub>2A</sub>AR), plays a crucial role in cancer treatment. Recently, A<sub>2A</sub>AR targeting adenosine analogs have been proposed as a potential therapeutic target for cancer treatment. However, the molecules targeting A<sub>2A</sub>AR and their mode of action in inhibiting glioblastoma cell progression remain unknown. We synthesized six adenosine derivatives substituted at the 9-, 2- and/or <em>N</em><sup>6-</sup> and/or 8- positions, and their anti-proliferative efficacy against the GBM cell lines LN229 and SNB19 was assessed. Molecular dynamic simulation integrated with experimental analyses, including cell cycle arrest, apoptosis assay, ligand binding assay, absorption, distribution, metabolism, excretion and toxicity (ADMET) profiling, PAMPA assay, and 3D spheroid analysis, were performed to identify the interaction efficacy of the potential derivative with A<sub>2A</sub>AR and its ability to prevent GBM cell progression. The most potent A<sub>2A</sub>AR derivative (ANR), 4-(2-((6-Amino-9-ethyl-8-(furan-2-yl)-9H-purin-2-yl)amino)ethyl)phenol (ANR 672) inhibits 5′-N-Ethylcarboxamidoadenosine (<strong>NECA</strong>)-induced cAMP validating the antagonistic property with higher cytotoxicity effect against GBM cells. ANR 672 showed higher affinity toward A<sub>2A</sub>AR (K<sub>i</sub> = 1.02 ± 0.06 nM) and exhibited significant IC<sub>50</sub> concentrations of ∼ 60–80 µM, than FDA approved drug istredefylline. The A<sub>2A</sub>AR-ANR 672 interaction profile showed well-defined hydrogen bonds and hydrophobic contacts, indicating a typical binding mechanism inside the receptor pocket and a higher degree of conformational flexibility than the A<sub>2A</sub>AR-Istradefylline complex. The antagonist effect of ANR 672 blocked the A<sub>2A</sub>AR signaling pathway, leading to necrosis-mediated cell death and cell cycle arrest at the S-phase in both the GBM cells. ANR 672 treated 3D tumour spheroids analysis with real-time spheroid volume and cell proliferation analysis revealed the potential ability of ANR 672 against GBM cell growth. Drug-likeness assessments also showed favorable pharmacokinetic profiles for ANR 672. Further validation of blood-brain barrier crossing potential revealed that ANR 672 possesses moderate permeability. Our findings shed light on how ANR 672 exerts its GBM-suppressive effect through the interaction of A<sub>2A</sub>AR. These preclinical results suggest that A<sub>2A</sub>AR blockade could be a unique strategy for treating GBM.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"207 ","pages":"Article 107039"},"PeriodicalIF":4.3,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143406466","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Synthesis of immunomodulatory biomimetic lipid polymer hybrid nanoparticles and application of zebrafish larvae in immunomodulation screening
IF 4.3 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-02-09 DOI: 10.1016/j.ejps.2025.107037
Aime F. Irabin , Tracey Ollewagen , Carine Smith , Rami Ahmed , Joshua Reineke , Roy Reijnders , Samantha L. Sampson , Nelita du Plessis , Admire Dube
Since the antibiotic golden era of the mid-20th century, there have been limited antibiotics approved, while antibiotic resistance continues to escalate disproportionately, outpacing the rate of novel antibiotic discovery. This imbalance poses a serious global health concern, with an estimated annual death toll of 10 million due to antibiotic resistance by 2050. There is a growing interest in immunotherapy as an alternative approach to conventional antibiotics due to its ability to target and stimulate immune system, leveraging its innate ability to self-eradicate pathogens. This study synthesized lipid polymer hybrid nanoparticles (LPHNPs) conjugated with two immunomodulatory agents, namely, curdlan and mycolic acid (MA), as a potential immunotherapy for bacterial infections. LPHNPs were synthesized using lecithin and polycaprolactone (PCL) at a 15 % lipid-to-polymer (w/w) ratio. Additionally, PCL-curdlan copolymer, comprising 15 % w/w curdlan, was successfully synthesized and used to conjugate the LPHNPs with various curdlan concentrations. Furthermore, The LPHNPs were conjugated with varying MA concentrations, with or without curdlan. In-vivo assessment of the immunomodulatory effect of the LPHNPs was conducted using a larval zebrafish model assessing behaviour and immunofluorescence, as indicators of immune stimulation. The data suggests that curdlan exhibits a more complex immunoregulatory role as demonstrated by the countered stimulated behavioural effect while inflammation remained heightened. This work also provides new insights that zebrafish larvae are a valuable screening tool in the development of nanoparticle immunotherapies.
{"title":"Synthesis of immunomodulatory biomimetic lipid polymer hybrid nanoparticles and application of zebrafish larvae in immunomodulation screening","authors":"Aime F. Irabin ,&nbsp;Tracey Ollewagen ,&nbsp;Carine Smith ,&nbsp;Rami Ahmed ,&nbsp;Joshua Reineke ,&nbsp;Roy Reijnders ,&nbsp;Samantha L. Sampson ,&nbsp;Nelita du Plessis ,&nbsp;Admire Dube","doi":"10.1016/j.ejps.2025.107037","DOIUrl":"10.1016/j.ejps.2025.107037","url":null,"abstract":"<div><div>Since the antibiotic golden era of the mid-20th century, there have been limited antibiotics approved, while antibiotic resistance continues to escalate disproportionately, outpacing the rate of novel antibiotic discovery. This imbalance poses a serious global health concern, with an estimated annual death toll of 10 million due to antibiotic resistance by 2050. There is a growing interest in immunotherapy as an alternative approach to conventional antibiotics due to its ability to target and stimulate immune system, leveraging its innate ability to self-eradicate pathogens. This study synthesized lipid polymer hybrid nanoparticles (LPHNPs) conjugated with two immunomodulatory agents, namely, curdlan and mycolic acid (MA), as a potential immunotherapy for bacterial infections. LPHNPs were synthesized using lecithin and polycaprolactone (PCL) at a 15 % lipid-to-polymer (w/w) ratio. Additionally, PCL-curdlan copolymer, comprising 15 % w/w curdlan, was successfully synthesized and used to conjugate the LPHNPs with various curdlan concentrations. Furthermore, The LPHNPs were conjugated with varying MA concentrations, with or without curdlan. <em>In-vivo</em> assessment of the immunomodulatory effect of the LPHNPs was conducted using a larval zebrafish model assessing behaviour and immunofluorescence, as indicators of immune stimulation. The data suggests that curdlan exhibits a more complex immunoregulatory role as demonstrated by the countered stimulated behavioural effect while inflammation remained heightened. This work also provides new insights that zebrafish larvae are a valuable screening tool in the development of nanoparticle immunotherapies.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"207 ","pages":"Article 107037"},"PeriodicalIF":4.3,"publicationDate":"2025-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143388179","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Enhanced delivery of azithromycin using asymmetric polyethersulfone membrane modified with KIT-6 mesoporous material: Optimization and mechanistic studies
IF 4.3 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-02-09 DOI: 10.1016/j.ejps.2025.107038
Mahya Samari , Soheila Kashanian , Sirus Zinadini , Hossein Derakhshankhah
This study presents the development of a novel drug delivery system designed for improving the release profile and sustained delivery of azithromycin (AZI), particularly aimed at applications requiring localized infection control and improved tissue compatibility. The system employs an asymmetric polyethersulfone (PES) membrane modified with KIT-6 mesoporous material, offering improved drug release performance and biocompatibility over conventional delivery platforms. Membrane optimization was achieved by systematically varying parameters such as thickness (150–600 µm), drug concentration (500–1500 mg/L), polymer content (13–21 % PES), pore maker percentage (0–4 % polyvinylpyrrolidone), and KIT-6 modifier percentage (0.5–2 %). Characterization included scanning electron microscopy, water contact angle measurements, porosity, tensile strength evaluation, and comprehensive bioactivity testing (cytotoxicity, antimicrobial efficacy, blood compatibility, and a novel tissue integrity assay).
The optimized formulation (17 % PES, 2 % PVP, 1 % KIT-6) achieved a controlled and sustained release profile with improved drug availability (464 mg/L) compared to unmodified membranes (252 mg/L), with a sustained release profile governed by the Higuchi model. Additionally, the membrane demonstrated superior biocompatibility (–90 % cell viability, low hemolysis at 1.2 %) and preserved tissue integrity better than unmodified counterparts, as evidenced by in vitro and ex vivo studies. Notably, the system showed robust reusability over prolonged use, indicating its potential as an effective, sustainable, and biocompatible solution for localized AZI delivery. These advantages position this system as a promising alternative for medical applications requiring precise drug release and minimal tissue disruption.
{"title":"Enhanced delivery of azithromycin using asymmetric polyethersulfone membrane modified with KIT-6 mesoporous material: Optimization and mechanistic studies","authors":"Mahya Samari ,&nbsp;Soheila Kashanian ,&nbsp;Sirus Zinadini ,&nbsp;Hossein Derakhshankhah","doi":"10.1016/j.ejps.2025.107038","DOIUrl":"10.1016/j.ejps.2025.107038","url":null,"abstract":"<div><div>This study presents the development of a novel drug delivery system designed for improving the release profile and sustained delivery of azithromycin (AZI), particularly aimed at applications requiring localized infection control and improved tissue compatibility. The system employs an asymmetric polyethersulfone (PES) membrane modified with KIT-6 mesoporous material, offering improved drug release performance and biocompatibility over conventional delivery platforms. Membrane optimization was achieved by systematically varying parameters such as thickness (150–600 µm), drug concentration (500–1500 mg/L), polymer content (13–21 % PES), pore maker percentage (0–4 % polyvinylpyrrolidone), and KIT-6 modifier percentage (0.5–2 %). Characterization included scanning electron microscopy, water contact angle measurements, porosity, tensile strength evaluation, and comprehensive bioactivity testing (cytotoxicity, antimicrobial efficacy, blood compatibility, and a novel tissue integrity assay).</div><div>The optimized formulation (17 % PES, 2 % PVP, 1 % KIT-6) achieved a controlled and sustained release profile with improved drug availability (464 mg/L) compared to unmodified membranes (252 mg/L), with a sustained release profile governed by the Higuchi model. Additionally, the membrane demonstrated superior biocompatibility (–90 % cell viability, low hemolysis at 1.2 %) and preserved tissue integrity better than unmodified counterparts, as evidenced by <em>in vitro</em> and <em>ex vivo</em> studies. Notably, the system showed robust reusability over prolonged use, indicating its potential as an effective, sustainable, and biocompatible solution for localized AZI delivery. These advantages position this system as a promising alternative for medical applications requiring precise drug release and minimal tissue disruption.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"207 ","pages":"Article 107038"},"PeriodicalIF":4.3,"publicationDate":"2025-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143398789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Cannabidiol—A friend or a foe?
IF 4.3 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-02-08 DOI: 10.1016/j.ejps.2025.107036
Bianca – Maria Tihăuan , Tatiana Onisei , Walter Slootweg , Daniel Gună , Ciprian Iliescu , Mariana – Carmen Chifiriuc
Cannabidiol (CBD), one of the main actives from Cannabis sativa has been perpetually explored lately for its therapeutic effects. Its main attributes, such as anti-inflammatory and antioxidant effects, snowball into pain management, epilepsy and seizure alleviation, anxiety relief, as well as numerous other implications through the entire metabolism. However, conventional administration routes challenge its therapeutic potential, with reported poor water solubility, hepatic degradation, gastric instability and erratic bioavailability observed in oral administration. As a result, the transdermal delivery systems have emerged as a promising alternative to oral or inhaled routes, offering improved bioavailability and targeted effects. The medical use of CBD throughout Europe, UK, USA or Australia is extensive and usually represented by pharmaceutical preparations recommended after conventional treatment routs fail. The non-medical use is limited by each country's own legislation, a wider range of products being available, but the irregular regulatory landscape coupled with the growing market of cannabinoid-infused products, emphasizes the need for standardized formulations and further clinical research. The present work critically examines the transdermal administration of cannabidiol, explores the skin's potential as a route and the strategies involved in using it for systemic targeting. We highlighted key challenges and provided insights into CBD`s variable bioavailability based on different administration routes and methods, thus compiling a literature-based absorption, distribution, metabolism, and excretion (ADME) study. We also explore the role of the endocannabinoid system, its function in various medical conditions, and the therapeutic effects associated with CBD, particularly in light of the varying legislation across countries. While the breadth of potential benefits is compelling, it is essential to emphasize the ongoing nature of CBD research as individual responses to it can vary significantly.
{"title":"Cannabidiol—A friend or a foe?","authors":"Bianca – Maria Tihăuan ,&nbsp;Tatiana Onisei ,&nbsp;Walter Slootweg ,&nbsp;Daniel Gună ,&nbsp;Ciprian Iliescu ,&nbsp;Mariana – Carmen Chifiriuc","doi":"10.1016/j.ejps.2025.107036","DOIUrl":"10.1016/j.ejps.2025.107036","url":null,"abstract":"<div><div>Cannabidiol (CBD), one of the main actives from <em>Cannabis sativa</em> has been perpetually explored lately for its therapeutic effects. Its main attributes, such as anti-inflammatory and antioxidant effects, snowball into pain management, epilepsy and seizure alleviation, anxiety relief, as well as numerous other implications through the entire metabolism. However, conventional administration routes challenge its therapeutic potential, with reported poor water solubility, hepatic degradation, gastric instability and erratic bioavailability observed in oral administration. As a result, the transdermal delivery systems have emerged as a promising alternative to oral or inhaled routes, offering improved bioavailability and targeted effects. The medical use of CBD throughout Europe, UK, USA or Australia is extensive and usually represented by pharmaceutical preparations recommended after conventional treatment routs fail. The non-medical use is limited by each country's own legislation, a wider range of products being available, but the irregular regulatory landscape coupled with the growing market of cannabinoid-infused products, emphasizes the need for standardized formulations and further clinical research. The present work critically examines the transdermal administration of cannabidiol, explores the skin's potential as a route and the strategies involved in using it for systemic targeting. We highlighted key challenges and provided insights into CBD`s variable bioavailability based on different administration routes and methods, thus compiling a literature-based absorption, distribution, metabolism, and excretion (ADME) study. We also explore the role of the endocannabinoid system, its function in various medical conditions, and the therapeutic effects associated with CBD, particularly in light of the varying legislation across countries. While the breadth of potential benefits is compelling, it is essential to emphasize the ongoing nature of CBD research as individual responses to it can vary significantly.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"208 ","pages":"Article 107036"},"PeriodicalIF":4.3,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143390247","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
期刊
European Journal of Pharmaceutical Sciences
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