Pub Date : 2025-04-21DOI: 10.1016/j.ejps.2025.107107
Miklós Bege , Krisztina Leiner , Miklós Lovas , Réka Pető , Ilona Bereczki , Jan Hodek , Jan Weber , Anett Kuczmog , Anikó Borbás
D-xylofuranosyl nucleoside analogues bearing alkylthio and glucosylthio substituents at the C3′-position were prepared by photoinitiated radical-mediated hydrothiolation reactions from the corresponding 2′,5′-di-O-silyl-3′-exomethylene uridine. Sequential desilylation and 5′-O-butyrylation of the 3′-thiosubstituted molecules produced a 24-membered nucleoside series with diverse substitution patterns, and the compounds were evaluated for their in vitro antiviral activity against three dangerous human RNA viruses, SARS-CoV-2, SINV and CHIKV. Eight compounds exhibited SARS-CoV-2 activity with low micromolar EC50 values in Vero E6 cells, and two of them also inhibited virus growth in human Calu cells. The best anti-SARS-CoV-2 activity was exhibited by 2′,5′-di-O-silylated 3′-C-alkylthio nucleosides. Twelve compounds showed in vitro antiviral activity against CHIKV and fourteen against SINV with low micromolar EC50 values, with the 5′-butyryl-2′-silyl-3′-alkylthio substitution pattern being the most favorable against both viruses. In the case of the tested nucleosides, removal of the 2′-O-silyl group completely abolished the antiviral activity of the compounds against all three viruses. Overall, the most potent antiviral agent was the disilylated 3′-glucosylthio xylonucleoside, which showed excellent and specific antiviral activity against SINV with an EC50 value of 3 μM and no toxic effect at the highest tested concentration of 120 μM.
{"title":"Synthesis of 3′-modified xylofuranosyl nucleosides bearing 5′-silyl or -butyryl groups and their antiviral effect against RNA viruses","authors":"Miklós Bege , Krisztina Leiner , Miklós Lovas , Réka Pető , Ilona Bereczki , Jan Hodek , Jan Weber , Anett Kuczmog , Anikó Borbás","doi":"10.1016/j.ejps.2025.107107","DOIUrl":"10.1016/j.ejps.2025.107107","url":null,"abstract":"<div><div>D-xylofuranosyl nucleoside analogues bearing alkylthio and glucosylthio substituents at the C3′-position were prepared by photoinitiated radical-mediated hydrothiolation reactions from the corresponding 2′,5′-di-O-silyl-3′-exomethylene uridine. Sequential desilylation and 5′-O-butyrylation of the 3′-thiosubstituted molecules produced a 24-membered nucleoside series with diverse substitution patterns, and the compounds were evaluated for their in vitro antiviral activity against three dangerous human RNA viruses, SARS-CoV-2, SINV and CHIKV. Eight compounds exhibited SARS-CoV-2 activity with low micromolar EC<sub>50</sub> values in Vero E6 cells, and two of them also inhibited virus growth in human Calu cells. The best anti-SARS-CoV-2 activity was exhibited by 2′,5′-di-O-silylated 3′-C-alkylthio nucleosides. Twelve compounds showed in vitro antiviral activity against CHIKV and fourteen against SINV with low micromolar EC<sub>50</sub> values, with the 5′-butyryl-2′-silyl-3′-alkylthio substitution pattern being the most favorable against both viruses. In the case of the tested nucleosides, removal of the 2′-O-silyl group completely abolished the antiviral activity of the compounds against all three viruses. Overall, the most potent antiviral agent was the disilylated 3′-glucosylthio xylonucleoside, which showed excellent and specific antiviral activity against SINV with an EC<sub>50</sub> value of 3 μM and no toxic effect at the highest tested concentration of 120 μM.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"209 ","pages":"Article 107107"},"PeriodicalIF":4.3,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143860266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-12DOI: 10.1016/j.ejps.2025.107092
Min Feng , Wei Gong , Xin Zhu , Juan Zhu , Junjie Hu , Weihua Xu , Zhichao Ma , Shengmiao Fu , Xinping Chen
As the world's only commercially available paclitaxel liposome, Lipusu (Lip) has been clinically used in chemotherapy for >20 years, but the design concept of Lip remains largely unchanged since its initial development. Based on the study of Acetyl-CoA-carboxylase 1 (ACC1) in nasopharyngeal carcinoma (NPC), we proposed the concept of next-generation liposomes (NGL) utilizing lipid demand balance. In this study, we evaluated the feasibility of ACC1 and integrin αVβ3 as NPC targets, and designed 10 conjugates of 5-tetradecyloxy-2-furoic acid (TOFA) and c(RGDfK) that can bind to Lip. Considering the results of chemical parameter prediction, molecular docking, molecular dynamics simulation (MD) and other aspects, we finally selected and synthesized the compound F, and successfully constructed F-Lip by simple incubation method. Compared with Lip, F-Lip showed stronger toxicity in both HONE-1 cells and corresponding tumor-bearing mice. In conclusion, by regulating the balance of lipid demand, the toxicity of Lip can be improved so as to achieve the goal of inhibiting the proliferation of NPC. This study provides a new model for the future design and development of Lip.
{"title":"Covalent binding of 5-tetradecyloxy-2-furoic acid (TOFA) and c(RGDfK) and its co-delivery with Lipusu, a novel synergistic strategy to inhibit the proliferation of nasopharyngeal cancer","authors":"Min Feng , Wei Gong , Xin Zhu , Juan Zhu , Junjie Hu , Weihua Xu , Zhichao Ma , Shengmiao Fu , Xinping Chen","doi":"10.1016/j.ejps.2025.107092","DOIUrl":"10.1016/j.ejps.2025.107092","url":null,"abstract":"<div><div>As the world's only commercially available paclitaxel liposome, Lipusu (Lip) has been clinically used in chemotherapy for >20 years, but the design concept of Lip remains largely unchanged since its initial development. Based on the study of Acetyl-CoA-carboxylase 1 (ACC1) in nasopharyngeal carcinoma (NPC), we proposed the concept of next-generation liposomes (NGL) utilizing lipid demand balance. In this study, we evaluated the feasibility of ACC1 and integrin α<sub>V</sub>β<sub>3</sub> as NPC targets, and designed 10 conjugates of 5-tetradecyloxy-2-furoic acid (TOFA) and c(RGDfK) that can bind to Lip. Considering the results of chemical parameter prediction, molecular docking, molecular dynamics simulation (MD) and other aspects, we finally selected and synthesized the compound F, and successfully constructed F-Lip by simple incubation method. Compared with Lip, F-Lip showed stronger toxicity in both HONE-1 cells and corresponding tumor-bearing mice. In conclusion, by regulating the balance of lipid demand, the toxicity of Lip can be improved so as to achieve the goal of inhibiting the proliferation of NPC. This study provides a new model for the future design and development of Lip.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"209 ","pages":"Article 107092"},"PeriodicalIF":4.3,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143863982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-11DOI: 10.1016/j.ejps.2025.107101
Szabolcs Fekete , Mateusz Imiołek , Fabrice Gritti , Matthew Lauber , Balasubrahmanyam Addepalli , MingCheng Xu
Emerging biopharmaceutical modalities, such as genetic medicines and RNA therapies, offer transformative potential for treating previously intractable diseases. However, these complex drugs present unique analytical challenges due to their intricate structures, sophisticated manufacturing processes, and modality-specific product quality attributes. Liquid chromatography (LC) has emerged as a versatile tool for addressing these challenges, enabling precise characterization and quality control strategies. This review highlights recent advancements in LC technologies, including low-adsorption hardware, ultra-wide pore size exclusion chromatography (SEC) columns, and innovative separation modes such as slalom chromatography and pressure-enhanced liquid chromatography (PELC). These developments tackle issues such as non-specific adsorption, carryover, and inadequate selectivity while improving resolution and robustness for large biomolecules like mRNA, adeno-associated viruses (AAVs), and lipid nanoparticles (LNPs). Novel approaches, such as tandem SEC systems, gradient SEC columns, and dual stationary phase gradients, further expand the scope of LC techniques by enhancing separations for diverse analyte sizes and complexities. Additionally, practical innovations like bracketed injection methods and new enzymatic tools for oligo-mapping improve reproducibility, efficiency, and confidence in RNA sequence analysis. These advancements not only address current analytical limitations but also pave the way for regulatory-compliant approaches, which will support the broader adoption of LC in both discovery and quality control settings. As the field continues to evolve, these innovations are poised to play a pivotal role in ensuring the safety, efficacy, and consistency of next-generation therapeutics.
{"title":"Selected new approaches and future perspectives in liquid chromatography for the analysis of emerging modalities","authors":"Szabolcs Fekete , Mateusz Imiołek , Fabrice Gritti , Matthew Lauber , Balasubrahmanyam Addepalli , MingCheng Xu","doi":"10.1016/j.ejps.2025.107101","DOIUrl":"10.1016/j.ejps.2025.107101","url":null,"abstract":"<div><div>Emerging biopharmaceutical modalities, such as genetic medicines and RNA therapies, offer transformative potential for treating previously intractable diseases. However, these complex drugs present unique analytical challenges due to their intricate structures, sophisticated manufacturing processes, and modality-specific product quality attributes. Liquid chromatography (LC) has emerged as a versatile tool for addressing these challenges, enabling precise characterization and quality control strategies. This review highlights recent advancements in LC technologies, including low-adsorption hardware, ultra-wide pore size exclusion chromatography (SEC) columns, and innovative separation modes such as slalom chromatography and pressure-enhanced liquid chromatography (PELC). These developments tackle issues such as non-specific adsorption, carryover, and inadequate selectivity while improving resolution and robustness for large biomolecules like mRNA, adeno-associated viruses (AAVs), and lipid nanoparticles (LNPs). Novel approaches, such as tandem SEC systems, gradient SEC columns, and dual stationary phase gradients, further expand the scope of LC techniques by enhancing separations for diverse analyte sizes and complexities. Additionally, practical innovations like bracketed injection methods and new enzymatic tools for oligo-mapping improve reproducibility, efficiency, and confidence in RNA sequence analysis. These advancements not only address current analytical limitations but also pave the way for regulatory-compliant approaches, which will support the broader adoption of LC in both discovery and quality control settings. As the field continues to evolve, these innovations are poised to play a pivotal role in ensuring the safety, efficacy, and consistency of next-generation therapeutics.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"209 ","pages":"Article 107101"},"PeriodicalIF":4.3,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143847769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-10DOI: 10.1016/j.ejps.2025.107100
Abdulaziz Saad Alshahrani , Sameh Saber , Ohoud Shafi Alruwaili , Zubida M. Al-Majdoub , Rabab S. Hamad , Mustafa Ahmed Abdel-Reheim , Bahaa Eldin Ali Khaled , Alaa Alibrahim , Asmaa Ramadan , Attalla F. El-kott , Ali S. AlSheri , Sally Negm , Elsayed A. Elmorsy , Amira Karam Khalifa , Rasha Abdelhady
Globally, the incidence and prevalence rates of ulcerative colitis (UC) show a rising pattern. The limited efficacy and significant adverse effects associated with current treatment options underscore the need for novel therapeutic approaches. It has been found that linagliptin, a dipeptidyl peptidase-4 inhibitor, activates AMPK in different disease conditions. The main objective of the present work was to elucidate the potential implications of the AMPK/FOXO3a mediated by linagliptin in rats with chronic colitis. The findings of the current report revealed the first robust in-vivo evidence advocating the coloprotective effect of linagliptin against dextran sodium sulfate-induced chronic UC in rats. It has demonstrated potential beyond its antidiabetic effects by modulating FOXO3a localization. By shifting FOXO3a from the cytosol to the nucleus, linagliptin enhanced the transcription of genes involved in attenuation of pro-inflammatory events and restoration of redox homeostasis. Nuclear FOXO3a also impacted NFκB activity, reducing inflammation. This conclusion was fundamentally supported by the documented improvements in histopathological changes evidenced by reduced inflammation, edema, crypt atrophy, and submucosal fibrosis. Moreover, decreased colon weight/length ratio, as well as reduced scores of disease activity and macroscopic damage indices, were observed. Furthermore, it corrected body weight loss during the time frame of the experiment. These findings underscore the anti-inflammatory potential of therapies that promote the nuclear localization of FOXO3a in inflammatory conditions. Linagliptin's ability to modulate FOXO3a localization might be particularly useful for diabetic patients suffering from inflammatory bowel diseases. However, further molecular investigations are required to validate the findings and to assess the clinical application of this approach as a valid tool for alleviating UC.
{"title":"Modulation of FOXO3a Nuclear Localization by Linagliptin (BI-1356) Reveals a New Therapeutic Target in Chronic Ulcerative Colitis","authors":"Abdulaziz Saad Alshahrani , Sameh Saber , Ohoud Shafi Alruwaili , Zubida M. Al-Majdoub , Rabab S. Hamad , Mustafa Ahmed Abdel-Reheim , Bahaa Eldin Ali Khaled , Alaa Alibrahim , Asmaa Ramadan , Attalla F. El-kott , Ali S. AlSheri , Sally Negm , Elsayed A. Elmorsy , Amira Karam Khalifa , Rasha Abdelhady","doi":"10.1016/j.ejps.2025.107100","DOIUrl":"10.1016/j.ejps.2025.107100","url":null,"abstract":"<div><div>Globally, the incidence and prevalence rates of ulcerative colitis (UC) show a rising pattern. The limited efficacy and significant adverse effects associated with current treatment options underscore the need for novel therapeutic approaches. It has been found that linagliptin, a dipeptidyl peptidase-4 inhibitor, activates AMPK in different disease conditions. The main objective of the present work was to elucidate the potential implications of the AMPK/FOXO3a mediated by linagliptin in rats with chronic colitis. The findings of the current report revealed the first robust in-vivo evidence advocating the coloprotective effect of linagliptin against dextran sodium sulfate-induced chronic UC in rats. It has demonstrated potential beyond its antidiabetic effects by modulating FOXO3a localization. By shifting FOXO3a from the cytosol to the nucleus, linagliptin enhanced the transcription of genes involved in attenuation of pro-inflammatory events and restoration of redox homeostasis. Nuclear FOXO3a also impacted NFκB activity, reducing inflammation. This conclusion was fundamentally supported by the documented improvements in histopathological changes evidenced by reduced inflammation, edema, crypt atrophy, and submucosal fibrosis. Moreover, decreased colon weight/length ratio, as well as reduced scores of disease activity and macroscopic damage indices, were observed. Furthermore, it corrected body weight loss during the time frame of the experiment. These findings underscore the anti-inflammatory potential of therapies that promote the nuclear localization of FOXO3a in inflammatory conditions. Linagliptin's ability to modulate FOXO3a localization might be particularly useful for diabetic patients suffering from inflammatory bowel diseases. However, further molecular investigations are required to validate the findings and to assess the clinical application of this approach as a valid tool for alleviating UC.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"209 ","pages":"Article 107100"},"PeriodicalIF":4.3,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143828652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-09DOI: 10.1016/j.ejps.2025.107099
Sameh Saber , Rabab S. Hamad , Elsayed A. Elmorsy , Mustafa Ahmed Abdel-Reheim , Alshaimaa A. Farrag , Amany M. Ismaiel , Zubida M. Al-Majdoub , Sara T. Elazab , Noura El Adle Khalaf , Hala Magdy Anwer , Ahmed Abdel-monem Elmetwally , Dalia M.Abdel Ghaffar , Shereen Hamed , Amira A. Haleem , Walid Mostafa Sayed Ahmed , Sherin Zohdy Mohamed , Karem Mohamed Salem , Rasha Abdelhady , Ahmed Shata , Asmaa Ramadan
Ischemia is a major contributor to acute kidney injury (AKI), for which current treatment options remain limited. One NAD+-dependent deacetylase that can preserve renal cells is SIRT1. To date, no research has directly explored the effects of E1231, a SIRT1 activator, in the context of renal ischemia-reperfusion (IR) injury. Enhancing NAD+ levels is essential for sustaining SIRT1 activity. Hence, the combined use of E1231 and SR647, a NAD+ precursor, could potentially amplify protective effects by supporting prolonged SIRT1 activation. This study is the first to investigate the therapeutic potential of combining E1231 and SR647 in mitigating unilateral renal IR injury. Rats treated with E1231/SR647 effectively demonstrated reduced tubular damage, inflammation, and necrosis. These improvements correlated with a reduced kidney-to-body weight ratio and increased urine output and flow rate. Additionally, rats with IR injury demonstrated reductions in serum creatinine, BUN, UAER, and cystatin C, as well as urinary NGAL and both serum and urinary KIM-1 levels. On the other hand, elevations in urine creatinine and creatinine CL were recorded. E1231 alone provided moderate functional recovery, which was negated when co-administered with a SIRT1 inhibitor. E1231/SR647 treatment upregulated SIRT1 levels and activity, subsequently enhancing FOXO3 activation. It also boosted Nrf2 levels and activity, upregulating the antioxidant protein expression of HO-1 and NQO1. Furthermore, E1231/SR647 reduced the inflammatory response by inhibiting NFκB activity. In conclusion, E1231/SR647 is a promising therapy that may protect renal function during ischemic events through the modulation of SIRT1/FOXO3 control over Nrf2 and NFκB pathways.
{"title":"E1231/SR647 protects against unilateral renal ischemia-reperfusion injury by modulating SIRT1/FOXO3 interactions with Nrf2 and NFκB pathways","authors":"Sameh Saber , Rabab S. Hamad , Elsayed A. Elmorsy , Mustafa Ahmed Abdel-Reheim , Alshaimaa A. Farrag , Amany M. Ismaiel , Zubida M. Al-Majdoub , Sara T. Elazab , Noura El Adle Khalaf , Hala Magdy Anwer , Ahmed Abdel-monem Elmetwally , Dalia M.Abdel Ghaffar , Shereen Hamed , Amira A. Haleem , Walid Mostafa Sayed Ahmed , Sherin Zohdy Mohamed , Karem Mohamed Salem , Rasha Abdelhady , Ahmed Shata , Asmaa Ramadan","doi":"10.1016/j.ejps.2025.107099","DOIUrl":"10.1016/j.ejps.2025.107099","url":null,"abstract":"<div><div>Ischemia is a major contributor to acute kidney injury (AKI), for which current treatment options remain limited. One NAD<sup>+</sup>-dependent deacetylase that can preserve renal cells is SIRT1. To date, no research has directly explored the effects of E1231, a SIRT1 activator, in the context of renal ischemia-reperfusion (IR) injury. Enhancing NAD<sup>+</sup> levels is essential for sustaining SIRT1 activity. Hence, the combined use of E1231 and SR647, a NAD<sup>+</sup> precursor, could potentially amplify protective effects by supporting prolonged SIRT1 activation. This study is the first to investigate the therapeutic potential of combining E1231 and SR647 in mitigating unilateral renal IR injury. Rats treated with E1231/SR647 effectively demonstrated reduced tubular damage, inflammation, and necrosis. These improvements correlated with a reduced kidney-to-body weight ratio and increased urine output and flow rate. Additionally, rats with IR injury demonstrated reductions in serum creatinine, BUN, UAER, and cystatin C, as well as urinary NGAL and both serum and urinary KIM-1 levels. On the other hand, elevations in urine creatinine and creatinine CL were recorded. E1231 alone provided moderate functional recovery, which was negated when co-administered with a SIRT1 inhibitor. E1231/SR647 treatment upregulated SIRT1 levels and activity, subsequently enhancing FOXO3 activation. It also boosted Nrf2 levels and activity, upregulating the antioxidant protein expression of HO-1 and NQO1. Furthermore, E1231/SR647 reduced the inflammatory response by inhibiting NFκB activity. In conclusion, E1231/SR647 is a promising therapy that may protect renal function during ischemic events through the modulation of SIRT1/FOXO3 control over Nrf2 and NFκB pathways.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"209 ","pages":"Article 107099"},"PeriodicalIF":4.3,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143833163","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-09DOI: 10.1016/j.ejps.2025.107098
Nannapat Sangfuang , Yuan Xie , Laura E. McCoubrey , Marissa Taub , Alessia Favaron , Yang Mai , Simon Gaisford , Abdul W. Basit
Biological ageing is a time-dependent process that has implications for health and disease. Cellular senescence is a key driver in ageing and age-related diseases. Senotherapeutic agents have been shown to slow biological ageing by eliminating senescent mammalian cells. Given the increasing awareness of the gut microbiome in regulating human health, this study aimed to investigate the effects of senotherapeutic agents as pharmacological interventions on the human gut microbiota. In this study, the bidirectional effects of four senotherapeutic agents, quercetin, fisetin, dasatinib, and sirolimus, with the gut microbiota sourced from healthy human donors were investigated. The results revealed that quercetin was completely biotransformed by the gut microbiota within six hours, while dasatinib was the most stable of the four compounds. Additionally, metagenomic analysis confirmed that all four compounds increased the abundance of bacterial species associated with healthy ageing (e.g., Bacteroides fragilis, Bifidobacterium longum, and Veillonella parvula), and decreased the abundance of pathogenic bacteria primarily associated with age-related diseases (e.g., Enterococcus faecalis and Streptococcus spp.). The findings from this study provide a comprehensive understanding of the pharmacobiomics of senotherapeutic interventions, highlighting the potential of microbiome-targeted senolytics in promoting healthy ageing.
{"title":"Investigating the bidirectional interactions between senotherapeutic agents and human gut microbiota","authors":"Nannapat Sangfuang , Yuan Xie , Laura E. McCoubrey , Marissa Taub , Alessia Favaron , Yang Mai , Simon Gaisford , Abdul W. Basit","doi":"10.1016/j.ejps.2025.107098","DOIUrl":"10.1016/j.ejps.2025.107098","url":null,"abstract":"<div><div>Biological ageing is a time-dependent process that has implications for health and disease. Cellular senescence is a key driver in ageing and age-related diseases. Senotherapeutic agents have been shown to slow biological ageing by eliminating senescent mammalian cells. Given the increasing awareness of the gut microbiome in regulating human health, this study aimed to investigate the effects of senotherapeutic agents as pharmacological interventions on the human gut microbiota. In this study, the bidirectional effects of four senotherapeutic agents, quercetin, fisetin, dasatinib, and sirolimus, with the gut microbiota sourced from healthy human donors were investigated. The results revealed that quercetin was completely biotransformed by the gut microbiota within six hours, while dasatinib was the most stable of the four compounds. Additionally, metagenomic analysis confirmed that all four compounds increased the abundance of bacterial species associated with healthy ageing (e.g., <em>Bacteroides fragilis, Bifidobacterium longum</em>, and <em>Veillonella parvula</em>), and decreased the abundance of pathogenic bacteria primarily associated with age-related diseases (e.g., <em>Enterococcus faecalis</em> and <em>Streptococcus</em> spp.). The findings from this study provide a comprehensive understanding of the pharmacobiomics of senotherapeutic interventions, highlighting the potential of microbiome-targeted senolytics in promoting healthy ageing.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"209 ","pages":"Article 107098"},"PeriodicalIF":4.3,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143833168","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Taking in consideration of previous studies in the field of biological relevance and the chelating properties of derivatives bearing the hydroxyquinoline skeleton, establishing cationic centre by direct amidation as well as preparation compound with amino acid character was proposed. In order to test anticancer activity of the synthesised compounds, the applying of preliminary biological screening systems was planned. This concept is demonstrated in the context of the synthesis and transformation of a bifunctional glycine-type precursor substituted with 5‑chloro-8-hydroxyquinoline to hybrids with amino acid and amine feature. Stabilization of the precursor and formed amide composed of N,N-dimethylethylamine via partially aromatic ortho-quinone methide intermediate was tested with different cyclic imines in [4 + 2] cycloaddition. In these [4 + 2] cycloaddition reactions, 1H NMR analysis of the crude reaction mixture proved the formation of a single product in all cases. The relative configuration of the two newly formed stereogenic centres was determined by 2D-NMR technique. Compared to the precursor, all new derivatives exhibited less potent anticancer activity. Based on biological evaluations, out of the synthesized compounds the derivative with amino acid feature and some amidated derivatives showed toxic activity against the Colo 205 cell line.
{"title":"Synthesis, transformations and biological evaluation of 5‑chloro-8-hydroxyquinoline hybrids","authors":"Dóra Hegedűs , Nikoletta Szemerédi , Dorka Gubó , Gabriella Spengler , István Szatmári","doi":"10.1016/j.ejps.2025.107084","DOIUrl":"10.1016/j.ejps.2025.107084","url":null,"abstract":"<div><div>Taking in consideration of previous studies in the field of biological relevance and the chelating properties of derivatives bearing the hydroxyquinoline skeleton, establishing cationic centre by direct amidation as well as preparation compound with amino acid character was proposed. In order to test anticancer activity of the synthesised compounds, the applying of preliminary biological screening systems was planned. This concept is demonstrated in the context of the synthesis and transformation of a bifunctional glycine-type precursor substituted with 5‑chloro-8-hydroxyquinoline to hybrids with amino acid and amine feature. Stabilization of the precursor and formed amide composed of <em>N,N</em>-dimethylethylamine via partially aromatic <em>ortho</em>-quinone methide intermediate was tested with different cyclic imines in [4 + 2] cycloaddition. In these [4 + 2] cycloaddition reactions, <sup>1</sup>H NMR analysis of the crude reaction mixture proved the formation of a single product in all cases. The relative configuration of the two newly formed stereogenic centres was determined by 2D-NMR technique. Compared to the precursor, all new derivatives exhibited less potent anticancer activity. Based on biological evaluations, out of the synthesized compounds the derivative with amino acid feature and some amidated derivatives showed toxic activity against the Colo 205 cell line.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"209 ","pages":"Article 107084"},"PeriodicalIF":4.3,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143799771","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}
Pub Date : 2025-04-03DOI: 10.1016/j.ejps.2025.107095
Jonas Langeraert, Elke Gasthuys, An Vermeulen
Inflammatory bowel disease (IBD) is characterized by a chronic inflammation of the intestinal mucosa, with predominant localization in the colon in ulcerative colitis (UC) or affecting the entire length of the gastrointestinal tract in Crohn's disease (CD). Recent advances in the drug development space have been marked by a return to orally administered small molecules with novel mechanisms of action such as Janus kinase inhibitors. Additionally, the prevalence of certain chronic conditions is higher in IBD patients, many of which are treated with orally administered drugs. Given the pathophysiology and localization of IBD, altered drug absorption from the gastrointestinal tract can be expected. This review discusses several physiological differences between the small and large intestine with the potential to influence drug absorption including pathophysiology related alterations associated with IBD. The main physiological parameters which are identified include luminal fluid volume, luminal pH, transit time, bile salt concentration, microbiome, absorptive surface area, permeability and metabolizing enzymes and transporters. Literature regarding these factors in IBD patients is marked with high heterogeneity in reporting of disease severity and location leading to difficulties in interpreting data across different studies. While the influence of most of these factors has been directly assessed in healthy volunteers, this is rarely the case for IBD patients. Furthermore, studies which used PBPK modelling to describe the PK of an orally administered drug in an IBD population and were able to verify their findings using clinical data are critically examined. These models were able to incorporate the pathophysiological changes associated with IBD and partly succeeded in adequately predicting drug absorption in this population. Given the limited amount of PBPK studies performed on a limited number of drugs, the developed models are most likely not suitable to be used as a general PBPK model for the IBD population.
{"title":"Small molecule drug absorption in inflammatory bowel disease and current implementation in physiologically- based pharmacokinetic models","authors":"Jonas Langeraert, Elke Gasthuys, An Vermeulen","doi":"10.1016/j.ejps.2025.107095","DOIUrl":"10.1016/j.ejps.2025.107095","url":null,"abstract":"<div><div>Inflammatory bowel disease (IBD) is characterized by a chronic inflammation of the intestinal mucosa, with predominant localization in the colon in ulcerative colitis (UC) or affecting the entire length of the gastrointestinal tract in Crohn's disease (CD). Recent advances in the drug development space have been marked by a return to orally administered small molecules with novel mechanisms of action such as Janus kinase inhibitors. Additionally, the prevalence of certain chronic conditions is higher in IBD patients, many of which are treated with orally administered drugs. Given the pathophysiology and localization of IBD, altered drug absorption from the gastrointestinal tract can be expected. This review discusses several physiological differences between the small and large intestine with the potential to influence drug absorption including pathophysiology related alterations associated with IBD. The main physiological parameters which are identified include luminal fluid volume, luminal pH, transit time, bile salt concentration, microbiome, absorptive surface area, permeability and metabolizing enzymes and transporters. Literature regarding these factors in IBD patients is marked with high heterogeneity in reporting of disease severity and location leading to difficulties in interpreting data across different studies. While the influence of most of these factors has been directly assessed in healthy volunteers, this is rarely the case for IBD patients. Furthermore, studies which used PBPK modelling to describe the PK of an orally administered drug in an IBD population and were able to verify their findings using clinical data are critically examined. These models were able to incorporate the pathophysiological changes associated with IBD and partly succeeded in adequately predicting drug absorption in this population. Given the limited amount of PBPK studies performed on a limited number of drugs, the developed models are most likely not suitable to be used as a general PBPK model for the IBD population.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"209 ","pages":"Article 107095"},"PeriodicalIF":4.3,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788368","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-03DOI: 10.1016/j.ejps.2025.107094
Patrycja Bełdzińska , Marcin Zakrzewski , Inez Mruk , Marceli Bogusławski , Natalia Derewońko , Katarzyna Bury , Dariusz Wyrzykowski , Grzegorz Gołuński , Michał Rychłowski , Jacek Piosik
Cancer is a leading cause of death worldwide, with nearly 10 million fatalities yearly. Consequently, despite the search for new therapeutic approaches, the use of classical chemotherapy, remains one of the main treatment regimens. Therefore, we evaluate the use of platinum nanoparticles (PtNPs) of different sizes as potential modulators of doxorubicin (DOX) activity.
In the presented research, we utilized a wide range of methods, including Spectroscopic measurements, Isothermal Titration Calorimetry, Dynamic Light Scattering, and Atomic Force Microscopy, as well as biological assays such as the Ames mutagenicity test on Salmonella enterica serovar Typhimurium TA98 and the alamarBlue cytotoxicity assay with Fluorescent Confocal Microscopy on non-cancerous HaCaT and cancerous MelJuSo cell lines, to investigate the interactions between PtNPs and DOX and the effect of diverse-sized nanoparticles on DOX activity.
The obtained results indicate the presence of direct interactions, particularly highlighting differences related to particles size. We confirmed that DOX affects the aggregation of nanoparticles, while the nanoparticles induce DOX fluorescence quenching. In terms of biological aspects, PtNPs reduced the mutagenicity of DOX, and increased the survival of non-cancerous HaCaT cells. Furthermore, 70 nm PtNPs significantly increased DOX effects on cancerous MelJuSo cells by negatively affecting their morphology and culture density.
To conclude, our research provided valuable insights into the interactions between PtNPs and DOX with particular emphasis on the nanoparticles’ size influence highlighting nanoparticles’ impact on DOX cytotoxicity providing a base for further research on the potential future modification in treatment approaches.
{"title":"Size dependent impact of platinum nanoparticles on doxorubicin activity","authors":"Patrycja Bełdzińska , Marcin Zakrzewski , Inez Mruk , Marceli Bogusławski , Natalia Derewońko , Katarzyna Bury , Dariusz Wyrzykowski , Grzegorz Gołuński , Michał Rychłowski , Jacek Piosik","doi":"10.1016/j.ejps.2025.107094","DOIUrl":"10.1016/j.ejps.2025.107094","url":null,"abstract":"<div><div>Cancer is a leading cause of death worldwide, with nearly 10 million fatalities yearly. Consequently, despite the search for new therapeutic approaches, the use of classical chemotherapy, remains one of the main treatment regimens. Therefore, we evaluate the use of platinum nanoparticles (PtNPs) of different sizes as potential modulators of doxorubicin (DOX) activity.</div><div>In the presented research, we utilized a wide range of methods, including Spectroscopic measurements, Isothermal Titration Calorimetry, Dynamic Light Scattering, and Atomic Force Microscopy, as well as biological assays such as the Ames mutagenicity test on <em>Salmonella enterica</em> serovar Typhimurium TA98 and the alamarBlue cytotoxicity assay with Fluorescent Confocal Microscopy on non-cancerous HaCaT and cancerous MelJuSo cell lines, to investigate the interactions between PtNPs and DOX and the effect of diverse-sized nanoparticles on DOX activity.</div><div>The obtained results indicate the presence of direct interactions, particularly highlighting differences related to particles size. We confirmed that DOX affects the aggregation of nanoparticles, while the nanoparticles induce DOX fluorescence quenching. In terms of biological aspects, PtNPs reduced the mutagenicity of DOX, and increased the survival of non-cancerous HaCaT cells. Furthermore, 70 nm PtNPs significantly increased DOX effects on cancerous MelJuSo cells by negatively affecting their morphology and culture density.</div><div>To conclude, our research provided valuable insights into the interactions between PtNPs and DOX with particular emphasis on the nanoparticles’ size influence highlighting nanoparticles’ impact on DOX cytotoxicity providing a base for further research on the potential future modification in treatment approaches.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"209 ","pages":"Article 107094"},"PeriodicalIF":4.3,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143785824","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}
Pub Date : 2025-04-02DOI: 10.1016/j.ejps.2025.107093
Xuan Zhang , Prathish K. Rajaraman , Frank Li , Sanghun Choi , Alejandro P. Comellas , Eric A. Hoffman , Sean B. Fain , David W. Kaczka , Benjamin M. Smith , Jiwoong Choi , Mario Castro , Sally E. Wenzel , Nizar N. Jarjour , Mark L. Schiebler , Elliot Israel , Bruce D. Levy , John V. Fahy , Serpil C. Erzurum , Andrew Babiskin , Minori Kinjo , Ching-Long Lin
Purpose
This study investigated asthma phenotypes and their associations with ventilation heterogeneity and particle deposition by utilizing Single-Photon Emission Computed Tomography (SPECT) imaging, quantitative Computed Tomography (qCT) imaging-based subgrouping, and a whole-lung computational model.
Materials and methods
Two datasets were analyzed: one from a combined SPECT and CT (SPECT/CT) study with six asthmatic subjects, and another from the Severe Asthma Research Program (SARP) with 209 asthmatic subjects. Data from 35 previously acquired healthy subjects served as a control group. Each subject underwent CT scans at full inspiration and expiration, along with pulmonary function testing (PFT). The SPECT/CT study included ventilation SPECT imaging. Key qCT variables such as airway diameter, wall thickness, percentage of air trapping (AirT%), and percentage of small airway disease (fSAD%) were assessed. A subject-specific whole-lung computational fluid and particle dynamics (CFPD) model predicted airway resistance, particle deposition fraction, and the coefficient of variation (CV) for ventilation heterogeneity. Subjects were categorized into four predefined asthma imaging subgroups/clusters with increasing severity (C1-C4). CFPD-predicted CVs were validated against SPECT measurements. We compared PFT, qCT, and CFPD variables across SARP clusters and analyzed particle deposition fractions in large conducting, small conducting, and respiratory airways.
Results
Cluster C4 exhibited a significantly distinct ventilation profile compared to other clusters and health controls. This distinction contrasted with the insignificant differences between ventilation profiles in severity subgroups defined by conventional spirometry-based guidelines. Airway resistance varied significantly across the asthma clusters. Although both C3 and C4 clusters represented severe asthma, only C4 showed a significant increase in AirT%, primarily due to fSAD%. Since inflammatory phenotypes differ — C3 with wall thickening in large and small conducting airways, and C4 with elevated fSAD% and Emph% in small conducting and respiratory airways — fine particles (∼5 μm) and extrafine particles (∼1 μm) are more effective at reaching the respective regions in C3 and C4. Given that C2 and C4 have hyper-responsive phenotypes with narrowed conducting airways, fine particles are more effective in reaching these areas. Airway enlargement in targeted segments of the left lower lobe resulted in improved particle deposition.
Conclusion
Our cluster-informed CFPD-based approach enhances the understanding of ventilation heterogeneity in asthma and holds potential for refining strategies for inhalational therapies.
{"title":"Assessment of ventilation heterogeneity and particle deposition in asthmatics using combined SPECT/CT imaging and computational modeling approaches","authors":"Xuan Zhang , Prathish K. Rajaraman , Frank Li , Sanghun Choi , Alejandro P. Comellas , Eric A. Hoffman , Sean B. Fain , David W. Kaczka , Benjamin M. Smith , Jiwoong Choi , Mario Castro , Sally E. Wenzel , Nizar N. Jarjour , Mark L. Schiebler , Elliot Israel , Bruce D. Levy , John V. Fahy , Serpil C. Erzurum , Andrew Babiskin , Minori Kinjo , Ching-Long Lin","doi":"10.1016/j.ejps.2025.107093","DOIUrl":"10.1016/j.ejps.2025.107093","url":null,"abstract":"<div><h3>Purpose</h3><div>This study investigated asthma phenotypes and their associations with ventilation heterogeneity and particle deposition by utilizing Single-Photon Emission Computed Tomography (SPECT) imaging, quantitative Computed Tomography (qCT) imaging-based subgrouping, and a whole-lung computational model.</div></div><div><h3>Materials and methods</h3><div>Two datasets were analyzed: one from a combined SPECT and CT (SPECT/CT) study with six asthmatic subjects, and another from the Severe Asthma Research Program (SARP) with 209 asthmatic subjects. Data from 35 previously acquired healthy subjects served as a control group. Each subject underwent CT scans at full inspiration and expiration, along with pulmonary function testing (PFT). The SPECT/CT study included ventilation SPECT imaging. Key qCT variables such as airway diameter, wall thickness, percentage of air trapping (AirT%), and percentage of small airway disease (fSAD%) were assessed. A subject-specific whole-lung computational fluid and particle dynamics (CFPD) model predicted airway resistance, particle deposition fraction, and the coefficient of variation (CV) for ventilation heterogeneity. Subjects were categorized into four predefined asthma imaging subgroups/clusters with increasing severity (C1-C4). CFPD-predicted CVs were validated against SPECT measurements. We compared PFT, qCT, and CFPD variables across SARP clusters and analyzed particle deposition fractions in large conducting, small conducting, and respiratory airways.</div></div><div><h3>Results</h3><div>Cluster C4 exhibited a significantly distinct ventilation profile compared to other clusters and health controls. This distinction contrasted with the insignificant differences between ventilation profiles in severity subgroups defined by conventional spirometry-based guidelines. Airway resistance varied significantly across the asthma clusters. Although both C3 and C4 clusters represented severe asthma, only C4 showed a significant increase in AirT%, primarily due to fSAD%. Since inflammatory phenotypes differ — C3 with wall thickening in large and small conducting airways, and C4 with elevated fSAD% and Emph% in small conducting and respiratory airways — fine particles (∼5 μm) and extrafine particles (∼1 μm) are more effective at reaching the respective regions in C3 and C4. Given that C2 and C4 have hyper-responsive phenotypes with narrowed conducting airways, fine particles are more effective in reaching these areas. Airway enlargement in targeted segments of the left lower lobe resulted in improved particle deposition.</div></div><div><h3>Conclusion</h3><div>Our cluster-informed CFPD-based approach enhances the understanding of ventilation heterogeneity in asthma and holds potential for refining strategies for inhalational therapies.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"209 ","pages":"Article 107093"},"PeriodicalIF":4.3,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143783890","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}
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