Pub Date : 2025-01-11DOI: 10.1016/j.ejps.2025.107012
Dimitri Romanovsky , Hanna Scherk , Bastian Föhr, Sabrina Babutzka, Jacqueline Bogedein, Yi Lu, Alice Reschigna, Stylianos Michalakis
Adeno-associated virus (AAV)-based vectors have emerged as an effective and widely used technology for somatic gene therapy approaches, including those targeting the retina. A major advantage of the AAV technology is the availability of a large number of serotypes that have either been isolated from nature or produced in the laboratory. These serotypes have different properties in terms of sensitivity to neutralizing antibodies, cellular transduction profile and efficiency. The infectivity of AAV vectors depends on the affinity to certain molecules on the cell surface, in particular to cellular glycosaminoglycans (GAGs) such as heparan sulfate proteoglycans (HSPGs). Here, we tested how altering HSPG affinity in AAV vectors affects cellular tropism and transduction efficiency. The previously developed AAV2.GL variant was used as a starting variant to alter or disrupt HSPG affinity. The HSPG-independent AAV9 serotype was used to introduce different HSPG-binding sites. As an indicator of HSPG affinity, we measured the binding strength of the vector variant on a heparin chromatography column. We show that modification of capsid-exposed residues has a strong impact on HSPG affinity, cellular tropism and transduction efficiency in HeLa cells and in vivo in mouse retina. Our study shows that key properties of AAV vectors can be tailored in different directions and used to improve tropism and efficiency.
{"title":"Heparan sulfate proteoglycan affinity of adeno-associated virus vectors: Implications for retinal gene delivery","authors":"Dimitri Romanovsky , Hanna Scherk , Bastian Föhr, Sabrina Babutzka, Jacqueline Bogedein, Yi Lu, Alice Reschigna, Stylianos Michalakis","doi":"10.1016/j.ejps.2025.107012","DOIUrl":"10.1016/j.ejps.2025.107012","url":null,"abstract":"<div><div>Adeno-associated virus (AAV)-based vectors have emerged as an effective and widely used technology for somatic gene therapy approaches, including those targeting the retina. A major advantage of the AAV technology is the availability of a large number of serotypes that have either been isolated from nature or produced in the laboratory. These serotypes have different properties in terms of sensitivity to neutralizing antibodies, cellular transduction profile and efficiency. The infectivity of AAV vectors depends on the affinity to certain molecules on the cell surface, in particular to cellular glycosaminoglycans (GAGs) such as heparan sulfate proteoglycans (HSPGs). Here, we tested how altering HSPG affinity in AAV vectors affects cellular tropism and transduction efficiency. The previously developed AAV2.GL variant was used as a starting variant to alter or disrupt HSPG affinity. The HSPG-independent AAV9 serotype was used to introduce different HSPG-binding sites. As an indicator of HSPG affinity, we measured the binding strength of the vector variant on a heparin chromatography column. We show that modification of capsid-exposed residues has a strong impact on HSPG affinity, cellular tropism and transduction efficiency in HeLa cells and in vivo in mouse retina. Our study shows that key properties of AAV vectors can be tailored in different directions and used to improve tropism and efficiency.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"206 ","pages":"Article 107012"},"PeriodicalIF":4.3,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142978057","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 : 2025-01-11DOI: 10.1016/j.ejps.2025.107005
Peiran Zhao , Xinyan Zhang , Jianfang Dong , Lianzhi Li , Xiao Meng , Lei Gao
In the endocrine system, anaplastic thyroid cancer (ATC) is extremely aggressive since it inhibits the majority of medications and treatments. Therefore, there is an immediate demand to identify new treatment approaches or drugs to deal with ATC. Recently, amino acid Schiff base copper complexes have received great attention due to their excellent anti-tumor activity. In this research, three copper(II) complexes, [Cu(o-van-D-Trp)(phen)](1), [Cu(o-van-D-Trp)(bipy)](2), [Cu(naph-D-Trp)(bipy)](3), [D-Trp = D-tryptophan; o-van = o-vanillin; naph = 2‑hydroxy-1- naphthaldehyde; phen = 1,10-phenanthroline; bipy = 2,2-biprydine], have been synthesized and investigated as potential anticancer agents. The crystal structure data of the complexes demonstrate that the central copper (II) atom forms a twisted polyhedral environment with nitrogen and oxygen atoms. The MTT results demonstrated that three complexes exhibited superior cytotoxicity against five cell lines of thyroid cancer (Cal-62 cells, ARO cells, KHM-5 m cells, BHP10–3 cells and K1 cells), especially complex 1 with the IC50 values of 0.59±0.05 μM, 2.36±0.47 μM, 1.10±0.87 μM, 0.75±0.09 μM, 1.72±0.06 μM, when cisplatin was used as a control. Research on antitumor mechanisms has demonstrated that complex 1 can significantly reduce the mitochondrial membrane potential, raise autophagy, and produce reactive oxygen species (ROS) in ARO cells in a dose-dependent manner. RNA sequencing study reveals that complex 1 may cause apoptosis in ARO cells and exhibit anticancer efficacy in vitro through ROS-mediated downregulation of Akt and p38 MAPK activation.
{"title":"In vitro study of the pro-apoptotic mechanism of amino acid Schiff base copper complexes on anaplastic thyroid cancer","authors":"Peiran Zhao , Xinyan Zhang , Jianfang Dong , Lianzhi Li , Xiao Meng , Lei Gao","doi":"10.1016/j.ejps.2025.107005","DOIUrl":"10.1016/j.ejps.2025.107005","url":null,"abstract":"<div><div>In the endocrine system, anaplastic thyroid cancer (ATC) is extremely aggressive since it inhibits the majority of medications and treatments. Therefore, there is an immediate demand to identify new treatment approaches or drugs to deal with ATC. Recently, amino acid Schiff base copper complexes have received great attention due to their excellent anti-tumor activity. In this research, three copper(II) complexes, [Cu(<em>o</em>-van-D-Trp)(phen)]<strong>(1)</strong>, [Cu(<em>o</em>-van-D-Trp)(bipy)]<strong>(2)</strong>, [Cu(naph-D-Trp)(bipy)]<strong>(3)</strong>, [D-Trp = D-tryptophan; o-van = <em>o</em>-vanillin; naph = 2‑hydroxy-1- naphthaldehyde; phen = 1,10-phenanthroline; bipy = 2,2-biprydine], have been synthesized and investigated as potential anticancer agents. The crystal structure data of the complexes demonstrate that the central copper (II) atom forms a twisted polyhedral environment with nitrogen and oxygen atoms. The MTT results demonstrated that three complexes exhibited superior cytotoxicity against five cell lines of thyroid cancer (Cal-62 cells, ARO cells, KHM-5 m cells, BHP10–3 cells and K1 cells), especially complex <strong>1</strong> with the IC<sub>50</sub> values of 0.59±0.05 μM, 2.36±0.47 μM, 1.10±0.87 μM, 0.75±0.09 μM, 1.72±0.06 μM, when cisplatin was used as a control. Research on antitumor mechanisms has demonstrated that complex <strong>1</strong> can significantly reduce the mitochondrial membrane potential, raise autophagy, and produce reactive oxygen species (ROS) in ARO cells in a dose-dependent manner. RNA sequencing study reveals that complex <strong>1</strong> may cause apoptosis in ARO cells and exhibit anticancer efficacy <em>in vitro</em> through ROS-mediated downregulation of Akt and p38 MAPK activation.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"206 ","pages":"Article 107005"},"PeriodicalIF":4.3,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970232","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 : 2025-01-09DOI: 10.1016/j.ejps.2025.107010
Keli Wang , Juefang Ding , Minlu Cheng , Xianjing Li , Huan Zhou , Qinxin Song , Yuanxun Yang , Juan Li , Li Ding
Purpose
To evaluate the drug-drug interactions (DDI) of tunodafil (youkenafil), a novel phosphodiesterase type 5 inhibitor, its inhibitory effects on CYP450 enzymes in vitro and its clinical trials in combination with ritonavir or omeprazole were conducted.
Methods
The inhibitory effect of tunodafil on seven major CYP450 enzymes in human liver microsomes was investigated by probe substrate method. The effect of tunodafil on the pharmacokinetics of omeprazole (CYP2C19 substrate) in 40 healthy subjects, who received a single dose of 40 mg omeprazole in combination with tunodafil on the day 8 after taking 100 mg tunodafil daily for 7 days, was assessed based on CYP2C19 genotypes. The clinical DDI of ritonavir (potent CYP3A4 inhibitor) on tunodafil was studied in 28 healthy subjects who received a single dose of 50 mg tunodafil in combination with ritonavir on the day 6 after taking ritonavir twice a day for 5 days.
Results
Tunodafil showed moderate inhibition on CYP2C19 and CYP3A4/5 in vitro. When co-administration omeprazole with tunodafil, the AUC of omeprazole in the Extensive, Intermediate and Poor Metabolizers increased by 26 %, 37 % and 21 %, respectively. After co-administration tunodafil with ritonavir, ritonavir increased the AUC and Cmax of tunodafil in human by about 78- fold and 13-fold respectively.
Conclusions
Tunodafil slightly increased omeprazole exposure in the Extensive and Intermediate Metabolizers of CYP2C19, but had no significant effect on omeprazole exposure in the Poor Metabolizers. Ritonavir could strongly inhibit the metabolism of tunodafil, and the combination of tunodafil with ritonavir should be prohibited.
{"title":"Drug interaction evaluation of the novel phosphodiesterase type 5 inhibitor tunodafil (youkenafil): Effects of tunodafil on omeprazole pharmacokinetics based on CYP2C19 gene polymorphism, and effects of ritonavir on tunodafil pharmacokinetics","authors":"Keli Wang , Juefang Ding , Minlu Cheng , Xianjing Li , Huan Zhou , Qinxin Song , Yuanxun Yang , Juan Li , Li Ding","doi":"10.1016/j.ejps.2025.107010","DOIUrl":"10.1016/j.ejps.2025.107010","url":null,"abstract":"<div><h3>Purpose</h3><div>To evaluate the drug-drug interactions (DDI) of tunodafil (youkenafil), a novel phosphodiesterase type 5 inhibitor, its inhibitory effects on CYP450 enzymes <em>in vitro</em> and its clinical trials in combination with ritonavir or omeprazole were conducted.</div></div><div><h3>Methods</h3><div>The inhibitory effect of tunodafil on seven major CYP450 enzymes in human liver microsomes was investigated by probe substrate method. The effect of tunodafil on the pharmacokinetics of omeprazole (CYP2C19 substrate) in 40 healthy subjects, who received a single dose of 40 mg omeprazole in combination with tunodafil on the day 8 after taking 100 mg tunodafil daily for 7 days, was assessed based on CYP2C19 genotypes. The clinical DDI of ritonavir (potent CYP3A4 inhibitor) on tunodafil was studied in 28 healthy subjects who received a single dose of 50 mg tunodafil in combination with ritonavir on the day 6 after taking ritonavir twice a day for 5 days.</div></div><div><h3>Results</h3><div>Tunodafil showed moderate inhibition on CYP2C19 and CYP3A4/5 <em>in vitro</em>. When co-administration omeprazole with tunodafil, the <em>AUC</em> of omeprazole in the Extensive, Intermediate and Poor Metabolizers increased by 26 %, 37 % and 21 %, respectively. After co-administration tunodafil with ritonavir, ritonavir increased the <em>AUC</em> and <em>C</em><sub>max</sub> of tunodafil in human by about 78- fold and 13-fold respectively.</div></div><div><h3>Conclusions</h3><div>Tunodafil slightly increased omeprazole exposure in the Extensive and Intermediate Metabolizers of CYP2C19, but had no significant effect on omeprazole exposure in the Poor Metabolizers. Ritonavir could strongly inhibit the metabolism of tunodafil, and the combination of tunodafil with ritonavir should be prohibited.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"206 ","pages":"Article 107010"},"PeriodicalIF":4.3,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970230","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 : 2025-01-08DOI: 10.1016/j.ejps.2025.107004
Hui Li , Rui Liu , Yuxin Guo , Anqi Wang , Ting Zhou , Shuhang Wang , Wei Wu
Triol-type ginsenoside Re (GS-Re) exhibits potent anti-myocardial ischemia-reperfusion effects, but its clinical use is hindered by poor bioavailability. This study evaluates the impact of β-cyclodextrin (β-CD) inclusion on GS-Re bioavailability and tissue dynamics in rat models. The GS-Re-β-CD complex was prepared using aqueous stirring and characterized. Male Wistar rats (200 ± 20 g) were administered GS-Re at a dose of 500 mg/kg. Plasma concentrations were quantified using UHPLC-MS/MS to evaluate pharmacokinetics and analyze metabolites in tissues and feces. Compared to the group receiving GS-Re alone, the GS-Re-β-CD inclusion complex exhibited significantly improved pharmacokinetic characteristics in rats: Maximum concentration (Cmax) increased by 1.86-fold. Area under the curve (AUC0–24 h) increased by 2.09-fold. Time to reach peak concentration (Tmax) was reduced, while the half-life (t1/2) was extended, suggesting a faster and prolonged absorption of GS-Re. Metabolite analysis showed higher concentrations of Rg1, Rg2, Rh1, F1, PPT, and Re in tissues with GS-Re-β-CD, while metabolite types remained unchanged. The inclusion of β-CD significantly enhanced the bioavailability and tissue concentration of GS-Re, as demonstrated by increased Cmax and AUC, along with a shorter Tmax and longer t1/2. These findings suggest that β-CD inclusion could be an effective strategy to improve the clinical applicability of GS-Re, providing valuable pharmacokinetic and tissue concentration insights for further development.
{"title":"Study on the impact of β-CD inclusion complex on the in vivo metabolism of ginsenoside Re: A pharmacokinetic, metabolite analysis, and tissue distribution investigation in a rat model","authors":"Hui Li , Rui Liu , Yuxin Guo , Anqi Wang , Ting Zhou , Shuhang Wang , Wei Wu","doi":"10.1016/j.ejps.2025.107004","DOIUrl":"10.1016/j.ejps.2025.107004","url":null,"abstract":"<div><div>Triol-type ginsenoside Re (GS-Re) exhibits potent anti-myocardial ischemia-reperfusion effects, but its clinical use is hindered by poor bioavailability. This study evaluates the impact of β-cyclodextrin (β-CD) inclusion on GS-Re bioavailability and tissue dynamics in rat models. The GS-Re-β-CD complex was prepared using aqueous stirring and characterized. Male Wistar rats (200 ± 20 g) were administered GS-Re at a dose of 500 mg/kg. Plasma concentrations were quantified using UHPLC-MS/MS to evaluate pharmacokinetics and analyze metabolites in tissues and feces. Compared to the group receiving GS-Re alone, the GS-Re-β-CD inclusion complex exhibited significantly improved pharmacokinetic characteristics in rats: Maximum concentration (Cmax) increased by 1.86-fold. Area under the curve (AUC<sub>0–24 h</sub>) increased by 2.09-fold. Time to reach peak concentration (T<sub>max</sub>) was reduced, while the half-life (t<sub>1/2</sub>) was extended, suggesting a faster and prolonged absorption of GS-Re. Metabolite analysis showed higher concentrations of Rg1, Rg2, Rh1, F1, PPT, and Re in tissues with GS-Re-β-CD, while metabolite types remained unchanged. The inclusion of β-CD significantly enhanced the bioavailability and tissue concentration of GS-Re, as demonstrated by increased C<sub>max</sub> and AUC, along with a shorter T<sub>max</sub> and longer t<sub>1/2</sub>. These findings suggest that β-CD inclusion could be an effective strategy to improve the clinical applicability of GS-Re, providing valuable pharmacokinetic and tissue concentration insights for further development.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"206 ","pages":"Article 107004"},"PeriodicalIF":4.3,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142963985","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 : 2025-01-07DOI: 10.1016/j.ejps.2025.107003
Jianwen Xu , Guimu Guo , Shuifang Zhou , Han Wang , Yuewen Chen , Rongfang Lin , Pinfang Huang , Cuihong Lin
Tacrolimus is extensively used for the prevention of graft rejection following solid organ transplantation in pregnant women. However, knowledge gaps in the dosage of tacrolimus for pregnant patients with different CYP3A5 genotypes and infection conditions have been identified. This study aimed to develop a pregnant physiologically based pharmacokinetic (PBPK) model to characterize the maternal and fetal pharmacokinetics of tacrolimus during pregnancy and explore and provide dosage adjustments. We developed PBPK models for nonpregnant patients and validated them via data from previous clinical studies using PK-Sim and Mobi software. To extrapolate to pregnancy, we considered anatomical, physiological, and metabolic alterations and simulated tacrolimus by adding six groups of IL-6 concentrations (0, 5, 25, 50, 500, and 5000 pg/mL). Models were verified by assessing goodness-of-fit plots and ratios of predicted-to-observed pharmacokinetic parameters.
The developed PBPK models adequately describe the available clinical data; the fold errors of the predicted and observed values of the area under the curve and peak plasma concentration were between 0.59 and 1.64, and the average folding error and the absolute average folding error values for all concentration–time data points were 1.15 and 1.36, respectively. The simulation results indicated that the area under the steady-state concentration‒time curve and trough concentrations decreased from the first to the third trimester of pregnancy. The trough concentrations were not within the therapeutic range (4–11 ng/mL) in pregnant patients with the CYP3A5 genotype for most of the infection conditions and exceeded its effective concentration in all the CYP3A5 nonexpressers. Based on the model-derived dosing regimen, the tacrolimus trough concentration in pregnant patients with different CYP3A5 genotypes could fall into the therapeutic window, which provided a clinical practice reference for dosage adjustments during pregnancy.
{"title":"Physiologically-based pharmacokinetic modeling to predict the exposure and provide dosage regimens of tacrolimus in pregnant women with infection disease","authors":"Jianwen Xu , Guimu Guo , Shuifang Zhou , Han Wang , Yuewen Chen , Rongfang Lin , Pinfang Huang , Cuihong Lin","doi":"10.1016/j.ejps.2025.107003","DOIUrl":"10.1016/j.ejps.2025.107003","url":null,"abstract":"<div><div>Tacrolimus is extensively used for the prevention of graft rejection following solid organ transplantation in pregnant women. However, knowledge gaps in the dosage of tacrolimus for pregnant patients with different CYP3A5 genotypes and infection conditions have been identified. This study aimed to develop a pregnant physiologically based pharmacokinetic (PBPK) model to characterize the maternal and fetal pharmacokinetics of tacrolimus during pregnancy and explore and provide dosage adjustments. We developed PBPK models for nonpregnant patients and validated them via data from previous clinical studies using PK-Sim and Mobi software. To extrapolate to pregnancy, we considered anatomical, physiological, and metabolic alterations and simulated tacrolimus by adding six groups of IL-6 concentrations (0, 5, 25, 50, 500, and 5000 pg/mL). Models were verified by assessing goodness-of-fit plots and ratios of predicted-to-observed pharmacokinetic parameters.</div><div>The developed PBPK models adequately describe the available clinical data; the fold errors of the predicted and observed values of the area under the curve and peak plasma concentration were between 0.59 and 1.64, and the average folding error and the absolute average folding error values for all concentration–time data points were 1.15 and 1.36, respectively. The simulation results indicated that the area under the steady-state concentration‒time curve and trough concentrations decreased from the first to the third trimester of pregnancy. The trough concentrations were not within the therapeutic range (4–11 ng/mL) in pregnant patients with the CYP3A5 genotype for most of the infection conditions and exceeded its effective concentration in all the CYP3A5 nonexpressers. Based on the model-derived dosing regimen, the tacrolimus trough concentration in pregnant patients with different CYP3A5 genotypes could fall into the therapeutic window, which provided a clinical practice reference for dosage adjustments during pregnancy.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"206 ","pages":"Article 107003"},"PeriodicalIF":4.3,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142946984","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 : 2025-01-06DOI: 10.1016/j.ejps.2025.107002
Elsayed A. Elmorsy , Hossam A. Elsisi , Abdullah S. Alkhamiss , Norah Suliman Alsoqih , Mostafa M. Khodeir , Abdulaziz A. Alsalloom , Ahmad A. Almeman , Sahar R. Elghandour , Eman Hassan Nadwa , Amira Karam khalifa , Bahaa Eldin Ali Khaled , Asmaa Ramadan , Manal M. Kamal , Thamir Saad Alsaeed , Mariam S. Alharbi , Abdel-Moneim Hafez Abdel-Moneim , Abousree T. Ellethy , Sameh Saber
Insulin resistance and diabetes are associated with non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) conditions, which are distinguished by metabolic dysfunction, oxidative stress and inflammation. Sirtuin 1 (SIRT1), a NAD+-dependent deacetylase, is fundamental in regulating metabolic pathways, reducing inflammation, and improving antioxidant defenses. This is the first study to investigate the effects of SRT1720, a SIRT1 activator, in diabetic rats on a high-fat diet. SRT1720 significantly lowered fasting blood glucose and insulin levels and enhanced glucose tolerance and HOMA-IR and QUICKI scores, indicating increased insulin sensitivity. The treatment also reduced total cholesterol, triglycerides, and LDL levels, showing amelioration of dyslipidemia. Moreover, SRT1720 lowered markers of liver fibrosis, including TGF-β, TIMP-1, Col1a1, and hydroxyproline, and decreased inflammation by reducing NFκB activity and pro-inflammatory cytokines (TNF-α and IL-6). Furthermore, SRT1720 augmented Nrf2 activity and HO-1 levels. Consequently, the SRT1720’s protective role improved liver function and histology and prolonged rats’ survival. These functions were suppressed by the co-administration of the SIRT1 inhibitor EX527, confirming that the beneficial effects of SRT1720 are SIRT1-dependent. Correlation analyses uncovered that increased SIRT1 activity was strongly associated with decreased oxidative stress, inflammation, insulin resistance, and fibrosis markers. To conclude, our results find that SRT1720 represents a promising therapeutic strategy for managing Type 2 diabetes in NAFLD or NASH patients possibly through the modulation of the SIRT1/Nrf2/NFκB signaling pathwa. SRT1720 could potentially halt or reverse the progression of these conditions and associated complications and merits further investigations.
{"title":"Activation of SIRT1 by SRT1720 alleviates dyslipidemia, improves insulin sensitivity and exhibits liver-protective effects in diabetic rats on a high-fat diet: New insights into the SIRT1/Nrf2/NFκB signaling pathway","authors":"Elsayed A. Elmorsy , Hossam A. Elsisi , Abdullah S. Alkhamiss , Norah Suliman Alsoqih , Mostafa M. Khodeir , Abdulaziz A. Alsalloom , Ahmad A. Almeman , Sahar R. Elghandour , Eman Hassan Nadwa , Amira Karam khalifa , Bahaa Eldin Ali Khaled , Asmaa Ramadan , Manal M. Kamal , Thamir Saad Alsaeed , Mariam S. Alharbi , Abdel-Moneim Hafez Abdel-Moneim , Abousree T. Ellethy , Sameh Saber","doi":"10.1016/j.ejps.2025.107002","DOIUrl":"10.1016/j.ejps.2025.107002","url":null,"abstract":"<div><div>Insulin resistance and diabetes are associated with non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) conditions, which are distinguished by metabolic dysfunction, oxidative stress and inflammation. Sirtuin 1 (SIRT1), a NAD<sup>+</sup>-dependent deacetylase, is fundamental in regulating metabolic pathways, reducing inflammation, and improving antioxidant defenses. This is the first study to investigate the effects of SRT1720, a SIRT1 activator, in diabetic rats on a high-fat diet. SRT1720 significantly lowered fasting blood glucose and insulin levels and enhanced glucose tolerance and HOMA-IR and QUICKI scores, indicating increased insulin sensitivity. The treatment also reduced total cholesterol, triglycerides, and LDL levels, showing amelioration of dyslipidemia. Moreover, SRT1720 lowered markers of liver fibrosis, including TGF-β, TIMP-1, Col1a1, and hydroxyproline, and decreased inflammation by reducing NFκB activity and pro-inflammatory cytokines (TNF-α and IL-6). Furthermore, SRT1720 augmented Nrf2 activity and HO-1 levels. Consequently, the SRT1720’s protective role improved liver function and histology and prolonged rats’ survival. These functions were suppressed by the co-administration of the SIRT1 inhibitor EX527, confirming that the beneficial effects of SRT1720 are SIRT1-dependent. Correlation analyses uncovered that increased SIRT1 activity was strongly associated with decreased oxidative stress, inflammation, insulin resistance, and fibrosis markers. To conclude, our results find that SRT1720 represents a promising therapeutic strategy for managing Type 2 diabetes in NAFLD or NASH patients possibly through the modulation of the SIRT1/Nrf2/NFκB signaling pathwa. SRT1720 could potentially halt or reverse the progression of these conditions and associated complications and merits further investigations.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"206 ","pages":"Article 107002"},"PeriodicalIF":4.3,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142947035","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 : 2025-01-01DOI: 10.1016/j.ejps.2024.106972
Kambez H. Benam , Carsten Ehrhardt , Josué Sznitman
{"title":"Editorial: Biologically inspired engineering of the lungs: Advances in preclinical pulmonary pathobiology models for translational and therapeutic applications","authors":"Kambez H. Benam , Carsten Ehrhardt , Josué Sznitman","doi":"10.1016/j.ejps.2024.106972","DOIUrl":"10.1016/j.ejps.2024.106972","url":null,"abstract":"","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"204 ","pages":"Article 106972"},"PeriodicalIF":4.3,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142738839","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 : 2025-01-01DOI: 10.1016/j.ejps.2024.106977
Narayan Acharya , Ramji Kandel , Priti Roy , Irfan Warraich , Kamaleshwar P Singh
Kidney fibrosis is a commonly observed pathological condition during development of chronic kidney disease. Therapeutic options currently available are effective only in slowing the progression of kidney fibrosis and there is no cure for this disease. Aberrant expression and excessive accumulation of extracellular matrix (ECM) proteins in the peritubular space is a characteristic pathological feature of fibrotic kidney. However, the molecular basis of aberrant regulation of fibrotic genes in kidneys is not clear. In this context, this study aimed to evaluate the role of epigenetic reprogramming in kidney fibrosis. Folic acid (FA)-induced acute kidney injury (AKI) and kidney fibrosis in mice as an in vivo model and long-term arsenic or FA-exposed fibrogenic HK-2 cells as an in vitro model were used to evaluate the role of DNA methylation and histone modifications in fibrosis. DNA demethylating agent 5aza2 deoxycytidine (5-aza-2-dC) and histone deacetylase inhibitor Trichostatin A (TSA) were used to treat FA-injected mice. Results of histopathological and immunofluorescence staining of kidney tissue, serum albumin- creatinine levels, body weight, and gene expression analysis revealed significant protective effects of 5-aza-2-dC and TSA in FA-induced AKI and fibrosis. Insignificant change in the expression of N-cadherin whereas a significant decrease in E-cadherin as well as an increase in the expression of Vimentin and α-SMA suggest partial EMT associated with fibrosis. Aberrant expression of epithelial-mesenchymal-transition (EMT) and ECM-regulators (MMP2, Smad7, and TIMP3) as well as fibrogenic signaling pathways (Notch, TGF-beta, and Wnt signaling), and their restoration by 5-aza-2-dC and TSA treatments suggest epigenetic reprogramming of these genes and signaling pathways during FA-induced fibrosis. In summary, this study provides new information on the role of epigenetic reprogramming of fibrogenic genes and signaling pathways during the development of kidney fibrosis. Attenuation of fibrosis after 5-aza-2-dC and TSA treatments suggest the promise of these epigenetic-based therapeutics in the clinical management of this disease.
肾纤维化是慢性肾脏疾病发展过程中常见的病理状态。目前可用的治疗方案仅在减缓肾纤维化的进展方面有效，而且这种疾病无法治愈。小管周围细胞外基质（ECM）蛋白的异常表达和过度积累是纤维化肾的一个特征性病理特征。然而，肾脏纤维化基因异常调控的分子基础尚不清楚。在此背景下，本研究旨在评估表观遗传重编程在肾纤维化中的作用。采用叶酸（FA）诱导的小鼠急性肾损伤（AKI）和肾纤维化作为体内模型，并采用长期砷或FA暴露的纤维化性HK-2细胞作为体外模型来评估DNA甲基化和组蛋白修饰在纤维化中的作用。用DNA去甲基化剂5aza2脱氧胞苷（5-aza-2-dC）和组蛋白去乙酰化酶抑制剂Trichostatin A （TSA）治疗fa注射小鼠。肾组织病理和免疫荧光染色、血清白蛋白-肌酐水平、体重和基因表达分析结果显示，5-aza-2-dC和TSA对fa诱导的AKI和纤维化具有显著的保护作用。N-cadherin的表达变化不显著，而E-cadherin的表达显著降低，Vimentin和α-SMA的表达增加，提示部分EMT与纤维化有关。上皮-间质转化（EMT）和ecm调节因子（MMP2、Smad7和TIMP3）以及纤维化信号通路（Notch、tgf - β和Wnt信号通路）的异常表达，以及5-aza-2-dC和TSA治疗对它们的恢复表明，在fa诱导的纤维化过程中，这些基因和信号通路发生了表观遗传重编程。总之，本研究为纤维化基因的表观遗传重编程和信号通路在肾纤维化发展过程中的作用提供了新的信息。5-aza-2-dC和TSA治疗后纤维化的衰减表明这些基于表观遗传学的治疗方法在该疾病的临床管理中有希望。
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