Pub Date : 2024-09-11DOI: 10.3389/fphar.2024.1447560
Jun-Fei Lu, Shang-Ping Xing, Xia Wei, Chun-Xia Yang, Gen-Shi Zhao, Xiao-Lin Ma, Xue-Mei Sun, Hong-Wei Guo, Zhi-Heng Su, Bin Fang, Jun Lin, Yan-Ying Liu, Dan Zhu
BackgroundChronic alcoholic liver disease (CALD) is a global health problem which includes multiple pathological processes such as immune inflammation and oxidative stress. 4-hydroxy-2(3H)-benzoxazolone (HBOA), an alkaloid isolated from Acanthus ilicifolius L, has been shown to exert hepatoprotective and immunomodulatory effects. However, its effects on CALD remain unclear. This study aimed to investigate the effects and underlying mechanisms of HBOA on CALD.MethodsRats were administered alcohol by gavage continuously for 12 weeks to establish the CALD model, and then treated with HBOA by gavage for 4 weeks. Transcriptomics and metabolomics were used to predict the potential mechanisms of the effects of HBOA on CALD. Liver histology and function, oxidative stress, inflammatory cytokines, and the TLR4/NF-κB pathway components were evaluated.ResultsHBOA significantly improved alcohol-induced liver injury and steatosis. It decreased the expression levels of pro-inflammatory cytokines (tumour necrosis factor-α [TNF-α], interleukin (IL)-1β, and IL-6), and increased the activities of antioxidant enzymes (superoxide dismutase [SOD], glutathione [GSH], and glutathione peroxidase [GSH-Px]). Western blotting confirmed that HBOA treatment largely diminished NF-κBp65 nuclear translocation. Comprehensive transcriptomics and metabolomics analyses indicated that HBOA regulated the glycerophospholipid metabolism pathway to achieve therapeutic effects in rats with CALD.ConclusionHBOA has a therapeutic effect on rats with CALD. Its mechanism of action mainly affects the glycerophospholipid metabolic pathway to promote lipid metabolism homeostasis by regulating the expression of Etnppl, Gpcpd1, and Pla2g4c. In addition, it may also inhibit the TLR4/NF-κB signaling pathway, thereby reducing the immune-inflammatory response.
{"title":"Elucidating the role of 4-hydroxy-2(3H)-benzoxazolone in chronic alcoholic liver disease via transcriptomics and metabolomics","authors":"Jun-Fei Lu, Shang-Ping Xing, Xia Wei, Chun-Xia Yang, Gen-Shi Zhao, Xiao-Lin Ma, Xue-Mei Sun, Hong-Wei Guo, Zhi-Heng Su, Bin Fang, Jun Lin, Yan-Ying Liu, Dan Zhu","doi":"10.3389/fphar.2024.1447560","DOIUrl":"https://doi.org/10.3389/fphar.2024.1447560","url":null,"abstract":"BackgroundChronic alcoholic liver disease (CALD) is a global health problem which includes multiple pathological processes such as immune inflammation and oxidative stress. 4-hydroxy-2(3H)-benzoxazolone (HBOA), an alkaloid isolated from <jats:italic>Acanthus ilicifolius</jats:italic> L, has been shown to exert hepatoprotective and immunomodulatory effects. However, its effects on CALD remain unclear. This study aimed to investigate the effects and underlying mechanisms of HBOA on CALD.MethodsRats were administered alcohol by gavage continuously for 12 weeks to establish the CALD model, and then treated with HBOA by gavage for 4 weeks. Transcriptomics and metabolomics were used to predict the potential mechanisms of the effects of HBOA on CALD. Liver histology and function, oxidative stress, inflammatory cytokines, and the TLR4/NF-κB pathway components were evaluated.ResultsHBOA significantly improved alcohol-induced liver injury and steatosis. It decreased the expression levels of pro-inflammatory cytokines (tumour necrosis factor-α [TNF-α], interleukin (IL)-1β, and IL-6), and increased the activities of antioxidant enzymes (superoxide dismutase [SOD], glutathione [GSH], and glutathione peroxidase [GSH-Px]). Western blotting confirmed that HBOA treatment largely diminished NF-κBp65 nuclear translocation. Comprehensive transcriptomics and metabolomics analyses indicated that HBOA regulated the glycerophospholipid metabolism pathway to achieve therapeutic effects in rats with CALD.ConclusionHBOA has a therapeutic effect on rats with CALD. Its mechanism of action mainly affects the glycerophospholipid metabolic pathway to promote lipid metabolism homeostasis by regulating the expression of <jats:italic>Etnppl</jats:italic>, <jats:italic>Gpcpd1,</jats:italic> and <jats:italic>Pla2g4c</jats:italic>. In addition, it may also inhibit the TLR4/NF-κB signaling pathway, thereby reducing the immune-inflammatory response.","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142201929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-11DOI: 10.3389/fphar.2024.1415265
Jialu Cui, Lin Lin, Feiran Hao, Zhuo Shi, Yehui Gao, Tingyu Yang, Chunqi Yang, Xiangjun Wu, Rong Gao, Yi Ru, Fangyang Li, Chengrong Xiao, Yue Gao, Yuguang Wang
Epimedium Folium has been extensively utilized for medicinal purposes in China for a significant period. This review undertakes a comprehensive examination of literature pertaining to Epimedium and its metabolites over the past decade, drawing from databases such as PubMed. Through meticulous organization and synthesis of pertinent research findings, including disease models, pharmacological effects, and related aspects, this narrative review sheds light on the principal pharmacological activities and associated mechanisms of Epimedium in safeguarding the reproductive system, promoting bone health, mitigating inflammation, and combating tumors and viral infections. Consequently, this review contributes to a more profound comprehension of the recent advances in Epimedium research.
{"title":"Comprehensive review of the traditional uses and the potential benefits of epimedium folium","authors":"Jialu Cui, Lin Lin, Feiran Hao, Zhuo Shi, Yehui Gao, Tingyu Yang, Chunqi Yang, Xiangjun Wu, Rong Gao, Yi Ru, Fangyang Li, Chengrong Xiao, Yue Gao, Yuguang Wang","doi":"10.3389/fphar.2024.1415265","DOIUrl":"https://doi.org/10.3389/fphar.2024.1415265","url":null,"abstract":"Epimedium Folium has been extensively utilized for medicinal purposes in China for a significant period. This review undertakes a comprehensive examination of literature pertaining to Epimedium and its metabolites over the past decade, drawing from databases such as PubMed. Through meticulous organization and synthesis of pertinent research findings, including disease models, pharmacological effects, and related aspects, this narrative review sheds light on the principal pharmacological activities and associated mechanisms of Epimedium in safeguarding the reproductive system, promoting bone health, mitigating inflammation, and combating tumors and viral infections. Consequently, this review contributes to a more profound comprehension of the recent advances in Epimedium research.","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142201933","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-11DOI: 10.3389/fphar.2024.1442723
Xiaosheng Zhu, Huai Huang, Mengjie Zou, Honglin Luo, Tianqi Liu, Shaoliang Zhu, Bin Ye
ObjectiveThis study aimed to investigate potential causal relationships between circulating metabolites and breast cancer risk using Mendelian randomization (MR) analysis.Materials and MethodsSummary-level genome-wide association study (GWAS) datasets for 249 circulating metabolites were obtained from the UK Biobank. GWAS datasets for estrogen receptor-positive (ER+) and estrogen receptor-negative (ER-) breast cancer were acquired from previous studies based on the Combined Oncoarray. Instrumental variables (IVs) were selected from single nucleotide polymorphisms (SNPs) associated with circulating metabolites, and MR analyses were conducted using the inverse-variance weighted (IVW) method as the primary analysis, with additional sensitivity analyses using other MR methods. Odds ratios (OR) and 95% confidence interval (CI) were used to estimate the association of circulating metabolites with breast cancer risk.ResultsThe IVW analysis revealed significant causal relationships between 79 circulating metabolites and ER + breast cancer risk, and 10 metabolites were significantly associated with ER-breast cancer risk. Notably, acetate (OR = 1.12, P = 0.03), HDL cholesterol (OR = 1.09, P < 0.001), ration of omega-6 fatty acids to total fatty acids ratio (OR = 1.09, P = 0.01), and phospholipids in large LDL (OR = 1.09, P < 0.001) were linked to an increased risk of ER + breast cancer, while linoleic acid (OR = 0.91, P < 0.001) monounsaturated fatty acids (OR = 0.91, P < 0.001), and total lipids in LDL (OR = 0.91, P < 0.001) were associated with a decreased risk. In ER-breast cancer, glycine, citrate, HDL cholesterol, cholesteryl esters in HDL, cholesterol to total lipids ratio in very large HDL, and cholesterol in large LDL were associated with an increased risk, while the free cholesterol to total lipids in very large HDL was linked to a decreased risk.ConclusionThis MR approach underscores aberrant lipid metabolism as a key process in breast tumorigenesis, and may inform future prevention and treatment strategies. To further elucidate the underlying mechanisms and explore the potential clinical implications, additional research is warranted to validate the observed associations in this study.
{"title":"Identification of circulating metabolites linked to the risk of breast cancer: a mendelian randomization study","authors":"Xiaosheng Zhu, Huai Huang, Mengjie Zou, Honglin Luo, Tianqi Liu, Shaoliang Zhu, Bin Ye","doi":"10.3389/fphar.2024.1442723","DOIUrl":"https://doi.org/10.3389/fphar.2024.1442723","url":null,"abstract":"ObjectiveThis study aimed to investigate potential causal relationships between circulating metabolites and breast cancer risk using Mendelian randomization (MR) analysis.Materials and MethodsSummary-level genome-wide association study (GWAS) datasets for 249 circulating metabolites were obtained from the UK Biobank. GWAS datasets for estrogen receptor-positive (ER+) and estrogen receptor-negative (ER-) breast cancer were acquired from previous studies based on the Combined Oncoarray. Instrumental variables (IVs) were selected from single nucleotide polymorphisms (SNPs) associated with circulating metabolites, and MR analyses were conducted using the inverse-variance weighted (IVW) method as the primary analysis, with additional sensitivity analyses using other MR methods. Odds ratios (OR) and 95% confidence interval (CI) were used to estimate the association of circulating metabolites with breast cancer risk.ResultsThe IVW analysis revealed significant causal relationships between 79 circulating metabolites and ER + breast cancer risk, and 10 metabolites were significantly associated with ER-breast cancer risk. Notably, acetate (OR = 1.12, <jats:italic>P</jats:italic> = 0.03), HDL cholesterol (OR = 1.09, <jats:italic>P</jats:italic> &lt; 0.001), ration of omega-6 fatty acids to total fatty acids ratio (OR = 1.09, <jats:italic>P</jats:italic> = 0.01), and phospholipids in large LDL (OR = 1.09, <jats:italic>P</jats:italic> &lt; 0.001) were linked to an increased risk of ER + breast cancer, while linoleic acid (OR = 0.91, <jats:italic>P</jats:italic> &lt; 0.001) monounsaturated fatty acids (OR = 0.91, <jats:italic>P</jats:italic> &lt; 0.001), and total lipids in LDL (OR = 0.91, <jats:italic>P</jats:italic> &lt; 0.001) were associated with a decreased risk. In ER-breast cancer, glycine, citrate, HDL cholesterol, cholesteryl esters in HDL, cholesterol to total lipids ratio in very large HDL, and cholesterol in large LDL were associated with an increased risk, while the free cholesterol to total lipids in very large HDL was linked to a decreased risk.ConclusionThis MR approach underscores aberrant lipid metabolism as a key process in breast tumorigenesis, and may inform future prevention and treatment strategies. To further elucidate the underlying mechanisms and explore the potential clinical implications, additional research is warranted to validate the observed associations in this study.","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142201975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The prevalence of dry eye disease (DED), a multifactorial ocular surface disease characterized by tear film instability, is increasing yearly. Qingxuan Run Mu Yin (QXRMY) is a traditional Chinese medicine (TCM) consisting of Radix Rehmanniae, Radix Scrophulariae, Rhizoma Atractylodis macrocephalae, Herba Dendrobii, Flos Lonicerae, Forsythia suspensa, Ophiopogon japonicus, Saposhnikovia divaricata, Radix Platycodi, and Radix Glycyrrhizae. It has excellent therapeutic effects on dry eye syndrome and a good anti-inflammatory effect on immune-related inflammation. However, the molecular mechanism of Qing Xuan Run Mu Yin in treating dry eye syndrome is largely unknown. The present study used an online database to identify potential target genes of QXRMY for treating DED. The possible mechanisms of these target genes for the treatment of DED were obtained through Gene Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) databases, Hub genes screened by Cytoscape and intersected with ferroptosis-related genes, and the essential genes were finally obtained based on the results of the analyses. DED cell model and rat model were constructed in this study to validate the critical genes and pathways, and it was confirmed that QXEMY alleviated DED by repressing ferroptosis through inhibiting the HMOX1/HIF-1 pathway. In conclusion, this study integrated network pharmacological analyses and experimental validation to provide an effective method to investigate the molecular mechanism of QXRMY in treating DED.
{"title":"Qingxuan Runmu Yin alleviates dry eye disease via inhibition of the HMOX1/HIF-1 pathway affecting ferroptosis","authors":"Jiadi Wang, Yue Liu, Beiting Zong, Shanshan Zhao, Yue Li, Zhirui Zhang, Jing Yao","doi":"10.3389/fphar.2024.1391946","DOIUrl":"https://doi.org/10.3389/fphar.2024.1391946","url":null,"abstract":"The prevalence of dry eye disease (DED), a multifactorial ocular surface disease characterized by tear film instability, is increasing yearly. Qingxuan Run Mu Yin (QXRMY) is a traditional Chinese medicine (TCM) consisting of <jats:italic>Radix Rehmanniae, Radix Scrophulariae, Rhizoma Atractylodis macrocephalae, Herba Dendrobii, Flos Lonicerae, Forsythia suspensa, Ophiopogon japonicus, Saposhnikovia divaricata, Radix Platycodi, and Radix Glycyrrhizae.</jats:italic> It has excellent therapeutic effects on dry eye syndrome and a good anti-inflammatory effect on immune-related inflammation. However, the molecular mechanism of Qing Xuan Run Mu Yin in treating dry eye syndrome is largely unknown. The present study used an online database to identify potential target genes of QXRMY for treating DED. The possible mechanisms of these target genes for the treatment of DED were obtained through Gene Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) databases, Hub genes screened by Cytoscape and intersected with ferroptosis-related genes, and the essential genes were finally obtained based on the results of the analyses. DED cell model and rat model were constructed in this study to validate the critical genes and pathways, and it was confirmed that QXEMY alleviated DED by repressing ferroptosis through inhibiting the HMOX1/HIF-1 pathway. In conclusion, this study integrated network pharmacological analyses and experimental validation to provide an effective method to investigate the molecular mechanism of QXRMY in treating DED.","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142201898","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
RationaleTranexamic acid (TXA) is a strong and specific plasminogen activator inhibitor with inhibitory effects on the matrix metalloproteases involved in the pathophysiology of osteoarthritis (OA) through targeting of the fibrinolysis pathway. In this study, we evaluated the analgesic and chondroprotective effects of a HA-tranexamic acid (HA/TXA) conjugate, compared to HA alone and placebo, in an animal model of knee OA.MethodsKnee OA was induced in 15 C57 b l/6J mice by IA injection of 0.75 mg of Monosodium IodoAcetate (MIA). At day 28, the mice received 1 IA injection of 10 µL of saline (control-group), or of HA or of HA/TXA. Tactile sensitivity was assessed using von Frey filaments. Stimulations started at 1 g and increased until a response was obtained (up to 4 g). A response to the stimulus was counted if the animal withdrew its paw. If the animal responded to the 1 g stimulation, stimulation was reduced until the lack of response was observed (up to 0.2 g). At day 56, mice were euthanized for knee histological assessment. Cartilage degradation was assessed using the OARSI score. Statistical analysis was performed on GraphPad Prism 8.0.2 software. Kruskal–Wallis or Mann-Whitney tests were performed as appropriate.ResultsJust before treatment administration, no intergroup difference in paw withdrawal threshold was observed. Throughout the experiment animals given saline and HA had a lower paw withdrawal threshold than those treated with HA/TXA (p < 0.01). In the control group OARSI score was 5.5 ± 0.6. In HA and HA + TXA treated mice the OARSI score was 3.2 ± 0.8 and 3.1 ± 0.5 (p < 0.01) showing that both treatments were able to reduce OA progression.ConclusionIn this animal model of MIA induced KOA, a single IA injection of a HA/TXA conjugate resulted in a greater efficacy on pain than both saline and HA. HA and HA/TXA exhibited chondroprotective effects compared to placebo.
{"title":"A single intraarticular injection of a tranexamic acid-modified hyaluronic acid (HA/TXA) alleviates pain and reduces OA development in a murine model of monosodium iodoacetate-induced osteoarthritis","authors":"Sybille Brochard, Karim Boumédiene, Jéromine Mercier, Véronique Agin, Thierry Conrozier, Catherine Baugé","doi":"10.3389/fphar.2024.1456495","DOIUrl":"https://doi.org/10.3389/fphar.2024.1456495","url":null,"abstract":"RationaleTranexamic acid (TXA) is a strong and specific plasminogen activator inhibitor with inhibitory effects on the matrix metalloproteases involved in the pathophysiology of osteoarthritis (OA) through targeting of the fibrinolysis pathway. In this study, we evaluated the analgesic and chondroprotective effects of a HA-tranexamic acid (HA/TXA) conjugate, compared to HA alone and placebo, in an animal model of knee OA.MethodsKnee OA was induced in 15 C<jats:sup>5</jats:sup>7 b l/6J mice by IA injection of 0.75 mg of Monosodium IodoAcetate (MIA). At day 28, the mice received 1 IA injection of 10 µL of saline (control-group), or of HA or of HA/TXA. Tactile sensitivity was assessed using von Frey filaments. Stimulations started at 1 g and increased until a response was obtained (up to 4 g). A response to the stimulus was counted if the animal withdrew its paw. If the animal responded to the 1 g stimulation, stimulation was reduced until the lack of response was observed (up to 0.2 g). At day 56, mice were euthanized for knee histological assessment. Cartilage degradation was assessed using the OARSI score. Statistical analysis was performed on GraphPad Prism 8.0.2 software. Kruskal–Wallis or Mann-Whitney tests were performed as appropriate.ResultsJust before treatment administration, no intergroup difference in paw withdrawal threshold was observed. Throughout the experiment animals given saline and HA had a lower paw withdrawal threshold than those treated with HA/TXA (<jats:italic>p</jats:italic> &lt; 0.01). In the control group OARSI score was 5.5 ± 0.6. In HA and HA + TXA treated mice the OARSI score was 3.2 ± 0.8 and 3.1 ± 0.5 (<jats:italic>p</jats:italic> &lt; 0.01) showing that both treatments were able to reduce OA progression.ConclusionIn this animal model of MIA induced KOA, a single IA injection of a HA/TXA conjugate resulted in a greater efficacy on pain than both saline and HA. HA and HA/TXA exhibited chondroprotective effects compared to placebo.","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142201931","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-11eCollection Date: 2024-01-01DOI: 10.3389/fphar.2024.1486719
Christina Dalla, Nouria Lakhdar-Ghazal, Tanya Calvey, Giuseppe Di Giovanni
{"title":"Editorial: Pharmacological actions of drugs in the brain: exploring the intricacies and potential therapeutic applications.","authors":"Christina Dalla, Nouria Lakhdar-Ghazal, Tanya Calvey, Giuseppe Di Giovanni","doi":"10.3389/fphar.2024.1486719","DOIUrl":"https://doi.org/10.3389/fphar.2024.1486719","url":null,"abstract":"","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11423190/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142344699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PurposeThis study aimed to investigate the antioxidative and neuroprotective effects of DJ-1 in mitigating retinal ganglion cell (RGC) damage induced by high glucose (HG).MethodsA diabetic mouse model and an HG-induced R28 cell model were employed for loss- and gain-of-function experiments. The expression levels of apoptosis and oxidative stress-related factors, including Bax, Bcl-2, caspase3, Catalase, MnSOD, GCLC, Cyto c, and GPx-1/2, were assessed in both animal and cell models using Western blotting. Retinal structure and function were evaluated through HE staining, electroretinogram, and RGC counting. Mitochondrial function and apoptosis were determined using JC-1 and TUNEL staining, and reactive oxygen species (ROS) measurement.ResultsIn the mouse model, hyperglycemia resulted in reduced retinal DJ-1 expression, retinal structural and functional damage, disrupted redox protein profiles, and mitochondrial dysfunction. Elevated glucose levels induced mitochondrial impairment, ROS generation, abnormal protein expression, and apoptosis in R28 cells. Augmenting DJ-1 expression demonstrated a restoration of mitochondrial homeostasis and alleviated diabetes-induced morphological and functional impairments both in vivo and in vitro.ConclusionThis study provides novel insights into the regulatory role of DJ-1 in mitochondrial dynamics, suggesting a potential avenue for enhancing RGC survival in diabetic retinopathy.
目的 本研究旨在探讨DJ-1在减轻高糖诱导的视网膜神经节细胞（RGC）损伤中的抗氧化和神经保护作用。方法 采用糖尿病小鼠模型和高糖诱导的R28细胞模型进行功能缺失和功能增益实验。用 Western 印迹法评估了动物模型和细胞模型中细胞凋亡和氧化应激相关因子的表达水平，包括 Bax、Bcl-2、caspase3、过氧化氢酶、MnSOD、GCLC、Cyto c 和 GPx-1/2。通过 HE 染色、视网膜电图和 RGC 计数评估视网膜结构和功能。结果在小鼠模型中，高血糖导致视网膜 DJ-1 表达减少、视网膜结构和功能损伤、氧化还原蛋白谱紊乱和线粒体功能障碍。葡萄糖水平升高会诱导线粒体损伤、ROS 生成、蛋白质表达异常和 R28 细胞凋亡。增加 DJ-1 的表达可恢复线粒体的稳态，减轻糖尿病诱导的体内和体外形态和功能损伤。 结论：这项研究为 DJ-1 在线粒体动力学中的调控作用提供了新的见解，为提高糖尿病视网膜病变中 RGC 的存活率提供了潜在的途径。
{"title":"DJ-1 regulates mitochondrial function and promotes retinal ganglion cell survival under high glucose-induced oxidative stress","authors":"Hanhan Peng, Haoyu Li, Benteng Ma, Xinyue Sun, Baihua Chen","doi":"10.3389/fphar.2024.1455439","DOIUrl":"https://doi.org/10.3389/fphar.2024.1455439","url":null,"abstract":"PurposeThis study aimed to investigate the antioxidative and neuroprotective effects of DJ-1 in mitigating retinal ganglion cell (RGC) damage induced by high glucose (HG).MethodsA diabetic mouse model and an HG-induced R28 cell model were employed for loss- and gain-of-function experiments. The expression levels of apoptosis and oxidative stress-related factors, including Bax, Bcl-2, caspase3, Catalase, MnSOD, GCLC, Cyto c, and GPx-1/2, were assessed in both animal and cell models using Western blotting. Retinal structure and function were evaluated through HE staining, electroretinogram, and RGC counting. Mitochondrial function and apoptosis were determined using JC-1 and TUNEL staining, and reactive oxygen species (ROS) measurement.ResultsIn the mouse model, hyperglycemia resulted in reduced retinal DJ-1 expression, retinal structural and functional damage, disrupted redox protein profiles, and mitochondrial dysfunction. Elevated glucose levels induced mitochondrial impairment, ROS generation, abnormal protein expression, and apoptosis in R28 cells. Augmenting DJ-1 expression demonstrated a restoration of mitochondrial homeostasis and alleviated diabetes-induced morphological and functional impairments both <jats:italic>in vivo</jats:italic> and <jats:italic>in vitro</jats:italic>.ConclusionThis study provides novel insights into the regulatory role of DJ-1 in mitochondrial dynamics, suggesting a potential avenue for enhancing RGC survival in diabetic retinopathy.","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142201973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tyrosinase is a key enzyme in melanin synthesis, and its natural inhibitors are receiving increasing attention. Rosa × damascena Herrm. essential oil (RDEO), as important functional metabolites, was widely known due to its biological activities. But its tyrosinase inhibitory activity has not been detailed investigated. Therefore, in this paper, RDEO was comprehensively investigated the tyrosinase inhibitory, followed by the phytochemical composition analysis. Activity screening results showed that RDEO exhibited effective anti-tyrosinase activity and was a reversible and mixed-type inhibitor. CD assay results revealed that RDEO could affect the conformation of tyrosinase to reduce the activity. In B16F10 cells, RDEO (25–100 μg/mL) could inhibit intracellular tyrosinase activity and decrease melanin content. Finally, GC-MS analysis of RDEO found that citronellol (21.22%), geraniol (14.1%), eicosane (11.03%), heneicosane (6.65%) and 1-nonadecene (5.16%) were its main phytochemical compositions. This study provided data support for Rosa × damascena Herrm. essential oil as one potential natural tyrosinase inhibitor and its applications in cosmetics and medicine.
{"title":"Rosa × damascena Herrm. essential oil: anti-tyrosinase activity and phytochemical composition","authors":"Qiuyan Wu, Wanting Fang, Hao Liu, Zhong Liu, Xuetao Xu","doi":"10.3389/fphar.2024.1451452","DOIUrl":"https://doi.org/10.3389/fphar.2024.1451452","url":null,"abstract":"Tyrosinase is a key enzyme in melanin synthesis, and its natural inhibitors are receiving increasing attention. <jats:italic>Rosa × damascena</jats:italic> Herrm. essential oil (RDEO), as important functional metabolites, was widely known due to its biological activities. But its tyrosinase inhibitory activity has not been detailed investigated. Therefore, in this paper, RDEO was comprehensively investigated the tyrosinase inhibitory, followed by the phytochemical composition analysis. Activity screening results showed that RDEO exhibited effective anti-tyrosinase activity and was a reversible and mixed-type inhibitor. CD assay results revealed that RDEO could affect the conformation of tyrosinase to reduce the activity. In B16F10 cells, RDEO (25–100 μg/mL) could inhibit intracellular tyrosinase activity and decrease melanin content. Finally, GC-MS analysis of RDEO found that citronellol (21.22%), geraniol (14.1%), eicosane (11.03%), heneicosane (6.65%) and 1-nonadecene (5.16%) were its main phytochemical compositions. This study provided data support for <jats:italic>Rosa × damascena</jats:italic> Herrm. essential oil as one potential natural tyrosinase inhibitor and its applications in cosmetics and medicine.","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142202023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-10DOI: 10.3389/fphar.2024.1476464
Cheima Amrouch, Davide Liborio Vetrano, Cecilia Damiano, Lu Dai, Amaia Calderón-Larrañaga, Maxim Grymonprez, Marco Proietti, Gregory Y. H. Lip, Søren P. Johnsen, Jonas W. Wastesson, Kristina Johnell, Delphine De Smedt, Mirko Petrovic
IntroductionCurrent research on potentially inappropriate prescribing (PIP) in polymedicated older adults with atrial fibrillation (AF) and multimorbidity is predominantly focused on PIP of oral anticoagulants (OAC). Our study aimed to assess (i) the overall prevalence of PIP in older multimorbid adults with AF, (ii) potential associated factors of PIP, and (iii) the association of PIP with adverse health outcomes in a nationwide sample of Swedish older adults.MethodsSwedish national registries were linked to establish a cohort with a 2-year follow-up of older adults (≥65y) who, on 1 January 2017, had a diagnosis of AF and had at least one comorbidity (n = 203,042). PIP was assessed using the reduced STOPP/START version 2 screening tool. The STOPP criteria identify potentially inappropriate prescribed medications (PIM), while the START criteria identify potential prescribing omissions (PPO). PIP is identified as having at least one PIM and/or PPO. Cox regression analyses were conducted to examine the association between PIP and adverse health outcomes: mortality, hospitalisation, stroke, bleeding, and falls.ResultsPIP was highly prevalent in older adults with AF, with both polypharmacy (69.6%) and excessive polypharmacy (85.9%). In the study population, benzodiazepines (22.9%), hypnotic Z-medications (17.8%) and analgesics (8.7%) were the most frequent PIM. Anticoagulants (34.3%), statins (11.1%), vitamin D and calcium (13.4%) were the most frequent PPO. Demographic factors and polypharmacy were associated with different PIM and PPO categories, with the nature of these associations differing based on the specific type of PIM and PPO. The co-occurrence of PIM and PPO, compared to appropriate prescribing, was associated with an increased risk of adverse health outcomes compared to all appropriately prescribed medications: cardiovascular (CV) (Hazard ratio (HR) [95% confidence interval] = 1.97 [1.88–2.07]) and overall mortality (HR = 2.09 [2.03–2.16]), CV (HR = 1.34 [1.30–1.37]) and overall hospitalisation (HR = 1.48 [1.46–1.51]), stroke (HR = 1.93 [1.78–2.10]), bleeding (HR = 1.10 [1.01–1.21]), and falls (HR = 1.63 [1.56–1.71]).ConclusionThe present study reports a high prevalence of PIP in multimorbid polymedicated older adults with AF. Additionally, a nuanced relationship between prescribing patterns, patient characteristics, and adverse health outcomes was observed. These findings emphasise the importance of implementing tailored interventions to optimise medication management in this patient population.
{"title":"Potentially inappropriate prescribing in polymedicated older adults with atrial fibrillation and multimorbidity: a Swedish national register-based cohort study","authors":"Cheima Amrouch, Davide Liborio Vetrano, Cecilia Damiano, Lu Dai, Amaia Calderón-Larrañaga, Maxim Grymonprez, Marco Proietti, Gregory Y. H. Lip, Søren P. Johnsen, Jonas W. Wastesson, Kristina Johnell, Delphine De Smedt, Mirko Petrovic","doi":"10.3389/fphar.2024.1476464","DOIUrl":"https://doi.org/10.3389/fphar.2024.1476464","url":null,"abstract":"IntroductionCurrent research on potentially inappropriate prescribing (PIP) in polymedicated older adults with atrial fibrillation (AF) and multimorbidity is predominantly focused on PIP of oral anticoagulants (OAC). Our study aimed to assess (i) the overall prevalence of PIP in older multimorbid adults with AF, (ii) potential associated factors of PIP, and (iii) the association of PIP with adverse health outcomes in a nationwide sample of Swedish older adults.MethodsSwedish national registries were linked to establish a cohort with a 2-year follow-up of older adults (≥65y) who, on 1 January 2017, had a diagnosis of AF and had at least one comorbidity (n = 203,042). PIP was assessed using the reduced STOPP/START version 2 screening tool. The STOPP criteria identify potentially inappropriate prescribed medications (PIM), while the START criteria identify potential prescribing omissions (PPO). PIP is identified as having at least one PIM and/or PPO. Cox regression analyses were conducted to examine the association between PIP and adverse health outcomes: mortality, hospitalisation, stroke, bleeding, and falls.ResultsPIP was highly prevalent in older adults with AF, with both polypharmacy (69.6%) and excessive polypharmacy (85.9%). In the study population, benzodiazepines (22.9%), hypnotic Z-medications (17.8%) and analgesics (8.7%) were the most frequent PIM. Anticoagulants (34.3%), statins (11.1%), vitamin D and calcium (13.4%) were the most frequent PPO. Demographic factors and polypharmacy were associated with different PIM and PPO categories, with the nature of these associations differing based on the specific type of PIM and PPO. The co-occurrence of PIM and PPO, compared to appropriate prescribing, was associated with an increased risk of adverse health outcomes compared to all appropriately prescribed medications: cardiovascular (CV) (Hazard ratio (HR) [95% confidence interval] = 1.97 [1.88–2.07]) and overall mortality (HR = 2.09 [2.03–2.16]), CV (HR = 1.34 [1.30–1.37]) and overall hospitalisation (HR = 1.48 [1.46–1.51]), stroke (HR = 1.93 [1.78–2.10]), bleeding (HR = 1.10 [1.01–1.21]), and falls (HR = 1.63 [1.56–1.71]).ConclusionThe present study reports a high prevalence of PIP in multimorbid polymedicated older adults with AF. Additionally, a nuanced relationship between prescribing patterns, patient characteristics, and adverse health outcomes was observed. These findings emphasise the importance of implementing tailored interventions to optimise medication management in this patient population.","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142201976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BackgroundProstate cancer (PCa) is the most common non-cutaneous malignancy in men globally. Sappan lignum, which exists in the heartwood of Caesalpinia sappan L., has antitumor effects; however, its exact mechanism of action remains unclear. This study elucidated the underlying mechanisms of Sappan lignum in PCa through network pharmacology approaches and molecular docking techniques. Moreover, the therapeutic effects of Sappan lignum on PCa were verified through in vitro experiments.MethodsThe constituent ingredients of Sappan lignum were retrieved from the HERB database. Active plant-derived compounds of Sappan lignum were screened based on gastrointestinal absorption and gastric drug properties. Disease targets for PCa were screened using unpaired and paired case datasets from the Gene Expression Omnibus. Intersection targets were used for gene ontology and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis. Core targets were identified through topological analysis parameters and their clinical relevance was validated through The Cancer Genome Atlas database. The affinity between the phytochemicals of Sappan lignum and core proteins was verified using the molecular docking technique. Validation experiments confirmed the significant potential of Sappan lignum in treating PCa.ResultsTwenty-one plant-derived compounds of Sappan lignum and 821 differentially expressed genes associated with PCa were collected. Among 32 intersection targets, 8 were screened according to topological parameters. KEGG analysis indicated that the antitumor effects of Sappan lignum on PCa were primarily associated with the p53 pathway. The molecular docking technique demonstrated a strong affinity between 3-deoxysappanchalcone (3-DSC) and core proteins, particularly cyclin B1 (CCNB1). CCNB1 expression correlated with clinicopathological features in patients with PCa. Experimental results revealed that 3-DSC exhibited anti-proliferative, anti-migratory, and pro-apoptotic effects on 22RV1 and DU145 cells while also causing G2/M phase cell cycle arrest, potentially through modulating the p53/p21/CDC2/CCNB1 pathway.ConclusionThis research highlights the promising therapeutic potential of Sappan lignum in treating PCa, with a particular focus on targeting the p53 pathway.
{"title":"Mechanisms of action of Sappan lignum for prostate cancer treatment: network pharmacology, molecular docking and experimental validation","authors":"Wenna Li, Honglin Jiang, Weina Zhang, Qiuyue Sun, Qiaoli Zhang, Jingnan Xu, Jinchang Huang, Yuxiang Wan","doi":"10.3389/fphar.2024.1407525","DOIUrl":"https://doi.org/10.3389/fphar.2024.1407525","url":null,"abstract":"BackgroundProstate cancer (PCa) is the most common non-cutaneous malignancy in men globally. <jats:italic>Sappan lignum</jats:italic>, which exists in the heartwood of Caesalpinia sappan L., has antitumor effects; however, its exact mechanism of action remains unclear. This study elucidated the underlying mechanisms of <jats:italic>Sappan lignum</jats:italic> in PCa through network pharmacology approaches and molecular docking techniques. Moreover, the therapeutic effects of <jats:italic>Sappan lignum</jats:italic> on PCa were verified through <jats:italic>in vitro</jats:italic> experiments.MethodsThe constituent ingredients of <jats:italic>Sappan lignum</jats:italic> were retrieved from the HERB database. Active plant-derived compounds of <jats:italic>Sappan lignum</jats:italic> were screened based on gastrointestinal absorption and gastric drug properties. Disease targets for PCa were screened using unpaired and paired case datasets from the Gene Expression Omnibus. Intersection targets were used for gene ontology and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis. Core targets were identified through topological analysis parameters and their clinical relevance was validated through The Cancer Genome Atlas database. The affinity between the phytochemicals of <jats:italic>Sappan lignum</jats:italic> and core proteins was verified using the molecular docking technique. Validation experiments confirmed the significant potential of <jats:italic>Sappan lignum</jats:italic> in treating PCa.ResultsTwenty-one plant-derived compounds of <jats:italic>Sappan lignum</jats:italic> and 821 differentially expressed genes associated with PCa were collected. Among 32 intersection targets, 8 were screened according to topological parameters. KEGG analysis indicated that the antitumor effects of <jats:italic>Sappan lignum</jats:italic> on PCa were primarily associated with the p53 pathway. The molecular docking technique demonstrated a strong affinity between 3-deoxysappanchalcone (3-DSC) and core proteins, particularly cyclin B1 (CCNB1). CCNB1 expression correlated with clinicopathological features in patients with PCa. Experimental results revealed that 3-DSC exhibited anti-proliferative, anti-migratory, and pro-apoptotic effects on 22RV1 and DU145 cells while also causing G2/M phase cell cycle arrest, potentially through modulating the p53/p21/CDC2/CCNB1 pathway.ConclusionThis research highlights the promising therapeutic potential of <jats:italic>Sappan lignum</jats:italic> in treating PCa, with a particular focus on targeting the p53 pathway.","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142201977","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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