Pub Date : 2025-03-02DOI: 10.1016/j.jare.2025.03.002
Jianmei Gao, Yifan He, Fuguo Shi, Fangqin Hou, Xiaoyu Wu, Yang Yi, Yuandong Zhang, Qihai Gong
Background
Sirt6-mediated gut microbiota plays a vital role in poststroke depression (PSD). Icariside Ⅱ (ICS Ⅱ) is a naturally-occurring neuroprotectant with Sirt6 induction potency. However, it is unknown whether ICS Ⅱ protects against PSD through modulation of gut microbiota.
Objective
This study aimed to reveal the effect and potential mechanisms of ICS Ⅱ on PSD, and the role of the microbiota-gut-brain axis was investigated.
Methods
Using middle cerebral artery occlusion (MCAO) and chronic unpredictable mild stress (CUMS) to establish post-stroke depression (PSD) mice, we assessed anti-depressant effects of ICS Ⅱ via behavioral tests, immunohistochemistry, and western blot. Transcriptome profiling, molecular docking, and surface plasmon resonance were used to identify key targets. 16S rDNA genomic-derived taxonomic profiling and fecal microbiota transplantation (FMT) were conducted to figure out the mechanistic role of the gut microbiota and short-chain fatty acids (SCFAs).
Results
ICS Ⅱ ameliorated depressive-like behaviors in PSD mice as evidenced by sucrose preference test, forced swimming test and tail suspension test. ICS Ⅱ restored mitochondrial function, reduced oxidative damage and pro-inflammatory cytokines both in brain and intestine through regulation of Sirt6/NF-κB pathway. ICS Ⅱ significantly increased the abundance of gut microbiota (such as Akkermansia and Ligilactobacillus), enhanced SCFAs concentrations, repaired intestinal barrier integrity and upreglated the tight junction protein expression. FMT from ICS II-treated mice replicated these benefits, confirming gut microbiota’s role. Mechanistically, ICS Ⅱ directly bound to Sirt6 and enhanced its activity. However, ICS Ⅱ-mediated neuroprotection was neutralized in PSD mice or hydrogen peroxide-induced enteric glial cells when Sirt6 was absent.
Conclusion
Our findings expand the pharmacological properties of ICS II by demonstrating its ability to ameliorate PSD through modulation of the microbiota-gut-brain axis. ICS Ⅱ, as a novel Sirt6 activator, could be translated into an alternative microbiota-targeted avenue for coping with PSD.
{"title":"Activation of Sirt6 by icariside Ⅱ alleviates depressive behaviors in mice with poststroke depression by modulating microbiota-gut-brain axis","authors":"Jianmei Gao, Yifan He, Fuguo Shi, Fangqin Hou, Xiaoyu Wu, Yang Yi, Yuandong Zhang, Qihai Gong","doi":"10.1016/j.jare.2025.03.002","DOIUrl":"https://doi.org/10.1016/j.jare.2025.03.002","url":null,"abstract":"<h3>Background</h3>Sirt6-mediated gut microbiota plays a vital role in poststroke depression (PSD). Icariside Ⅱ (ICS Ⅱ) is a naturally-occurring neuroprotectant with Sirt6 induction potency. However, it is unknown whether ICS Ⅱ protects against PSD through modulation of gut microbiota.<h3>Objective</h3>This study aimed to reveal the effect and potential mechanisms of ICS Ⅱ on PSD, and the role of the microbiota-gut-brain axis was investigated.<h3>Methods</h3>Using middle cerebral artery occlusion (MCAO) and chronic unpredictable mild stress (CUMS) to establish post-stroke depression (PSD) mice, we assessed anti-depressant effects of ICS Ⅱ <em>via</em> behavioral tests, immunohistochemistry, and western blot. Transcriptome profiling, molecular docking, and surface plasmon resonance were used to identify key targets. 16S rDNA genomic-derived taxonomic profiling and fecal microbiota transplantation (FMT) were conducted to figure out the mechanistic role of the gut microbiota and short-chain fatty acids (SCFAs).<h3>Results</h3>ICS Ⅱ ameliorated depressive-like behaviors in PSD mice as evidenced by sucrose preference test, forced swimming test and tail suspension test. ICS Ⅱ restored mitochondrial function, reduced oxidative damage and pro-inflammatory cytokines both in brain and intestine through regulation of Sirt6/NF-κB pathway. ICS Ⅱ significantly increased the abundance of gut microbiota (such as<!-- --> <!-- -->Akkermansia and Ligilactobacillus), enhanced SCFAs concentrations, repaired intestinal barrier integrity and upreglated the tight junction protein expression. FMT from ICS II-treated mice replicated these benefits, confirming gut microbiota’s role. Mechanistically, ICS Ⅱ directly bound to Sirt6 and enhanced its activity. However, ICS Ⅱ-mediated neuroprotection was neutralized in PSD mice or hydrogen peroxide-induced enteric glial cells when Sirt6 was absent.<h3>Conclusion</h3>Our findings expand the pharmacological properties of ICS II by demonstrating its ability to ameliorate PSD through modulation of the microbiota-gut-brain axis. ICS Ⅱ, as a novel Sirt6 activator, could be translated into an alternative microbiota-targeted avenue for coping with PSD.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"39 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532827","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Although the adverse health effects of PM2.5 exposure has been well documented, evidence of its adverse effect on overall outpatient visits was still limited. Besides, the adverse health effects of PM2.5 exposure get complicated due to various components within the particles. So far, little is known about the relationship between PM2.5 components and overall outpatient visits.
Objectives
This study aims to evaluate the causal relationships between long-term exposure to primary chemical components of PM2.5 and outpatient visits, while estimating the mixture effect and relative contribution of the components.
Methods
Based on nationwide provincial-level surveillance data of outpatient visits in China and well-validated simulations of PM2.5 components concentration, we employed the Difference-In-Differences (DID) approach to evaluate the causal relationships between long-term exposure to primary chemical components of PM2.5 and outpatient visits, and used a Bayesian Weighted Quantile Sum (BWQS) regression to assess the mixture effect of the components.
Results
We found a 20.44% increase in the risk (IR%) of outpatient visits following each InterQuartile Range (IQR) increment in PM2.5 concentration. Our estimation further suggested a 17.07%, 15.91%, and 14.04% increase in the risk of outpatient visits for organic matter, sulfate, and nitrate, but non-significant increases for other components. However, when considering the inter-components correlation, sulfate and black carbon contributed most (42.3% and 28.1%, respectively) to the overall mixture effect of PM2.5 which was indicated by a 4.84% increase (95%CI: 1.92%, 7.83%) in the risk of outpatient visits following every unit increase in the overall BWQS index. Additionally, stratified analyses showed a stronger association among aged provinces and provinces with lower education rates.
Conclusion
Our findings would improve understanding of the individual and mixture impact of major chemical components of PM2.5 and may contribute to more targeted and optimized environmental programs for pollution control.
{"title":"The causal links between long-term exposure to major chemical components of PM2.5 and overall outpatient visits in mainland China: A nationwide study in the difference-in-differences framework","authors":"Shuaiqi Zhang, Zhibing Chen, Zhicheng Du, Shenghao Wang, Dan Chen, Xingling Ruan, Ziqiang Lin, Zihan Zheng, Kunying Li, Xudan Chen, Zhishen Wu, Qing Qin, Man Zhang, Shuming Zhu, Shaomin Wu, Fangfang Zeng, Ying Wang, Wangjian Zhang","doi":"10.1016/j.jare.2025.02.041","DOIUrl":"https://doi.org/10.1016/j.jare.2025.02.041","url":null,"abstract":"<h3>Introduction</h3>Although the adverse health effects of PM<sub>2.5</sub> exposure has been well documented, evidence of its adverse effect on overall outpatient visits was still limited. Besides, the adverse health effects of PM<sub>2.5</sub> exposure get complicated due to various components within the particles. So far, little is known about the relationship between PM<sub>2.5</sub> components and overall outpatient visits.<h3>Objectives</h3>This study aims to evaluate the causal relationships between long-term exposure to primary chemical components of PM<sub>2.5</sub> and outpatient visits, while estimating the mixture effect and relative contribution of the components.<h3>Methods</h3>Based on nationwide provincial-level surveillance data of outpatient visits in China and well-validated simulations of PM<sub>2.5</sub> components concentration, we employed the Difference-In-Differences (DID) approach to evaluate the causal relationships between long-term exposure to primary chemical components of PM<sub>2.5</sub> and outpatient visits, and used a Bayesian Weighted Quantile Sum (BWQS) regression to assess the mixture effect of the components.<h3>Results</h3>We found a 20.44% increase in the risk (<em>IR%</em>) of outpatient visits following each InterQuartile Range (<em>IQR</em>) increment in PM<sub>2.5</sub> concentration. Our estimation further suggested a 17.07%, 15.91%, and 14.04% increase in the risk of outpatient visits for organic matter, sulfate, and nitrate, but non-significant increases for other components. However, when considering the inter-components correlation, sulfate and black carbon contributed most (42.3% and 28.1%, respectively) to the overall mixture effect of PM<sub>2.5</sub> which was indicated by a 4.84% increase (95%<em>CI</em>: 1.92%, 7.83%) in the risk of outpatient visits following every unit increase in the overall BWQS index. Additionally, stratified analyses showed a stronger association among aged provinces and provinces with lower education rates.<h3>Conclusion</h3>Our findings would improve understanding of the individual and mixture impact of major chemical components of PM<sub>2.5</sub> and may contribute to more targeted and optimized environmental programs for pollution control.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"38 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-01DOI: 10.1016/j.jare.2024.03.026
Shengjie Li , Aoxiang Zhuge , Hui Chen , Shengyi Han , Jian Shen , Kaicen Wang , Jiafeng Xia , He Xia , Shiman Jiang , Youhe Wu , Lanjuan Li
Introduction
Inflammatory bowel disease (IBD) is a global disease with limited therapy. It is reported that sedanolide exerts anti-oxidative and anti-inflammatory effects as a natural phthalide, but its effects on IBD remain unclear.
Objectives
In this study, we investigated the impacts of sedanolide on dextran sodium sulfate (DSS)-induced colitis in mice.
Methods
The mice were administered sedanolide or vehicle followed by DSS administration, after which colitis symptoms, inflammation levels, and intestinal barrier function were evaluated. Transcriptome analysis, 16S rRNA sequencing, and targeted metabolomics analysis of bile acids and lipids were performed.
Results
Sedanolide protected mice from DSS-induced colitis, suppressed the inflammation, restored the weakened epithelial barrier, and modified the gut microbiota by decreasing bile salt hydrolase (BSH)-expressing bacteria. The downregulation of BSH activity by sedanolide increased the ratio of conjugated/unconjugated bile acids (BAs), thereby inhibiting the intestinal farnesoid X receptor (FXR) pathway. The roles of the FXR pathway and gut microbiota were verified using an intestinal FXR-specific agonist (fexaramine) and germ-free mice, respectively. Furthermore, we identified the key effector ceramide, which is regulated by sphingomyelin phosphodiesterase 3 (SMPD3). The protective effects of ceramide (d18:1/16:0) against inflammation and the gut barrier were demonstrated in vitro using the human cell line Caco-2.
Conclusion
Sedanolide could reshape the intestinal flora and influence BA composition, thus inhibiting the FXR-SMPD3 pathway to stimulate the synthesis of ceramide, which ultimately alleviated DSS-induced colitis in mice. Overall, our research revealed the protective effects of sedanolide against DSS-induced colitis in mice, which indicated that sedanolide may be a clinical treatment for colitis. Additionally, the key lipid ceramide (d18:1/16:0) was shown to mediate the protective effects of sedanolide, providing new insight into the associations between colitis and lipid metabolites.
{"title":"Sedanolide alleviates DSS-induced colitis by modulating the intestinal FXR-SMPD3 pathway in mice","authors":"Shengjie Li , Aoxiang Zhuge , Hui Chen , Shengyi Han , Jian Shen , Kaicen Wang , Jiafeng Xia , He Xia , Shiman Jiang , Youhe Wu , Lanjuan Li","doi":"10.1016/j.jare.2024.03.026","DOIUrl":"10.1016/j.jare.2024.03.026","url":null,"abstract":"<div><h3>Introduction</h3><div>Inflammatory bowel disease (IBD) is a global disease with limited therapy. It is reported that sedanolide exerts anti-oxidative and anti-inflammatory effects as a natural phthalide, but its effects on IBD remain unclear.</div></div><div><h3>Objectives</h3><div>In this study, we investigated the impacts of sedanolide on dextran sodium sulfate (DSS)-induced colitis in mice.</div></div><div><h3>Methods</h3><div>The mice were administered sedanolide or vehicle followed by DSS administration, after which colitis symptoms, inflammation levels, and intestinal barrier function were evaluated. Transcriptome analysis, 16S rRNA sequencing, and targeted metabolomics analysis of bile acids and lipids were performed.</div></div><div><h3>Results</h3><div>Sedanolide protected mice from DSS-induced colitis, suppressed the inflammation, restored the weakened epithelial barrier, and modified the gut microbiota by decreasing bile salt hydrolase (BSH)-expressing bacteria. The downregulation of BSH activity by sedanolide increased the ratio of conjugated/unconjugated bile acids (BAs), thereby inhibiting the intestinal farnesoid X receptor (FXR) pathway. The roles of the FXR pathway and gut microbiota were verified using an intestinal FXR-specific agonist (fexaramine) and germ-free mice, respectively. Furthermore, we identified the key effector ceramide, which is regulated by sphingomyelin phosphodiesterase 3 (SMPD3). The protective effects of ceramide (d18:1/16:0) against inflammation and the gut barrier were demonstrated in vitro using the human cell line Caco-2.</div></div><div><h3>Conclusion</h3><div>Sedanolide could reshape the intestinal flora and influence BA composition, thus inhibiting the FXR-SMPD3 pathway to stimulate the synthesis of ceramide, which ultimately alleviated DSS-induced colitis in mice. Overall, our research revealed the protective effects of sedanolide against DSS-induced colitis in mice, which indicated that sedanolide may be a clinical treatment for colitis. Additionally, the key lipid ceramide (d18:1/16:0) was shown to mediate the protective effects of sedanolide, providing new insight into the associations between colitis and lipid metabolites.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"69 ","pages":"Pages 413-426"},"PeriodicalIF":11.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140604261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Astrocytes are glial-type cells that protect neurons from toxic insults and support neuronal functions and metabolism in a healthy brain. Leveraging these physiological functions, transplantation of astrocytes or their derivatives has emerged as a potential therapeutic approach for neurodegenerative disorders.
Methods
To substantiate the clinical application of astrocyte-based therapy, we aimed to prepare human astrocytes with potent therapeutic capacities from human pluripotent stem cells (hPSCs). To that end, we used ventral midbrain patterning during the differentiation of hPSCs into astrocytes, based on the roles of midbrain-specific factors in potentiating glial neurotrophic/anti-inflammatory activity. To assess the therapeutic effects of human midbrain-type astrocytes, we transplanted them into mouse models of Parkinson's disease (PD) and Alzheimer's disease (AD).
Results
Through a comprehensive series of in-vitro and in-vivo experiments, we were able to establish that the midbrain-type astrocytes exhibited the abilities to effectively combat oxidative stress, counter excitotoxic glutamate, and manage pathological protein aggregates. Our strategy for preparing midbrain-type astrocytes yielded promising results, demonstrating the strong therapeutic potential of these cells in various neurotoxic contexts. Particularly noteworthy is their efficacy in PD and AD-specific proteopathic conditions, in which the midbrain-type astrocytes outperformed forebrain-type astrocytes derived by the same organoid-based method.
Conclusion
The enhanced functions of the midbrain-type astrocytes extended to their ability to release signaling molecules that inhibited neuronal deterioration and senescence while steering microglial cells away from a pro-inflammatory state. This success was evident in both in-vitro studies using human cells and in-vivo experiments conducted in mouse models of PD and AD. In the end, our human midbrain-type astrocytes demonstrated remarkable effectiveness in alleviating neurodegeneration, neuroinflammation, and the pathologies associated with the accumulation of α-synuclein and Amyloid β proteins.
{"title":"Preparation of human astrocytes with potent therapeutic functions from human pluripotent stem cells using ventral midbrain patterning","authors":"Ye Rim Nam , Minji Kang , Minji Kim , Min Jong Seok , Yunseon Yang , Young Eun Han , Soo-Jin Oh , Do Gyeong Kim , Hyeon Son , Mi-Yoon Chang , Sang-Hun Lee","doi":"10.1016/j.jare.2024.03.012","DOIUrl":"10.1016/j.jare.2024.03.012","url":null,"abstract":"<div><h3>Introduction</h3><div>Astrocytes are glial-type cells that protect neurons from toxic insults and support neuronal functions and metabolism in a healthy brain. Leveraging these physiological functions, transplantation of astrocytes or their derivatives has emerged as a potential therapeutic approach for neurodegenerative disorders.</div></div><div><h3>Methods</h3><div>To substantiate the clinical application of astrocyte-based therapy, we aimed to prepare human astrocytes with potent therapeutic capacities from human pluripotent stem cells (hPSCs). To that end, we used ventral midbrain patterning during the differentiation of hPSCs into astrocytes, based on the roles of midbrain-specific factors in potentiating glial neurotrophic/anti-inflammatory activity. To assess the therapeutic effects of human midbrain-type astrocytes, we transplanted them into mouse models of Parkinson's disease (PD) and Alzheimer's disease (AD).</div></div><div><h3>Results</h3><div>Through a comprehensive series of <em>in-vitro</em> and <em>in-vivo</em> experiments, we were able to establish that the midbrain-type astrocytes exhibited the abilities to effectively combat oxidative stress, counter excitotoxic glutamate, and manage pathological protein aggregates. Our strategy for preparing midbrain-type astrocytes yielded promising results, demonstrating the strong therapeutic potential of these cells in various neurotoxic contexts. Particularly noteworthy is their efficacy in PD and AD-specific proteopathic conditions, in which the midbrain-type astrocytes outperformed forebrain-type astrocytes derived by the same organoid-based method.</div></div><div><h3>Conclusion</h3><div>The enhanced functions of the midbrain-type astrocytes extended to their ability to release signaling molecules that inhibited neuronal deterioration and senescence while steering microglial cells away from a pro-inflammatory state. This success was evident in both <em>in-vitro</em> studies using human cells and <em>in-vivo</em> experiments conducted in mouse models of PD and AD. In the end, our human midbrain-type astrocytes demonstrated remarkable effectiveness in alleviating neurodegeneration, neuroinflammation, and the pathologies associated with the accumulation of α-synuclein and Amyloid β proteins.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"69 ","pages":"Pages 181-196"},"PeriodicalIF":11.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140195368","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Autoimmune uveitis (AU) is a severe intraocular autoimmune disorder with a chronic disease course and a high rate of blindness. Kurarinone (KU), a major component of the traditional Chinese medicine Sophorae Flavescentis Radix, possesses a wide spectrum of activities and has been used to treat several inflammation-related diseases.
Objective
We aimed to investigate the effects of KU on AU and its modulatory mechanisms.
Methods
We used an experimental autoimmune uveitis (EAU) animal model and characterized the comprehensive immune landscape of KU-treated EAU mice using single-cell RNA sequencing (scRNA-seq). The retina and lymph nodes were analyzed. The siRNAs and selective inhibitors were used to study the signaling pathway. The effect of KU on peripheral blood mononuclear cells (PBMCs) from uveitis patients was also examined.
Results
We found that KU relieved chorioretinal lesions and immune cell infiltration in EAU model mice. Subsequent single-cell analysis revealed that KU downregulated the EAU-upregulated expression of inflammatory and autoimmune-related genes and suppressed pathways associated with immune cell differentiation, activation, and migration in a cell-specific manner. KU was implicated in restoring T helper 17 (Th17)/regulatory T (Treg) cell balance by alleviating inflammatory injury and elevating the expression of modulatory mediators in Tregs, while simultaneously ameliorating excessive inflammation by Th17 cells. Furthermore, Rac1 and the Id2/Pim1 axis potentiated the pathogenicity of Th17 cells during EAU, which was inhibited by KU treatment, contributing to the amelioration of EAU-induced inflammation and treatment of AU. In addition, KU suppressed inflammatory cytokine production in activated human PBMCs by inhibiting Rac1. Integration of the glucocorticoid-treated transcriptome suggests that KU has immunomodulatory effects on lymphocytes.
Conclusion
Our study constructed a high-resolution atlas of the immunoregulatory effects of KU treatment on EAU and identified its potential therapeutic mechanisms, which hold great promise in treating autoimmune disorders.
简介自身免疫性葡萄膜炎（AU）是一种严重的眼内自身免疫性疾病，病程慢性，致盲率高。Kurarinone (KU)是中药槐花的主要成分，具有广泛的活性，已被用于治疗多种炎症相关疾病：我们旨在研究 KU 对 AU 的影响及其调节机制：方法：我们使用实验性自身免疫性葡萄膜炎（EAU）动物模型，并使用单细胞RNA测序（scRNA-seq）表征了KU处理的EAU小鼠的综合免疫格局。对视网膜和淋巴结进行了分析。使用 siRNAs 和选择性抑制剂研究信号通路。我们还研究了 KU 对葡萄膜炎患者外周血单核细胞（PBMCs）的影响：结果：我们发现 KU 能缓解 EAU 模型小鼠的脉络膜视网膜病变和免疫细胞浸润。随后的单细胞分析表明，KU 下调了 EAU 上调的炎症和自身免疫相关基因的表达，并以细胞特异性的方式抑制了与免疫细胞分化、活化和迁移相关的通路。KU通过减轻炎症损伤和提高Tregs中调节介质的表达，同时改善Th17细胞的过度炎症，从而恢复T辅助细胞17（Th17）/调节性T（Treg）细胞的平衡。此外，Rac1和Id2/Pim1轴在EAU期间增强了Th17细胞的致病性，而KU治疗抑制了这种致病性，从而有助于改善EAU诱导的炎症和治疗AU。此外，KU 还能通过抑制 Rac1 抑制活化的人 PBMCs 中炎性细胞因子的产生。整合糖皮质激素处理的转录组表明，KU对淋巴细胞具有免疫调节作用：我们的研究构建了KU治疗对EAU免疫调节作用的高分辨率图谱，并确定了其潜在的治疗机制，这为治疗自身免疫性疾病带来了巨大希望。
{"title":"Kurarinone regulates Th17/Treg balance and ameliorates autoimmune uveitis via Rac1 inhibition","authors":"Chenyang Gu , Yidan Liu , Jianjie Lv , Chun Zhang , Zhaohao Huang , Qi Jiang , Yuehan Gao , Tianyu Tao , Yuhan Su , Binyao Chen , Renbing Jia , Xiuxing Liu , Wenru Su","doi":"10.1016/j.jare.2024.03.013","DOIUrl":"10.1016/j.jare.2024.03.013","url":null,"abstract":"<div><h3>Introduction</h3><div>Autoimmune uveitis (AU) is a severe intraocular autoimmune disorder with a chronic disease course and a high rate of blindness. Kurarinone (KU), a major component of the traditional Chinese medicine Sophorae Flavescentis Radix, possesses a wide spectrum of activities and has been used to treat several inflammation-related diseases.</div></div><div><h3>Objective</h3><div>We aimed to investigate the effects of KU on AU and its modulatory mechanisms.</div></div><div><h3>Methods</h3><div>We used an experimental autoimmune uveitis (EAU) animal model and characterized the comprehensive immune landscape of KU-treated EAU mice using single-cell RNA sequencing (scRNA-seq). The retina and lymph nodes were analyzed. The siRNAs and selective inhibitors were used to study the signaling pathway. The effect of KU on peripheral blood mononuclear cells (PBMCs) from uveitis patients was also examined.</div></div><div><h3>Results</h3><div>We found that KU relieved chorioretinal lesions and immune cell infiltration in EAU model mice. Subsequent single-cell analysis revealed that KU downregulated the EAU-upregulated expression of inflammatory and autoimmune-related genes and suppressed pathways associated with immune cell differentiation, activation, and migration in a cell-specific manner. KU was implicated in restoring T helper 17 (Th17)/regulatory T (Treg) cell balance by alleviating inflammatory injury and elevating the expression of modulatory mediators in Tregs, while simultaneously ameliorating excessive inflammation by Th17 cells. Furthermore, Rac1 and the Id2/Pim1 axis potentiated the pathogenicity of Th17 cells during EAU, which was inhibited by KU treatment, contributing to the amelioration of EAU-induced inflammation and treatment of AU. In addition, KU suppressed inflammatory cytokine production in activated human PBMCs by inhibiting Rac1. Integration of the glucocorticoid-treated transcriptome suggests that KU has immunomodulatory effects on lymphocytes.</div></div><div><h3>Conclusion</h3><div>Our study constructed a high-resolution atlas of the immunoregulatory effects of KU treatment on EAU and identified its potential therapeutic mechanisms, which hold great promise in treating autoimmune disorders.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"69 ","pages":"Pages 381-398"},"PeriodicalIF":11.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140208721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-01DOI: 10.1016/j.jare.2024.03.028
Liangchun Li , Renlin Zheng , Rongqin Sun
Background
The construction of gels from low molecular weight gelators (LMWG) has been extensively studied in the fields of bio-nanotechnology and other fields. However, the understanding gaps still prevent the prediction of LMWG from the full design of those gel systems. Gels with multicomponent become even more complicated because of the multiple interference effects coexist in the composite gel systems.
Aim of review
This review emphasizes systems view on the understanding of multicomponent low molecular weight gels (MLMWGs), and summarizes recent progress on the construction of desired networks of MLMWGs, including self-sorting and co-assembly, as well as the challenges and approaches to understanding MLMWGs, with the hope that the opportunities from natural products and peptides can speed up the understanding process and close the gaps between the design and prediction of structures.
Key scientific concepts of review
This review is focused on three key concepts. Firstly, understanding the complicated multicomponent gels systems requires a systems perspective on MLMWGs. Secondly, several protocols can be applied to control self-sorting and co-assembly behaviors in those multicomponent gels system, including the certain complementary structures, chirality inducing and dynamic control. Thirdly, the discussion is anchored in challenges and strategies of understanding MLMWGs, and some examples are provided for the understanding of multicomponent gels constructed from small natural products and subtle designed short peptides.
{"title":"Understanding multicomponent low molecular weight gels from gelators to networks","authors":"Liangchun Li , Renlin Zheng , Rongqin Sun","doi":"10.1016/j.jare.2024.03.028","DOIUrl":"10.1016/j.jare.2024.03.028","url":null,"abstract":"<div><h3>Background</h3><div>The construction of gels from low molecular weight gelators (LMWG) has been extensively studied in the fields of bio-nanotechnology and other fields. However, the understanding gaps still prevent the prediction of LMWG from the full design of those gel systems. Gels with multicomponent become even more complicated because of the multiple interference effects coexist in the composite gel systems.</div></div><div><h3>Aim of review</h3><div>This review emphasizes systems view on the understanding of multicomponent low molecular weight gels (MLMWGs), and summarizes recent progress on the construction of desired networks of MLMWGs, including self-sorting and co-assembly, as well as the challenges and approaches to understanding MLMWGs, with the hope that the opportunities from natural products and peptides can speed up the understanding process and close the gaps between the design and prediction of structures.</div></div><div><h3>Key scientific concepts of review</h3><div>This review is focused on three key concepts. Firstly, understanding the complicated multicomponent gels systems requires a systems perspective on MLMWGs. Secondly, several protocols can be applied to control self-sorting and co-assembly behaviors in those multicomponent gels system, including the certain complementary structures, chirality inducing and dynamic control. Thirdly, the discussion is anchored in challenges and strategies of understanding MLMWGs, and some examples are provided for the understanding of multicomponent gels constructed from small natural products and subtle designed short peptides.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"69 ","pages":"Pages 91-106"},"PeriodicalIF":11.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140343608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-01DOI: 10.1016/j.jare.2024.03.025
Yisheng Chen , Xiaofeng Chen , Zhiwen Luo , Xueran Kang , Yunshen Ge , Renwen Wan , Qian Wang , Zhihua Han , Fangqi Li , Zhongcheng Fan , Yuchun Xie , Beijie Qi , Xintao Zhang , Zhenwei Yang , John H Zhang , Danping Liu , Yuzhen Xu , Dongyan Wu , Shiyi Chen
Introduction
Alzheimer's Disease (AD), a progressive neurodegenerative disorder, is marked by cognitive deterioration and heightened neuroinflammation. The influence of Insulin-like Growth Factor 1 Receptor (IGF1R) and its post-translational modifications, especially sumoylation, is crucial in understanding the progression of AD and exploring novel therapeutic avenues.
Objectives
This study investigates the impact of exercise on the sumoylation of IGF1R and its role in ameliorating AD symptoms in APP/PS1 mice, with a specific focus on neuroinflammation and innovative therapeutic strategies.
Methods
APP/PS1 mice were subjected to a regimen of moderate-intensity exercise. The investigation encompassed assessments of cognitive functions, alterations in hippocampal protein expressions, neuroinflammatory markers, and the effects of exercise on IGF1R and SUMO1 nuclear translocation. Additionally, the study evaluated the efficacy of KPT-330, a nuclear export inhibitor, as an alternative to exercise.
Results
Exercise notably enhanced cognitive functions in AD mice, possibly through modulations in hippocampal proteins, including Bcl-2 and BACE1. A decrease in neuroinflammatory markers such as IL-1β, IL-6, and TNF-α was observed, indicative of reduced neuroinflammation. Exercise modulated the nuclear translocation of SUMO1 and IGF1R in the hippocampus, thereby facilitating neuronal regeneration. Mutant IGF1R (MT IGF1R), lacking SUMO1 modification sites, showed reduced SUMOylation, leading to diminished expression of pro-inflammatory cytokines and apoptosis. KPT-330 impeded the formation of the IGF1R/RanBP2/SUMO1 complex, thereby limiting IGF1R nuclear translocation, inflammation, and neuronal apoptosis, while enhancing cognitive functions and neuron proliferation.
Conclusion
Moderate-intensity exercise effectively mitigates AD symptoms in mice, primarily by diminishing neuroinflammation, through the reduction of IGF1R Sumoylation. KPT-330, as a potential alternative to physical exercise, enhances the neuroprotective role of IGF1R by inhibiting SUMOylation through targeting XPO1, presenting a promising therapeutic strategy for AD.
{"title":"Exercise-Induced Reduction of IGF1R Sumoylation Attenuates Neuroinflammation in APP/PS1 Transgenic Mice","authors":"Yisheng Chen , Xiaofeng Chen , Zhiwen Luo , Xueran Kang , Yunshen Ge , Renwen Wan , Qian Wang , Zhihua Han , Fangqi Li , Zhongcheng Fan , Yuchun Xie , Beijie Qi , Xintao Zhang , Zhenwei Yang , John H Zhang , Danping Liu , Yuzhen Xu , Dongyan Wu , Shiyi Chen","doi":"10.1016/j.jare.2024.03.025","DOIUrl":"10.1016/j.jare.2024.03.025","url":null,"abstract":"<div><h3>Introduction</h3><div>Alzheimer's Disease (AD), a progressive neurodegenerative disorder, is marked by cognitive deterioration and heightened neuroinflammation. The influence of Insulin-like Growth Factor 1 Receptor (IGF1R) and its post-translational modifications, especially sumoylation, is crucial in understanding the progression of AD and exploring novel therapeutic avenues.</div></div><div><h3>Objectives</h3><div>This study investigates the impact of exercise on the sumoylation of IGF1R and its role in ameliorating AD symptoms in APP/PS1 mice, with a specific focus on neuroinflammation and innovative therapeutic strategies.</div></div><div><h3>Methods</h3><div>APP/PS1 mice were subjected to a regimen of moderate-intensity exercise. The investigation encompassed assessments of cognitive functions, alterations in hippocampal protein expressions, neuroinflammatory markers, and the effects of exercise on IGF1R and SUMO1 nuclear translocation. Additionally, the study evaluated the efficacy of KPT-330, a nuclear export inhibitor, as an alternative to exercise.</div></div><div><h3>Results</h3><div>Exercise notably enhanced cognitive functions in AD mice, possibly through modulations in hippocampal proteins, including Bcl-2 and BACE1. A decrease in neuroinflammatory markers such as IL-1β, IL-6, and TNF-α was observed, indicative of reduced neuroinflammation. Exercise modulated the nuclear translocation of SUMO1 and IGF1R in the hippocampus, thereby facilitating neuronal regeneration. Mutant IGF1R (MT IGF1R), lacking SUMO1 modification sites, showed reduced SUMOylation, leading to diminished expression of pro-inflammatory cytokines and apoptosis. KPT-330 impeded the formation of the IGF1R/RanBP2/SUMO1 complex, thereby limiting IGF1R nuclear translocation, inflammation, and neuronal apoptosis, while enhancing cognitive functions and neuron proliferation.</div></div><div><h3>Conclusion</h3><div>Moderate-intensity exercise effectively mitigates AD symptoms in mice, primarily by diminishing neuroinflammation, through the reduction of IGF1R Sumoylation. KPT-330, as a potential alternative to physical exercise, enhances the neuroprotective role of IGF1R by inhibiting SUMOylation through targeting XPO1, presenting a promising therapeutic strategy for AD.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"69 ","pages":"Pages 279-297"},"PeriodicalIF":11.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140399653","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-01DOI: 10.1016/j.jare.2024.04.001
Ling Yan , Yaqi Cao , Linhai Hou , Tianyu Luo , Meiqi Li , Shengjie Gao , Lei Wang , Kangliang Sheng , Lei Zheng
Introduction
MicroRNAs (miRNAs) involve in destabilising messenger RNA or repressing translation of target molecules. Ginger-derived exosome-like nanoparticles (GELNs) play a crucial role in modulating intestinal inflammation. Moreover, GELNs contain highly heterogeneous miRNA. However, the role of miRNAs derived from GELNs in immunomodulation remains unclear.
Objectives
This study aimed to elucidate the molecular basis of the unique biological effects mediated by miRNA derived from GELNs on macrophages.
Methods
GELNs were isolated using a combination of commercial exosome isolation kits and the differential centrifugation method, and the lipid composition of GELNs was determined using liquid chromatography-mass spectrometry. Subsequently, PKH26 labelled GELNs were taken up by macrophages. Furthermore, the modulation of inflammatory and immune responses by GELNs or osa-miR164d was assessed through the RNA-seq, RT-qPCR, online databases, and dual luciferase reporter assays to explore the underlying mechanisms of osa-miR164d. Biomimetic exosomes loaded with osa-miR164d were prepared using a microfluidic mixing device and systematically characterized. The therapeutic effects of osa-miR164d on relieving colitis were evaluated.
Results
We report for the first time that GELNs-derived osa-miR164d is a regulatory factor of reprogramming macrophage polarization, thereby inhibiting the intestinal inflammatory response. Mechanistically, osa-miR164d directly targets the 3′-UTRs of TAB1, which regulates macrophage polarization through the downregulation of NF-κB expression. In addition, We have designed a biomimetic exosome mimicking GELNs to deliver osa-miR164d (osa-miR164d-MGELNs). Notably, the osa-miR164d-MGELNs can efficiently reprogram macrophages to alleviate colitis-related symptoms.
Conclusion
Our findings enhance the systematic understanding of how GELNs-derived osa-miR164d mediates cross-kingdom communication and provide an original engineering paradigm for mimicking GELNs to transfer miRNA.
{"title":"Ginger exosome-like nanoparticle-derived miRNA therapeutics: A strategic inhibitor of intestinal inflammation","authors":"Ling Yan , Yaqi Cao , Linhai Hou , Tianyu Luo , Meiqi Li , Shengjie Gao , Lei Wang , Kangliang Sheng , Lei Zheng","doi":"10.1016/j.jare.2024.04.001","DOIUrl":"10.1016/j.jare.2024.04.001","url":null,"abstract":"<div><h3>Introduction</h3><div>MicroRNAs (miRNAs) involve in destabilising messenger RNA or repressing translation of target molecules. Ginger-derived exosome-like nanoparticles (GELNs) play a crucial role in modulating intestinal inflammation. Moreover, GELNs contain highly heterogeneous miRNA. However, the role of miRNAs derived from GELNs in immunomodulation remains unclear.</div></div><div><h3>Objectives</h3><div>This study aimed to elucidate the molecular basis of the unique biological effects mediated by miRNA derived from GELNs on macrophages.</div></div><div><h3>Methods</h3><div>GELNs were isolated using a combination of commercial exosome isolation kits and the differential centrifugation method, and the lipid composition of GELNs was determined using liquid chromatography-mass spectrometry. Subsequently, PKH26 labelled GELNs were taken up by macrophages. Furthermore, the modulation of inflammatory and immune responses by GELNs or osa-miR164d was assessed through the RNA-seq, RT-qPCR, online databases, and dual luciferase reporter assays to explore the underlying mechanisms of osa-miR164d. Biomimetic exosomes loaded with osa-miR164d were prepared using a microfluidic mixing device and systematically characterized. The therapeutic effects of osa-miR164d on relieving colitis were evaluated.</div></div><div><h3>Results</h3><div>We report for the first time that GELNs-derived osa-miR164d is a regulatory factor of reprogramming macrophage polarization, thereby inhibiting the intestinal inflammatory response. Mechanistically, osa-miR164d directly targets the 3′-UTRs of TAB1, which regulates macrophage polarization through the downregulation of NF-κB expression. In addition, We have designed a biomimetic exosome mimicking GELNs to deliver osa-miR164d (osa-miR164d-MGELNs). Notably, the osa-miR164d-MGELNs can efficiently reprogram macrophages to alleviate colitis-related symptoms.</div></div><div><h3>Conclusion</h3><div>Our findings enhance the systematic understanding of how GELNs-derived osa-miR164d mediates cross-kingdom communication and provide an original engineering paradigm for mimicking GELNs to transfer miRNA.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"69 ","pages":"Pages 1-15"},"PeriodicalIF":11.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140604240","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-01DOI: 10.1016/j.jare.2024.04.002
Bin Liu , Ihtisham Bukhari , Fazhan Li , Feifei Ren , Xue Xia , Baitong Hu , Haipeng Liu , Thomas F Meyer , Barry J. Marshall , Alfred Tay , Yuming Fu , Wanqing Wu , Youcai Tang , Yang Mi , Peng-Yuan Zheng
Introduction
Helicobacter pylori (H. pylori) infection has been associated with gastric carcinogenesis. However, the precise involvement of LRP8, the low-density lipoprotein receptor-related protein 8, in H. pylori pathogenesis and gastric cancer (GC) remains poorly understood.
Objectives
To investigate the potential role of LRP8 in H. pylori infection and gastric carcinogenesis.
Methods
Three-dimensional human-derived gastric organoids (hGO) and gastric cancer organoids (hGCO) were synthesized from the tissues obtained from human donors. In this work, multi-omics combined with in vivo and in vitro studies were conducted to investigate the potential involvement of LRP8 in H. pylori-induced GC.
Results
We found that H. pylori infection significantly upregulated the expression of LRP8 in human GC tissues, cells, organoids, and mouse gastric mucous. In particular, LRP8 exhibited a distinct enrichment in cancer stem cells (CSC). Functionally, silencing of LRP8 affected the formation and proliferation of tumor spheroids, while increased expression of LRP8 was associated with increased proliferation and stemness of GC cells and organoids. Mechanistically, LRP8 promotes the binding of E-cadherin to β-catenin, thereby promoting nuclear translocation and transcriptional activity of β-catenin. Furthermore, LRP8 interacts with the cytotoxin-associated gene A (CagA) to form the CagA/LRP8/β-catenin complex. This complex further amplifies H. pylori-induced β-catenin nuclear translocation, leading to increased transcription of inflammatory factors and CSC markers. Clinical analysis demonstrated that abnormal overexpression of LRP8 is correlated with a poor prognosis and resistance to 5-Fluorouracil in patients with GC.
Conclusion
Our findings provide valuable information on the molecular intricacies of H. pylori-induced gastric carcinogenesis, offering potential therapeutic targets and prognostic markers for GC.
{"title":"Enhanced LRP8 expression induced by Helicobacter pylori drives gastric cancer progression by facilitating β-Catenin nuclear translocation","authors":"Bin Liu , Ihtisham Bukhari , Fazhan Li , Feifei Ren , Xue Xia , Baitong Hu , Haipeng Liu , Thomas F Meyer , Barry J. Marshall , Alfred Tay , Yuming Fu , Wanqing Wu , Youcai Tang , Yang Mi , Peng-Yuan Zheng","doi":"10.1016/j.jare.2024.04.002","DOIUrl":"10.1016/j.jare.2024.04.002","url":null,"abstract":"<div><h3>Introduction</h3><div><em>Helicobacter pylori (H. pylori)</em> infection has been associated with gastric carcinogenesis. However, the precise involvement of LRP8, the low-density lipoprotein receptor-related protein 8, in <em>H. pylori</em> pathogenesis and gastric cancer (GC) remains poorly understood.</div></div><div><h3>Objectives</h3><div>To investigate the potential role of LRP8 in <em>H. pylori</em> infection and gastric carcinogenesis.</div></div><div><h3>Methods</h3><div>Three-dimensional human-derived gastric organoids (hGO) and gastric cancer organoids (hGCO) were synthesized from the tissues obtained from human donors. In this work, multi-omics combined with <em>in vivo and in vitro</em> studies were conducted to investigate the potential involvement of LRP8 in <em>H. pylori-</em>induced GC.</div></div><div><h3>Results</h3><div>We found that <em>H. pylori</em> infection significantly upregulated the expression of LRP8 in human GC tissues, cells, organoids, and mouse gastric mucous. In particular, LRP8 exhibited a distinct enrichment in cancer stem cells (CSC). Functionally, silencing of LRP8 affected the formation and proliferation of tumor spheroids, while increased expression of LRP8 was associated with increased proliferation and stemness of GC cells and organoids. Mechanistically, LRP8 promotes the binding of E-cadherin to β-catenin, thereby promoting nuclear translocation and transcriptional activity of β-catenin. Furthermore, LRP8 interacts with the cytotoxin-associated gene A (CagA) to form the CagA/LRP8/β-catenin complex. This complex further amplifies <em>H. pylori</em>-induced β-catenin nuclear translocation, leading to increased transcription of inflammatory factors and CSC markers. Clinical analysis demonstrated that abnormal overexpression of LRP8 is correlated with a poor prognosis and resistance to 5-Fluorouracil in patients with GC.</div></div><div><h3>Conclusion</h3><div>Our findings provide valuable information on the molecular intricacies of <em>H. pylori</em>-induced gastric carcinogenesis, offering potential therapeutic targets and prognostic markers for GC.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"69 ","pages":"Pages 299-312"},"PeriodicalIF":11.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140772557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
With prevalence of chronic kidney disease (CKD) in worldwide, the strategies to recover renal function via tissue regeneration could provide alternatives to kidney replacement therapies. However, due to relatively low reproducibility of renal basal cells and limited bioactivities of implanted biomaterials along with the high probability of substance-inducible inflammation and immunogenicity, kidney tissue regeneration could be challenging.
Objectives
To exclude various side effects from cell transplantations, in this study, we have induced extracellular vesicles (EVs) incorporated cell-free hybrid PMEZ scaffolds.
Methods
Hybrid PMEZ scaffolds incorporating essential bioactive components, such as ricinoleic acid grafted Mg(OH)2 (M), extracellular matrix (E), and alpha lipoic acid-conjugated ZnO (Z) based on biodegradable porous PLGA (P) platform was successfully manufactured. Consecutively, for functional improvements, melatonin-modulated extracellular vesicles (mEVs), derived from the human umbilical cord MSCs in chemically defined media without serum impurities, were also loaded onto PMEZ scaffolds to construct the multiplexed PMEZ/mEV scaffold.
Results
With functionalities of Mg(OH)2 and extracellular matrix-loaded PLGA scaffolds, the continuous nitric oxide-releasing property of modified ZnO and remarkably upregulated regenerative functionalities of mEVs showed significantly enhanced kidney regenerative activities. Based on these, the structural and functional restoration has been practically achieved in 5/6 nephrectomy mouse models that mimicked severe human CKD.
Conclusion
Our study has proved the combinatory bioactivities of the biodegradable PLGA-based multiplexed scaffold for kidney tissue regeneration in 5/6 nephrectomy mouse representing a severe CKD model. The optimal microenvironments for the morphogenetic formations of renal tissues and functional restorations have successfully achieved the combinatory bioactivities of remarkable components for PMEZ/mEV, which could be a promising therapeutic alternative for CKD treatment.
{"title":"Multiplexed PLGA scaffolds with nitric oxide-releasing zinc oxide and melatonin-modulated extracellular vesicles for severe chronic kidney disease","authors":"Won-Kyu Rhim , Jiwon Woo , Jun Yong Kim , Eun Hye Lee , Seung-Gyu Cha , Da-Seul Kim , Seung-Woon Baek , Chun Gwon Park , Bum Soo Kim , Tae Gyun Kwon , Dong Keun Han","doi":"10.1016/j.jare.2024.03.018","DOIUrl":"10.1016/j.jare.2024.03.018","url":null,"abstract":"<div><h3>Introduction</h3><div>With prevalence of chronic kidney disease (CKD) in worldwide, the strategies to recover renal function <em>via</em> tissue regeneration could provide alternatives to kidney replacement therapies. However, due to relatively low reproducibility of renal basal cells and limited bioactivities of implanted biomaterials along with the high probability of substance-inducible inflammation and immunogenicity, kidney tissue regeneration could be challenging.</div></div><div><h3>Objectives</h3><div>To exclude various side effects from cell transplantations, in this study, we have induced extracellular vesicles (EVs) incorporated cell-free hybrid PMEZ scaffolds.</div></div><div><h3>Methods</h3><div>Hybrid PMEZ scaffolds incorporating essential bioactive components, such as ricinoleic acid grafted Mg(OH)<sub>2</sub> (M), extracellular matrix (E), and alpha lipoic acid-conjugated ZnO (Z) based on biodegradable porous PLGA (P) platform was successfully manufactured. Consecutively, for functional improvements, melatonin-modulated extracellular vesicles (mEVs), derived from the human umbilical cord MSCs in chemically defined media without serum impurities, were also loaded onto PMEZ scaffolds to construct the multiplexed PMEZ/mEV scaffold.</div></div><div><h3>Results</h3><div>With functionalities of Mg(OH)<sub>2</sub> and extracellular matrix-loaded PLGA scaffolds, the continuous nitric oxide-releasing property of modified ZnO and remarkably upregulated regenerative functionalities of mEVs showed significantly enhanced kidney regenerative activities. Based on these, the structural and functional restoration has been practically achieved in 5/6 nephrectomy mouse models that mimicked severe human CKD.</div></div><div><h3>Conclusion</h3><div>Our study has proved the combinatory bioactivities of the biodegradable PLGA-based multiplexed scaffold for kidney tissue regeneration in 5/6 nephrectomy mouse representing a severe CKD model. The optimal microenvironments for the morphogenetic formations of renal tissues and functional restorations have successfully achieved the combinatory bioactivities of remarkable components for PMEZ/mEV, which could be a promising therapeutic alternative for CKD treatment.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"69 ","pages":"Pages 75-89"},"PeriodicalIF":11.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140308373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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