CELL BIOCHEMISTRY AND FUNCTION
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2024
·Vol. 42
·期 3
·e4005
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IF 2.8
Nannan Ding,Shanyue Sun,Shuting Zhou,Zhimei Lv,Rong Wang
Tubulointerstitial fibrosis is an inevitable consequence of all progressive chronic kidney disease (CKD) and contributes to a substantial health burden worldwide. Icariin, an active flavonoid glycoside obtained from Epimedium species, exerts potential antifibrotic effect. The study aimed to explore the protective effects of icariin against tubulointerstitial fibrosis in unilateral ureteral obstruction (UUO)-induced CKD mice and TGF-β1-treated HK-2 cells, and furthermore, to elucidate the underlying mechanisms. The results demonstrated that icariin significantly improved renal function, alleviated tubular injuries, and reduced fibrotic lesions in UUO mice. Furthermore, icariin suppressed renal inflammation, reduced oxidative stress as evidenced by elevated superoxide dismutase activity and decreased malondialdehyde level. Additionally, TOMM20 immunofluorescence staining and transmission electron microscope revealed that mitochondrial mass and morphology of tubular epithelial cells in UUO mice was restored by icariin. In HK-2 cells treated with TGF-β1, icariin markedly decreased profibrotic proteins expression, inhibited inflammatory factors, and protected mitochondria along with preserving mitochondrial morphology, reducing reactive oxygen species (ROS) and mitochondrial ROS (mtROS) overproduction, and preserving membrane potential. Further investigations demonstrated that icariin could activate nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway both in vivo and in vitro, whereas inhibition of Nrf2 by ML385 counteracted the protective effects of icariin on TGF-β1-induced HK-2 cells. In conclusion, icariin protects against renal inflammation and tubulointerstitial fibrosis at least partly through Nrf2-mediated attenuation of mitochondrial dysfunction, which suggests that icariin could be developed as a promising therapeutic candidate for the treatment of CKD. Significance statement Tubulointerstitial fibrosis is an unavoidable consequence of advancing chronic kidney disease (CKD) and imposes a substantial global health burden. However, few effective therapeutic agents are available at present. The present study investigated the ameliorative effects of icariin on tubulointerstitial fibrosis (TIF) both in vivo and in vitro, and demonstrated that icariin inhibited inflammation and oxidative stress, at least partially, through improving Nrf2 activity and subsequent mitochondrial function, and eventually mitigated TIF and preserved renal function, suggesting that icariin could be developed as a promising therapeutic candidate for the treatment of CKD.
研究领域:
药理学
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肾脏生理学
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Biomaterials Science
·
2024
·
IF 5.8
Qin Wang,Xuedan Nie,Yifan Song,Haiyan Qiu,Liting Chen,He Zhu,Xueli Zhang,Mengru Yang,Xiaohui Xu,Peidan Chen,Chao Zhang,Jia Xu,Yeping Ren,Wenting Shang
Immune-mediated glomerular diseases lead to chronic kidney disease (CKD), primarily through mechanisms such as immune cell overactivation, mitochondrial dysfunction and imbalance of reactive oxygen species (ROS). We have developed an ultra-small nanodrug composed of Mn3O4 nanoparticles which is functionalized with biocompatible ligand citrate (C-Mn3O4 NPs) to maintain cellular redox balance in an animal model of oxidative injury. Furthermore, this ultra-small nanodrug, loaded with tacrolimus (Tac), regulated the activity of immune cells. We established a doxorubicin (DOX)-induced CKD model in SD rats using conditions of oxidative distress. The results demonstrate the ROS scavenging capability of Mn3O4 NPs, which mimics enzymatic activity, and the immunosuppressive effect of tacrolimus. This combination promotes targeted accumulation in the renal region with sustained drug release through the enhanced permeability and retention (EPR) effect. Tac@C-Mn3O4 protects the structural and functional integrity of mitochondria from oxidative damage while eliminating excess ROS to maintain cellular redox homeostasis, thereby suppressing the overexpression of pro-inflammatory cytokines to restore kidney function and preserve a normal kidney structure, reducing inflammation and regulating antioxidant stress pathways. This dual-pronged treatment strategy also provides novel strategies for CKD management and demonstrates substantial potential for clinical translational application.
研究领域:
纳米医学
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药理学
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免疫学
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肾脏生理学
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氧化应激研究
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产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2024
·
IF 13.3
Qiqi Wang,Changjun Mu,Ya'nan Yu,Xia Feng,Yang He,Li Chen
Current patients with chronic kidney disease (CKD) suffer from either accumulation of advanced glycation end products (AGEs) or inefficient clearance of the middle molecule uremic toxins, threatening their long-term survival rate. In particular, conventional hemodialysis membranes cannot prevent AGEs formation because of continuous oxidative stress from reactive oxygen species (ROS). Herein, a persistent ROS scavenging and efficient uremic toxin clearance of hemodialysis membrane is proposed by the in situ deposition of a gallic acid-Ti 3 C 2 T x MXene (GA-MXene) n multilayers through a self-assembly method, where n denotes the number of deposition layers. These hemodialysis membranes have a highly interconnecting composite laminate with tunable pore size. In the dialysis experiment, the (GA-MXene) 2 membrane with the vertical nano-slits shows the highest middle molecule uremic toxin clearance of 80.0% compared with state-of-the-art hemodialysis membranes, which has been approximately equal to the clearance of small molecule urea. Furthermore, GA conferring efficient ROS scavenging rate over dialysis treatment time allows anti-oxidative activities to inhibit AGEs’ formation. (GA-MXene) n multilayers enhanced the serum total antioxidant capacity and suppressed lipid peroxidation from oxidative damage. Ultimately, the (GA-MXene) n hemodialysis membranes provide excellent anticoagulant properties and cytocompatibility through the heparin-mimicking sulfonated Ti 3 C 2 T x MXene and biological activity of GA. This work facilitates the blood purification application of MXenes and opens up an avenue for developing functional multilayers for high-performance hemodialysis membranes and beyond.
研究领域:
材料科学
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生物医学工程
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纳米技术
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肾脏医学
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产品关联
DOI
高影响因子
Advanced Healthcare Materials
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2023
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IF 10
Qianqian Wu,Lu Yang,Ling Zou,Wang Yang,Qingshan Liu,Anwei Zhang,Jiang Cao,Guangyou Shi,Jian He,Xiaochao Yang
The over production of reactive oxygen species (ROS) plays a critical role in the progression of chronic kidney disease (CKD). Organic ROS scavengers currently used for CKD treatment do not satisfy low dosage and high efficiency requirements. Ceria nanomaterials featured with renewable ROS scavenging activity are potential candidates for CKD treatment. Herein, a method for the synthesis of ceria nanoclusters (NCs) featured with small size of ≈1.2 nm is reported. The synthesized NCs are modified by three hydrophilic ligands with different molecular weights, including succinic acid (SA), polyethylene glycol diacid 600 (PEG600), and polyethylene glycol diacid 2000 (PEG2000). The surface modified NCs exhibit excellent ROS scavenging activity due to the high Ce 3+ /Ce 4+ ratio in their crystal structures. Compared with bigger-sized ceria nanoparticles (NPs) (≈45 nm), NCs demonstrate smoother blood concentration-time curve, lower organ accumulation, and faster metabolic rate superiorities. The administration of NCs to CKD mice, especially PEG600 and PEG2000 modified NCs, can effectively inhibit oxidative stress, inflammation, renal fibrosis, and apoptosis in their kidneys. Due to these benefits, the constructed NCs can ameliorate the progression of CKD. These findings suggest that NCs is a potential redox nanomedicine for future clinical treatment of CKD.
研究领域:
纳米技术
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药学
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肾病学
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
LABORATORY INVESTIGATION
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2023
·
IF 5
Rui Yu,Yan Wu,Ping He,Yu Bai,Yongzhe Zhang,Xiaohui Bian,Guangping Sun,Beiru Zhang
Renal fibrosis is the major pathologic manifestation of chronic kidney disease (CKD). LIM and cysteine-rich domains 1 (LMCD1) is upregulated in the kidney tissue from patients with CKD and the transforming growth factor β1 (TGF-β1)–treated human renal tubular epithelial cell line human kidney 2 (HK-2) (Gene Expression Omnibus: GSE66494 and GSE23338). Previously, we have demonstrated that the knockdown of LMCD1 ameliorated renal fibrosis in mice by blocking the activation of the extracellular signal-regulated kinase pathway. In this study, we sought to further investigate whether LMCD1 affects TGF-β1–induced epithelial–mesenchymal transition (EMT) of kidney tubular epithelial cells and its potential role in the TGF-β1/Smad signaling pathway. First, we confirmed that LMCD1 expression was increased in the fibrotic kidneys of patients with CKD compared with that in normal kidneys and that LMCD1 was predominantly localized in the renal tubules. LMCD1 and mesenchymal markers were upregulated in obstructed kidney tissues of mice at 21 days after unilateral ureteral obstruction surgery compared with the tissues in sham mice. Next, we demonstrated that TGF-β1 significantly increased LMCD1 expression through Smad-mediated transcription in HK-2 cells in vitro. In turn, LMCD1 acted as a transcriptional coactivator of E2F transcription factor 1 to promote the transcription of TGF-β1 . Moreover, TGF-β1 increased the interaction between LMCD1 and Smad ubiquitination regulatory factor 2 (Smurf2) and accelerated Smurf2-mediated LMCD1 degradation via the ubiquitination system. The knockdown of LMCD1 inhibited TGF-β1–induced EMT in both HK-2 cells and unilateral ureteral obstruction mice. Our results indicate a positive feedback loop between TGF-β1 and LMCD1 for EMT induction in HK-2 cells and that Smurf2 acts as a negative regulator in this process by accelerating LMCD1 degradation.
研究领域:
肾病学
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细胞生物学
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分子生物学
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病理学
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产品关联
DOI
PubMed
高影响因子
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