Theranostics
·
2024
·Vol. 14
·期 19
·7534
·
IF 12.4
Wenfang He,Chenguang Ding,Ting Lin,Binqi Wang,Wenjing Wang,Zhichao Deng,Taian Jin,Yiwei Shang,Danna Zheng,Ting Bai,Mingzhen Zhang,Runqing Li,Juan Jin,Qiang He
Rationale : Ischemia-reperfusion-induced acute kidney injury (IR-AKI), characterized by the abrupt decline in renal function, is distinguished by the intricate interplay between oxidative stress and inflammation. In this study, a reactive oxygen species (ROS) scavenger-CF@PDA was developed to effectively target antioxidant and anti-inflammatory pathways to disrupt the oxidative stress-inflammation cycle in IR-AKI. Methods : UV-vis absorption spectra, FTIR spectra, and TEM were employed to determine the successful construction of CF@P. ABTS, TMB, and NBT analyses were performed to detect the antioxidant ability and enzyme-mimicking ability of CF@P. In vitro and in vitro , the antioxidant/anti-inflammatory effect of CF@P was detected by MTT, qPCR, fluorescence, and flow cytometry. Multi-omics revealed the mechanism of CF@P in IR-AKI therapy, and molecular docking was further used to determine the mechanism. MRI and photoacoustic imaging were employed to explore the dual-mode imaging capacity of CF@P in IR-AKI management. Results : CF@P could disrupt the oxidative stress-inflammatory cascade by scavenging ROS, reducing pro-inflammatory cytokines, and modulation of macrophage polarization. Subsequent multi-omics indicated that the renal protective effects may be attributed to the inhibition of pyruvate dehydrogenase kinase 4 (PDK4). Metabolomics demonstrated that CF@P could improve the production of antioxidant compounds and reduce nephrotoxicity. Additionally, CF@P exhibited promising capabilities in T1-MRI and photoacoustic imaging for AKI management. Conclusions : Collectively, CF@P, possessing antioxidant/anti-inflammatory properties by inhibiting PDK4, as well as imaging capabilities and superior biocompatibility, holds promise as a therapeutic strategy for IR-AKI.
研究领域:
医学
·
药理学
·
生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Advanced Research
·
2026
·
IF 17.1
Jiaxin Su,Lingcheng Wu,Huiru Zhu,Haoru Wang,Xiaoya He,Bing Liang,Jinhua Cai
Introduction Acute kidney injury (AKI) is a devastating global health burden. Its pathogenesis, particularly in ischemia/reperfusion (I/R) injury, centers on a vicious cycle between a reactive oxygen species (ROS)-driven inflammatory storm and severe mitochondrial dysfunction in renal tubular cells. While activation of the SIRT1/PGC-1α pathway is a promising therapeutic target for mitochondrial recovery, its potent agonist resveratrol (Rsv) suffers from poor bioavailability, and monotherapy fails to address the concomitant inflammatory pathology. Objective This study aimed to develop a kidney-targeted theranostic nanoplatform that synergistically breaks this pathological cycle. We hypothesized that a nanoplatform co-delivering Rsv and a ROS-scavenging component could concurrently suppress inflammation via direct ROS elimination and restore mitochondrial homeostasis via SIRT1/PGC-1α activation, with integrated magnetic resonance imaging (MRI) capability for monitoring. Methods We engineered a theranostic nanoplatform designated Rsv@HMnO 2 -HA (HMRH NPs). The platform was constructed by loading Rsv into hollow mesoporous manganese dioxide (HMnO 2 ) nanozymes, followed by surface coating with hyaluronic acid (HA) for active targeting to CD44 receptors over expressed on injured renal tubules. The system’s physicochemical properties were thoroughly characterized. Its therapeutic efficacy and theranostic performance were systematically evaluated in a well-established murine model of renal I/R-induced AKI, using a combination of biochemical assays, histological analysis, molecular biology techniques, and in vivo MRI. Results HMRH NPs successfully accumulated in injured kidneys and disassembled in situ. The HMnO 2 shell effectively scavenged excess ROS, attenuating the inflammatory response. The co-released Rsv activated the SIRT1/PGC-1α pathway, restored mitochondrial biogenesis, and improved cellular energy homeostasis. The released Mn 2+ ions enabled clear T 1 -weighted MRI contrast, allowing real-time visualization of renal targeting and therapeutic progression. Conclusion The results conclusively demonstrate that the HMRH NPs successfully implements a synergistic two-pronged therapeutic strategy. By co-delivering a ROS-scavenger and a mitochondrial-regenerative agent directly to the site of injury, the platform effectively disrupts the critical pathological crosstalk between inflammation and mitochondrial damage in AKI. This work presents a holistic, targeted, and image-guided nanomedicine strategy, offering a promising approach for the effective treatment and monitoring of AKI.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Theranostics
·
2023
·
IF 12.4
Mingrui Xiong,Hong Chen,Yu Fan,Muchuan Jin,Dong Yang,Yuchen Chen,Yu Zhang,Robert B. Petersen,Hua Su,Anlin Peng,Congyi Wang,Ling Zheng,Kun Huang
Rationale: Ischemia-reperfusion injury (I/R) is a common cause of acute kidney injury (AKI). Post-ischemic recovery of renal blood supply plays an important role in attenuating injury. Exogenous application of elabela (ELA) peptides has been demonstrated by us and others to alleviate AKI, partly through its receptor APJ. However, the endogenous role of ELA in renal I/R remains unclear. Methods: Renal tubule specific ELA knockout ( Apela Ksp KO) mice challenged with bilateral or unilateral I/R were used to investigate the role of endogenous ELA in renal I/R. RNA-sequencing analysis was performed to unbiasedly investigate altered genes in kidneys of Apela Ksp KO mice. Injured mice were treated with ELA32 peptide, Nω-hydroxy-nor-L-arginine (nor-NOHA), prostaglandin E2 (PGE2), Paricalcitol, ML221 or respective vehicles, individually or in combination. Results: ELA is mostly expressed in renal tubules. Aggravated pathological injury and further reduction of renal microvascular blood flow were observed in Apela Ksp KO mice during AKI and the following transition to chronic kidney disease (AKI-CKD). RNA-seq analysis suggested that two blood flow regulators, arginine metabolizing enzyme arginase 2 (ARG2) and PGE2 metabolizing enzyme carbonyl reductases 1 and 3 (CBR1/3), were altered in injured Apela Ksp KO mice. Notably, combination application of an ARG2 inhibitor nor-NOHA, and Paricalcitol, a clinically used activator for PGE2 synthesis, alleviated injury-induced AKI/AKI-CKD stages and eliminated the worst outcomes observed in Apela Ksp KO mice. Moreover, while the APJ inhibitor ML221 blocked the beneficial effects of ELA32 peptide on AKI, it showed no effect on combination treatment of nor-NOHA and Paricalcitol. Conclusions: An endogenous tubular ELA-APJ axis regulates renal microvascular blood flow that plays a pivotal role in I/R-induced AKI. Furthermore, improving renal blood flow by inhibiting ARG2 and activating PGE2 is an effective treatment for AKI and prevents the subsequent AKI-CKD transition.
研究领域:
肾病学
·
药理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Aging-US
·
2022
·
IF 5.955
Zhifen Wu,Jian Pan,Jurong Yang,Dongshan Zhang
The pathogenesis of acute kidney injury (AKI) is not fully understood. To date, the exact role and regulatory mechanism of long non-coding RNA (lncRNA)136131 in AKI remains unclear. Here, we demonstrate that lncRNA136131 in BUMPT cells is induced by antimycin A. Furthermore, after incubating BUMPT cells in antimycin for two hours, lncRNA136131 prevented BUMPT cell apoptosis and cleaved caspase-3 expression. Mechanistically, lncRNA136131 sponged miR-378a-3p and then increased the expression of Rab10 to suppress apoptosis. Finally, I/R-induced decline of renal function, tubular damage, renal tubular cells apoptosis, and the upregulation of cleaved caspase-3 were aggravated by lncRNA136131 siRNA. In contrast, this effect was attenuated by the overexpression of lncRNA136131. In conclusion, lncRNA136131 protected against I/R-induced AKI progression by targeting miR-378a-3p/Rab10 and may be utilized as a novel target for AKI therapeutics.
研究领域:
分子生物学
·
肾脏病学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Science Advances
·
2020
·Vol. 6
·期 41
·
IF 13.117
Di Liu,Gaofeng Shu,Feiyang Jin,Jing Qi,Xiaoling Xu,Yan Du,Hui Yu,Jun Wang,Mingchen Sun,Yuchan You,Minxia Zhu,Meixuan Chen,Luwen Zhu,Qiying Shen,Xiaoying Ying,Xuefang Lou,Saiping Jiang,Yongzhong Du
The development of drugs with rapid distribution in the kidney and long-term retention in the renal tubule is a breakthrough for enhanced treatment of acute kidney injury (AKI). Here, l-serine–modified chitosan (SC) was synthesized as a potential AKI kidney–targeting agent due to the native cationic property of chitosan and specific interaction between kidney injury molecule–1 (Kim-1) and serine. Results indicated that SC was rapidly accumulated and long-term retained in ischemia-reperfusion–induced AKI kidneys, especially in renal tubules, which was possibly due to the specific interactions between SC and Kim-1. SC-TK-SS31 was then prepared by conjugating SS31, a mitochondria-targeted antioxidant, to SC via reactive oxygen species (ROS)–sensitive thioketal linker. Because of the effective renal distribution combined with ROS-responsive drug release behavior, the administration of SC-TK-SS31 led to an enhanced therapeutic effect of SS31 by protecting mitochondria from damage and reducing the oxidative stress, inflammation, and cell apoptosis.
研究领域:
药学
·
肾病学
·
药物递送系统
·
材料科学
✓ 已验证
DOI
PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
·
2026
·
IF 5.2
Hongchuang Ma,Nan Shen,Xin Liu,Fangfang Zhou,Chuanming Hao,Qun Luo
Background Acute kidney injury (AKI) remains a major clinical challenge lacking effective pharmacological interventions. Ferroptosis has emerged as a critical mechanism contributing to renal tubular injury. While p -coumaric acid (pCA), a natural phenolic compound, has been reported to exert renoprotective effects, its regulatory role in ferroptosis, particularly under different pathological contexts of AKI, remains incompletely understood. Methods A folic acid (FA, 250 mg/kg)–induced AKI model was established in mice treated with pCA (10 and 50 mg/kg). Renal function, histopathology, inflammatory responses, and ferroptosis-related markers were evaluated. Integrated transcriptomic and metabolomic analyses were performed to identify global regulatory alterations. Mechanistic studies were conducted in erastin-treated HK-2 cells. NRF2 signaling involvement was further assessed using pharmacological inhibition. Results pCA treatment significantly improved renal function, attenuated tubular injury, and suppressed inflammatory responses in FA-induced AKI. Multi-omics integration revealed that pCA markedly reprogrammed metabolic and transcriptional networks associated with ferroptosis and redox homeostasis. Mechanistically, pCA restored antioxidant capacity and normalized the expression of ferroptosis-related proteins. Notably, pCA activated NRF2 signaling, leading to upregulation of downstream targets involved in ferroptosis regulation. Inhibition of NRF2 partially abolished the cytoprotective and anti-ferroptotic effects of pCA in vitro. Conclusion pCA alleviates FA-induced AKI by suppressing ferroptosis through NRF2-dependent regulation of redox and metabolic homeostasis, highlighting NRF2 as a potential therapeutic target for AKI.
✓ 已验证
DOI
PubMed
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2024
·
IF 3.3
Yalin Yang,Shuang Jiang,Yu Mu,Chilu Liu,Yanxing Han,Jiandong Jiang,Yuhong Wang
The incidence of contrast-induced acute kidney injury (CI-AKI) has escalated to become the third most prevalent cause of hospital-acquired AKI, with a lack of efficacious interventions. Berberine (BBR) possesses diverse pharmacological effects and exhibits renoprotective properties; however, limited knowledge exists regarding its impact on CI-AKI. Therefore, our study aimed to investigate the protective effects and underlying mechanisms of BBR on CI-AKI in a mice model, focusing on the nucleotide-binding oligomerization domain-like pyrin domain-containing protein 3 (NLRP3) inflammasome and mitophagy. The CI-AKI mice model was established by administering L-NAME, indomethacin (10 mg/kg), and iohexol (11 g/kg) following water deprivation. A pretreatment of 100 mg/kg of BBR was orally administered to the mice for two weeks. Renal injury markers, damage-associated molecular patterns (DAMPs), renal histopathology, mitochondrial morphology, autophagosomes, and potential mechanisms were investigated. BBR effectively reduced levels of renal injury biomarkers such as serum cystatin C, urea nitrogen, and creatinine, downregulated the protein levels of kidney injury molecule 1 (KIM1), and mitigated renal histomorphological damage. Moreover, BBR reduced DAMPs, including high mobility group box 1 (HMGB1), heat shock protein 70 (HSP70), and uric acid (UA). It also alleviated oxidative stress and inflammatory factors such as monocyte chemotactic protein 1 (MCP-1), tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), and interleukin 1 beta (IL-1β). Furthermore, the activation of NLRP3 inflammasome was attenuated in the BBR pretreatment group, as evidenced by both mRNA and protein levels. Electron microscopy and Western blotting examination revealed that BBR mitigated mitochondrial damage and enhanced mitophagy. Additionally, BBR increased the P-AMPK/AMPK ratio. These findings indicate that BBR exerts a protective effect against CI-AKI by suppressing NLRP3 inflammasome activation and modulating mitophagy, providing a potential therapeutic strategy for its prevention.
研究领域:
药理学
·
肾病学
·
炎症
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
International Journal of Biological Sciences
·
2023
·
IF 9.2
Xianke Zhou,Yadie Xiang,Dier Li,Menghua Zhong,Xue Hong,Yuan Gui,Wenjian Min,Yudan Chen,Xi Zeng,Haili Zhu,Youhua Liu,Shijia Liu,Peng Yang,Fanfan Hou,Dong Zhou,Haiyan Fu
Acute kidney injury (AKI) is a refractory clinical syndrome with limited effective treatments. Amid AKI, activation of the extracellular signal-regulated kinase (ERK) cascade plays a critical role in promoting kidney repair and regeneration. However, a mature ERK agonist in treating kidney disease remains lacking. This study identified limonin, a member of the class of compounds known as furanolactones, as a natural ERK2 activator. Employing a multidisciplinary approach, we systemically dissected how limonin mitigates AKI. Compared to vehicles, pretreatment of limonin significantly preserved kidney functions after ischemic AKI. We revealed that ERK2 is a significant protein linked to the limonin's active binding sites through structural analysis. The molecular docking study showed a high binding affinity between limonin and ERK2, which was confirmed by the cellular thermal shift assay and microscale thermophoresis. Mechanistically, we further validated that limonin promoted tubular cell proliferation and reduced cell apoptosis after AKI by activating ERK signaling pathway in vivo . In vitro and ex vivo , blockade of ERK abolished limonin's capacity of preventing tubular cell death under hypoxia stress. Our results indicated that limonin is a novel ERK2 activator with strong translational potential in preventing or mitigating AKI.
研究领域:
药理学
·
肾病学
·
分子生物学
·
临床研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Yinghan Wang,Pengyu Xue,Liang Gao,Xuefei Wang,Shilin Zhou,Xiaochen Wu,Chuanlong Guo
Cisplatin induced acute kidney injury (AKI) is clinically prevalent, with a complex pathogenesis and a lack of effective therapeutic drugs. Polydatin (Po) has excellent biological activity, but its low solubility and bioavailability limit its application. In this study, fucoidan (Fu) and carboxymethyl chitosan (Cs) self-assembled into nanoparticles through electrostatic interactions/hydrogen bonding and loaded Po (Fu/Cs Po NPs). In vitro studies found that Fu/Cs Po NPs protected human renal tubular epithelial (HK-2) cells from cisplatin induced damage and accumulation of reactive oxygen species (ROS). Mechanistic studies showed that Fu/Cs Po NPs inhibited cisplatin induced DNA damage and activation of cyclic guanosine monophosphate synthase (cGAS) and intron gene stimulator (STING) pathways. In vivo studies showed that Fu/Cs Po NPs treatment alleviated cisplatin induced AKI symptoms, including elevated blood urea nitrogen (BUN) and serum creatinine (SCr), as well as pathological damage to kidney tissues. In vivo mechanism studies also showed that Fu/Cs Po NPs treatment inhibited cisplatin induced DNA damage and activation of the cGAS-STING pathway. The pharmacokinetic and tissue distribution results demonstrated that the Fu/Cs delivery system enhanced the bioavailability and kidney accumulation of Po in vivo . In summary, our study provided potential drugs for the treatment of cisplatin induced AKI.
研究领域:
药理学
·
肾病学
·
药物递送系统
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2025
·
IF 9.6
Tong Yu,Yeqing Wang,Yi Kong,Jianwei Wang,Hong Yun,Yunchao Wang,Fuqiang Hu,Zhongxin Zhu,Hong Yuan
Drug delivery system (DDS) is an important branch of pharmaceutics. Rational modification of the physicochemical properties of DDSs can further improve their targeting efficiency. Herein, a bionic DDS is reported for AKI that is scRNA-seq-guided, custom-designed, and prepared, targeting the Key Cell Subtype for Pathological Progression (KCS-PP) of acute kidney injury (AKI). Specifically, scRNA-seq is utilized to identify a specific renal tubular epithelial cell subtype (PTIs) as the KCS-PP for AKI from numerous cellular subtypes. Additionally, specific cell adhesion molecules (VCAM1 and ICAM1) are identified as the Targeting Drug Delivery Mediators (TDDMs) for PTIs from a list of 1000 marker genes of PTIs. Based on this progress, PTI-targeting bionic DDS, named BRNCs@AMMOs is custom-designed and prepared, and used them for AKI treatment in vitro and in vivo. In vitro, BRNCs@AMMOs shows that its adhesion ability in PTI model cells is 3.2 times that in normal cells. In vivo, 6 h after renal pelvis injection, the MFI of BRNCs@AMMOs-DiI in AKI kidneys is 3.7 times that of sham kidneys. The findings demonstrate that BRNCs@AMMOs exhibits prolonged retention in PTI model cells and AKI kidneys. Overall, the custom-designed and prepared PTI-targeting bionic DDS, may promote the customized design and preparation of DDSs for different diseases and targets, is reported.
研究领域:
药剂学
·
药物递送
·
分子医学
·
纳米技术
·
转化医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOORGANIC CHEMISTRY
·
2021
·
IF 5.275
Hongbo Wang,Jiawei Zuo,Liang Zha,Xia Jiang,Caixia Wu,Yong-An Yang,Wenjian Tang,Tianlu Shi
To develop new anti-inflammatory drugs for the prevention and treatment of acute kidney injury, a series of novel glycyrrhetic ureas were designed, synthesized and evaluated for anti-inflammatory activity using RAW264.7 cells. Compounds 5r-5u (2.04, 2.50, 3.25 and 2.48 μM, respectively) with acidic or neutral amino acid showed potent anti-inflammatory activity (IC 50 = 2–3 μM for NO inhibition), amongst them, compound 5r also inhibited tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in a dose-dependent manner. In cisplatin-induced AKI mice model, compound 5r significantly reduced the level of pro-inflammatory factors, ameliorated the pathological damage of kidney tissue, and maintained the normal metabolic capacity.
研究领域:
药理学
·
药物化学
·
炎症研究
·
肾病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Small
·
2023
·
IF 13.3
You Huang,Ke Chen,Ling Liu,Huizhen Ma,Xiaoning Zhang,Kexin Tan,Yuan Li,Ying Liu,Changlong Liu,Hao Wang,Xiao-Dong Zhang
Near-infrared-II (NIR-II) imaging has shown great potential for monitoring the pathological progression and deep tissue imaging but is limited to present unmet NIR-II agent. Present fluorophores show a promising prospect for NIR-II imaging, but brightness and photostability are still highly challenging during real-time monitoring. In this work, atom-engineered NIR-II Au 24 Cd 1 clusters with ultrahigh brightness, stability, and photostability are developed via single atomic Cd doping. Single atom Cd substitutions contribute to Cd 4d state in HOMO and redistribution of energy level near the gap, exhibiting 56-fold fluorescence enhancement of Au 24 Cd 1 clusters. Meanwhile, single atomic Cd reinforces Cd Au bond energy, formation energy, and stabilized cluster structure, leading to persistent stability for up to 1 month without decay, as well as excellent photostability of 1 h without photobleaching, much longer than clinically approved indocyanine green (<5 min). In vivo imaging shows gold clusters can monitor acute kidney injury (AKI) even after 72 h of injury, enabling evaluating progression at a very long window. Meanwhile, the bioactive gold clusters can alleviate AKI-induced oxidative stress damage and acute neuroinflammation. Single atom-engineered gold clusters exhibit molecular tracking and diagnostic prospect in kidney-related diseases.
研究领域:
生物医学工程
·
纳米技术
·
分子成像
·
肾脏病理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）