Chinese Journal of Natural Medicines
·
2025
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IF 4.9
Weimin Liang,Jindi Lu,Ping Yu,Meiqun Cai,Danni Xie,Xini Chen,Xi Zhang,Lingmin Tian,Liyan Yan,Wenxun Lan,Zhongqiu Liu,Xuefeng Zhou,Lan Tang
This study investigates the pharmacokinetics and metabolic characteristics of three marine-derived piericidins as potential drug leads for kidney disease: piericidin A (PA) and its two glycosides (GPAs), glucopiericidin A (GPA) and 13-hydroxyglucopiericidin A (13-OH-GPA). The research aims to facilitate lead selection and optimization for developing a viable preclinical candidate. Rapid absorption of PA and GPAs in mice was observed, characterized by short half-lives and low bioavailability. Glycosides and hydroxyl groups significantly enhanced the absorption rate (13-OH-GPA > GPA > PA). PA and GPAs exhibited metabolic instability in liver microsomes due to Cytochrome P450 enzymes (CYPs) and uridine diphosphoglucuronosyl transferases (UGTs). Glucuronidation emerged as the primary metabolic pathway, with UGT1A7, UGT1A8, UGT1A9, and UGT1A10 demonstrating high elimination rates (30%-70%) for PA and GPAs. This rapid glucuronidation may contribute to the low bioavailability of GPAs. Despite its low bioavailability (2.69%), 13-OH-GPA showed higher kidney distribution (19.8%) compared to PA (10.0%) and GPA (7.3%), suggesting enhanced biological efficacy in kidney diseases. Modifying the C-13 hydroxyl group appears to be a promising approach to improve bioavailability. In conclusion, this study provides valuable metabolic insights for the development and optimization of marine-derived piericidins as potential drug leads for kidney disease.
研究领域:
药理学
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生物化学
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海洋药物学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2022
·
IF 5.714
Ke Lin,Wu Luo,Na Yang,Lan Su,Hao Zhou,Xiang Hu,Yi Wang,Zia A. Khan,Weijian Huang,Gaojun Wu,Guang Liang
Background Kidney damage is a frequent event in the course of hypertension. Recent researches highlighted a critical role of non-hemodynamic activities of angiotensin II (Ang II) in hypertension-associated kidney fibrosis and inflammation. These activities are mediated through toll-like receptors (TLRs) but the mechanisms by which Ang II links TLRs to downstream inflammatory and fibrogenic responses is not fully known. In this study, we investigated the role of TLR adapter protein called myeloid differentiation primary-response protein-88 (MyD88) as the potential link. Methods C57BL/6 mice were administered Ang II by micro-osmotic pump infusion for 4 weeks to develop nephropathy. Mice were treated with small-molecule MyD88 inhibitor LM8. In vitro , MyD88 was blocked using siRNA or LM8 in Ang II-challenged renal tubular epithelial cells. Results We show that MyD88 is mainly located in tubular epithelial cells and Ang II increases the interaction between TLR4 and MyD88. This interaction activates MAPKs and nuclear factor-κB (NF-κB), leading to increased production of inflammatory and fibrogenic factors. Inhibition of MyD88 by siRNA or selective inhibitor LM8 supresses MyD88-TLR4 interaction, NF-κB activation, and elaboration of inflammatory cytokines and fibrosis-associated factors. These protective actions resulted in decreased renal pathological changes and preserved renal function in LM8-treated hypertensive mice, without affecting hypertension. Conclusion These results demonstrate that Ang II induces inflammation and fibrosis in renal tubular epithelial cells through MyD88 and present MyD88 as a potential point of intervention for hypertension-associated kidney disease.
研究领域:
药理学
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肾病学
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免疫学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
PHYSIOLOGICAL RESEARCH
·
2024
·Vol. 73
·期 5
·779
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IF 1.9
Lu BAI,Qian CHEN,Yanqing LI,Fen WU,Mingzhe JIN,Yuhong CHEN,Xu TENG,Sheng JIN,Huanfang FAN,Yuming WU
Trimethylamine N-oxide (TMAO), a bioactive metabolite of gut microbes, plays a pivotal role in the pathogenesis of kidney diseases by activating programmed cell death (PCD) pathways. However, whether trimethylamine (TMA) contributes to chronic kidney injury and which kind of PCD is involved in TMA-induced chronic kidney injury has not been previously evaluated. To observe the effect of TMA, male C57BL/6J mice were randomly divided into two groups: the Control group and the TMA group. The mice in the TMA group were intraperitoneally injected with 100 μmol/kg/day TMA for three months, whereas the mice in the Control group were injected with normal saline for the same period. After three months, plasma creatinine and blood urea nitrogen levels, indicators of kidney function, increased significantly in the TMA group as compared with those in the Control group. Furthermore, Masson staining assay showed that TMA treatment led to a larger area of fibrosis than the Control group. TMA treatment did not change the Bax/Bcl-2 ratio, RIP1, RIP3 and MLKL phosphorylation, or iron and malondialdehyde levels in kidney tissues, indicating that apoptosis, ferroptosis and necroptosis were not involved in TMA-induced chronic kidney injury. However, compared with the Control group, TMA treatment significantly upregulated NLRP3, Caspase-1, IL-1β, cleaved-Caspase 8, Caspase-8, and ZBP1 protein expression in kidney tissues. These results indicated that the ZBP1-NLRP3 inflammasome pathway was involved in TMA-induced chronic kidney injury. In conclusion, our studies revealed that the ZBP1-NLRP3 inflammasome may take part in the progression of TMA induced chronic kidney injury.
研究领域:
肾脏病学
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免疫学
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微生物学
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分子生物学
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病理学
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DOI
高影响因子
PHYSIOLOGICAL RESEARCH
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2025
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IF 2
D Shao,L Bai,Q Chen,Y Chen,Z Qiu,Y Liu,S Jin,Y Wu,J Dai
Trimethylamine N-oxide (TMAO) is involved in the development of kidney disease. However, the specific mechanism by which it leads to kidney injury is unclear. This study explored the role of regulated cell death in TMAO-induced kidney injury. We constructed a TMAO-induced chronic kidney injury model by intraperitoneal injection of TMAO (100 micromol/kg/day for three months). Plasma creatinine (Cre) and urea nitrogen (BUN) levels were measured to evaluate kidney function. Masson staining was used to evaluate kidney pathological changes. The expression levels of regulated cell death-related proteins were measured using western blotting. Plasma Cre and BUN, the area of kidney fibrosis in the TMAO group significantly increased. The western blotting results showed cleaved-Caspase-8, Caspase-8, Caspase-1, NOD-like receptor protein 3 (NLRP3), interleukin-1beta (IL-1beta), cleaved-gasdermin D (cleaved-GSDMD), Z-DNA binding protein 1 (ZBP1), phosphorylation of receptor-interacting protein kinase 3 (RIP3) and mixed-lineage kinase domain-like pseudokinase (MLKL) significantly elevated in the TMAO group. The transferrin receptor 1 (TFR1), ferritin heavy chain (FTH), ferroportin (FPN), nuclear factor erythroid 2-related factor 2 (NRF2), and glutathione peroxidase 4 (GPX4) protein expression in kidney tissue of the TMAO group significantly up-regulated. However, there was no change in iron and MDA levels. The results suggested that PANoptosis, including pyroptosis, apoptosis, and necroptosis components, might be involved in TMAO-induced chronic kidney injury.
研究领域:
肾脏病学
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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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药理学
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产品关联
DOI
PubMed
高影响因子
ACS Applied Nano Materials
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2022
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IF 6.14
Liang Zhang,Li-Zong Su,Zhou Yu,Lu-Yi Su,Yi Zheng,Pei Song,Ya-Hao Wang,Yi-Bin Pan,Bin Zheng
Creatinine level in body fluid has been most used for early diagnosis of kidney function and renal diseases; therefore, it is desirable to develop a rapid and quantitative method for creatinine detection. Herein, surface-enhanced Raman spectroscopy (SERS) based on evaporation-induced optimal hotspots of Au nanocubes has been employed to quantitatively detect creatinine in human serum. Time-dependent SERS measurements during the evaporating process clearly prove that the optimal hotspots are formed on the eve of droplet drying of a Au sol and analyte mixture. The reproducibility tested by independent droplet experiments shows a relative standard deviation of SERS intensity of about 4.16%. Furthermore, the quantitative analysis of creatinine shows a clear linear fitting between the logarithmic SERS intensity and the creatinine concentrations with a correlation coefficient of 0.987. The creatinine level in the serum from volunteers estimated by this method shows an average difference of less than 5% compared to that by the clinical Jaffe reaction method. The evaporation-induced optimal hotspot method with good reproducibility offers a simple and feasible way for practical SERS detection.
研究领域:
分析化学
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纳米技术
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生物医学工程
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临床化学
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产品关联
DOI
高影响因子
RSC Advances
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2020
·Vol. 10
·期 19
·11257-11262
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IF 3.119
Xitong Huang,Zhiming Xu,Ji-Hua Liu,Bo-Yang Yu,Jiangwei Tian
MicroRNA-21 (miRNA-21) is a significant biomarker which is closely related to some kinds of diseases, such as cancer, cardiovascular disease and kidney disease. Therefore, the detection of miRNA-21 is of great importance and can provide essential information for disease diagnosis. In this study, we report a facile, sensitive assay for miRNA-21 detection using personal glucose meters (PGM). Biotinylated DNA strand linked invertase (Inv) is conjugated on the surface of streptavidin-coated magnetic beads (MBs) to form a MBs–DNA–Inv complex. Target miRNA-21 in the detection system is captured by the MBs–DNA–Inv probe through DNA/RNA hybridization. The duplex-specific nuclease (DSN) enzyme specifically cleaves the DNA to recycle the target miRNA and release invertase, thereby triggering the dual signal amplification and ensuring high sensitivity. Besides, we establish a linear relationship between PGM and different concentrations of miRNA-21 in the range of 10 to 200 pM. The limit of detection is 1.8 pM, which is more sensitive than some of the previous reports. In addition, the biosensor exhibits excellent sequence selectivity and single-base mutation can be discriminated. Moreover, the expression of miRNA-21 is confirmed in urine from mice by our method, which is in good accordance with the qRT-PCR result. Therefore, a dependable, low-cost strategy for the detection of miRNA has been established and it meets the latest analytical demands for miRNA determination that is suitable for the public.
研究领域:
生物传感器
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分子生物学
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分析化学
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疾病诊断
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DOI
PubMed
高影响因子
Metabolites
·
2021
·Vol. 11
·期 3
·142
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IF 4.932
Changfeng Hu,Yu Du,Xiaofen Xu,Haichang Li,Qiao Duan,Zhijun Xie,Chengping Wen,Xianlin Han
Lupus nephritis (LN) is an inflammatory renal disease of patients with systemic lupus erythematosus with lots of immune complexes deposited in kidneys. Accumulated studies have demonstrated the close relationships among dyslipidaemia, inflammation, and autoimmune response, and oxidative stress in the patients. Lipids play numerous important roles in biological process and cellular functions. Herein, shotgun lipidomics was employed to quantitatively analyze cellular lipidomes in the renal tissue of MRL/lpr mice in the progression of LN (including pre-LN and LN state) with/without treated with glucocorticoids (GCs). The levels of cytokines (i.e., TNF-α (Tumor necrosis factor alpha) and IL-6 (Interleukin 6)) in the serum were measured by ELISA (enzyme-linked immunosorbent assay) kits. Renal histopathological changes and C3 deposition in the glomeruli of the mice were also determined. Lipidomics analysis revealed that the ectopic fat deposition and the aberrant metabolism of lipids that were relevant to oxidative stress (e.g., 4-hydroxyalkenal, ceramide, lysophospholipid species, etc.) always existed in the development of LN. Moreover, the anti-inflammatory FAHFA (fatty acid ester of hydroxyl fatty acid) species in the kidney tissue could largely reflect the severity of LN. Thus, they were a potential early biomarker for LN. In addition, the study also revealed that treatment with GCs could prevent the progression of LN, but greatly aggravate the aberrant metabolism of the lipids, particularly when used for a long time.Keywords:lupus nephritis;lipidomics;autoimmune reaction;FAHFAs;oxidative stress
研究领域:
免疫学
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肾脏疾病
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脂质代谢
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DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
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2019
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IF 3.17
Hailin Liu,Xiuli Zhang,Xinglong Zhong,Zehua Li,Shaoai Cai,Pingzhen Yang,Caiwen Ou,Minsheng Chen
The risk of cardiovascular events in patients with chronic kidney disease is tremendously increased due to vascular calcification . Local vascular inflammation significantly promotes vascular calcification. A previous study has shown that puerarin inhibits calcification of mouse vascular smooth muscle cells (VSMCs) in vitro, but whether puerarin can inhibit vascular calcification in vivo and the underlying mechanisms remain unclear. In this study, we found that rat VSMCs treated with calcifying medium showed more mineral deposition, and this effect was inhibited by puerarin in a dose-dependent manner, as detected by alizarin red staining and calcium content assay. Puerarin also prevented the trans-differentiation of VSMCs into osteoblast-like cells, indicated by down-regulation of bone-related genes including Runx2 and BMP2 . In vivo study of uremic rats induced by renal nephrectomy further confirmed the inhibitory effect of puerarin on vascular calcification in uremic rats. Puerarin treatment significantly prevented mineral deposition in rat aortas and down-regulated the expression of Runx2 and BMP2. Furthermore, we detected the levels of pro-inflammatory cytokines including IL-1β, IL-6, IL-18 and TNFα in vitro and in vivo . The levels of IL-1β were remarkably increased in both calcified VSMCs and aortas of uremic rats, while puerarin treatment markedly decreased the expression of IL-1β. In addition, we found that puerarin reduced IL-1β possibly through targeting NLRP3/Caspase1/IL-1β and NF-κB signaling pathways and inhibiting the generation of reactive oxygen species . Taken together, we demonstrated that puerarin has the capability of inhibiting vascular calcification in uremic rats by inhibiting inflammation.
研究领域:
药理学
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心血管疾病
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肾脏疾病
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炎症
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产品关联
DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2020
·
IF 5.115
Shuping Wei,Chaoli Xu,Yidan Zhang,Zhongqing Shi,Min Wu,Bin Yang
Objective To investigate the antifibrotic effect of the combination of a PPARγ agonist-loaded nanoparticle-microbubble complex with ultrasound (US) exposure on renal interstitial fibrosis (RIF). Materials and Methods Polylactide-co-glycolide (PLGA) nanoparticles were used to load PPARγ agonist (rosiglitazone, RSG) and prepare PLGA-RSG nanoparticles (PLNPs-RSG); then, a novel complex between PLNPs-RSG and SonoVue microbubbles (MBs) (PLNPs-RSG-MBs) was prepared. The size distribution, zeta potentials, RSG-loading capacity and entrapment efficiency were measured, and the release of RSG was assessed using a UV-vis spectrophotometer. The in vitro cytotoxicity and in vivo systemic toxicity assays were performed. The cellular uptake assessment was performed using a confocal laser scanning microscope (CLSM). The in vivo biodistribution assessment was performed using fluorescence imaging with a near-infrared (NIR) imaging system. Furthermore, this complex was administered to a unilateral ureteral obstruction (UUO) rat model with the assistance of US exposure to investigate the antifibrotic effect. Results This PLNPs-RSG-MBs complex had a size of 2199.5± 988.1 nm and a drug-loading efficiency of 28.5%. In vitro cytotoxicity and in vivo systemic toxicity assays indicated that the PLNPs-RSG-MBs complex displayed excellent biocompatibility. In addition, the complex showed high cellular uptake efficiency in vitro and kidney-targeting ability in vivo. In a UUO rat model, the combination of the PLNPs-RSG-MBs complex with US exposure significantly reduced collagen deposition and successfully attenuated renal fibrosis. Conclusion The combination of the PLNPs-RSG-MBs complex with US exposure may be a promising approach for the treatment of RIF.
研究领域:
药理学
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纳米技术
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医学影像学
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肾脏疾病
✓ 已验证
DOI
PubMed
高影响因子
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