Foods
·
2024
·Vol. 13
·期 4
·591
·
IF 4.7
Xi Peng,Kai Liu,Xing Hu,Deming Gong,Guowen Zhang
Background: Hyperuricaemia (HUA) is a disorder of purine metabolism in the body. We previously synthesized a hesperitin (Hsp)-Cu(II) complex and found that the complex possessed strong uric acid (UA)-reducing activity in vitro. In this study we further explored the complex’s UA-lowering and nephroprotective effects in vivo. Methods: A mouse with HUA was used to investigate the complex’s hypouricemic and nephroprotective effects via biochemical analysis, RT-PCR, and Western blot. Results: Hsp-Cu(II) complex markedly decreased the serum UA level and restored kidney tissue damage to normal in HUA mice. Meanwhile, the complex inhibited liver adenosine deaminase (ADA) and xanthine oxidase (XO) activities to reduce UA synthesis and modulated the protein expression of urate transporters to promote UA excretion. Hsp-Cu(II) treatment significantly suppressed oxidative stress and inflammatory in the kidney, reduced the contents of cytokines and inhibited the activation of the nucleotide-binding oligomerization domain (NOD)-like receptor thermal protein domain associated protein 3 (NLRP3) inflammatory pathway. Conclusions: Hsp-Cu(II) complex reduced serum UA and protected kidneys from renal inflammatory damage and oxidative stress by modulating the NLRP3 pathway. Hsp-Cu(II) complex may be a promising dietary supplement or nutraceutical for the therapy of hyperuricemia.
研究领域:
药理学
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生物化学
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分子生物学
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炎症研究
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产品关联
DOI
PubMed
高影响因子
Food & Function
·
2025
·
IF 5.4
Xiaoran Kong,Li Zhao,He Huang,Qiaozhen Kang,Jike Lu,Jia-Qing Zhu
Hyperuricemia is chronic metabolic disease with a high incidence, and it has become the “fourth highest” health risk in modern times. Isorhamnetin is a natural flavonoid found in a variety of plants, especially fruits such as buckthorn. In vivo hyperuricemia ameliorating effect of isorhamnetin and the specific molecular mechanism were profoundly investigated through a hyperuricemia mice model in the present study. The results demonstrated that isorhamnetin showed a significant uric acid-lowering effect in mice. Isorhamnetin was able to reduce uric acid production by inhibiting XOD activity. On the other hand, it reduced the expression of GLUT9 to inhibit uric acid reabsorption and enhanced the expression of ABCG2, OAT1, and OAT3 to promote uric acid excretion. Metabolomics analysis revealed that isorhamnetin gavage restored the purine metabolism and riboflavin metabolism disorders, and thus significantly alleviated the hyperuricemia in mice. Further, the alleviating effect of isorhamnetin on hyperuricemia-induced renal inflammation and its specific mechanism were explored through network pharmacology and molecular validation experiments. Network pharmacology predicted that seven targets were enriched in the PI3K/AKT pathway (CDK6, SYK, KDR, RELA, PIK3CG, IGF1R, MCL1) and four targets were enriched in the NF-κB pathway (SYK, PARP1, PTGS2, RELA). Western blot validated that isorhamnetin inhibited the phosphorylation of PI3K and AKT and down-regulated the expression of NF-κB p65. It indicated that isorhamnetin could inhibit the PI3K/AKT/NF-κB signaling pathway to reduce the levels of renal inflammatory factors (TNF-α, IL-β and IL-6) and ultimately ameliorate the hyperuricemia-induced renal inflammation in mice. This study will provide comprehensive and penetrating theoretical basis for the application of isorhamnetin in the field of functional foods or dietary supplements to improve hyperuricemia.
研究领域:
药理学
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代谢生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
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
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2025
·
IF 8.5
Meng-xiao Wang,Ke-ke Luo,Meng-yao Tian,Wen-ya Gao,Shan Jiang,Yan Zhang,Jian Yang,Nan Si,Shi-lan Ding,Xiao-lu Wei,Yu-yang Liu,Bao-lin Bian,Yan-yan Zhou,Hong-jie Wang
The diagnosis and treatment of chronic glomerulonephritis (CGN) during childhood pose distinct challenges. Acteoside (ACT) is the primary active ingredient extracted from the leaves of Rehmannia glutinosa by our research group, accounting for 2.15 %, which possess multiple biological activities, especially for nephropathy treatment. However, its mechanism intervention on CGN in children remains obscure. In this study, we established a model of purinomycin aminonucleoside (PAN)-induced CGN in childhood rats to assess the potential therapeutic effect and underlying mechanisms of ACT. Leveraging network pharmacology and multi-omics technology, we delved into the effects and mechanisms of ACT intervention on CGN. And these findings were further corroborated through qRT-PCR, western blot and targeted metabolomics. Our results demonstrated that ACT had significantly efficient in the treatment of CGN in childhood rats by improving the key indicators and pathological changes. Further, ACT could significantly regulate differences in endogenous small molecules and genes based on non-target metabolomics and transcriptomics. Meanwhile, target capture analysis found the crucial targets of ACT treatment in CGN. Integrated analysis of multi-omics study indicated that PI3K/Akt signaling pathway and its downstream amino acid metabolism were significantly enriched, hinting at the essential regulatory pathway for ACT in treating of CGN. Finally, through qRT-PCR, western blot and targeted metabolomics, it was verified that ACT could ameliorate CGN through Cxcr4-PI3K-Akt-eNOS signaling pathway, thereby regulating amino acid metabolism. The collective results were consistent with those of multi-omics analysis. Our study illuminated that ACT had notable curative effect on CGN rats, and preliminarily elucidated its mechanism of action. Our research will provide solid basis for the treatment of chronic glomerulonephritis in children with ACT and developing it into innovative traditional Chinese medicine.
研究领域:
药理学
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分子生物学
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肾脏病学
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产品关联
DOI
PubMed
高影响因子
Immunity Inflammation and Disease
·
2024
·Vol. 12
·期 1
·e1168
·
IF 3.1
Feng Yang,Yanyan Zhang,Lei Dong,Zhichao Song
Background The vast majority of systemic lupus erythematosus patients develop lupus nephritis (LN) with severe renal manifestations, such as inflammatory responses, oxidative stress, and fibrosis. The purpose of this research was to investigate Cordyceps cicadae as a potential therapeutic target for treating inflammatory responses, oxidative stress, and fibrosis in LN. Methods The effects of C. cicadae on lupus symptoms in mice with LN were determined. MRL/lpr mice were treated with C. cicadae (4 g/kg/day, i.e., CC group, n = 8) or an equal volume of saline (model group, n = 8), and MRL/MP mice were treated with an equal volume of saline (control group, n = 8). Renal function indices, renal pathology, inflammatory markers, oxidative stress markers, and renal interstitial fibrosis levels were evaluated after C. cicadae treatment. Western blot analysis was performed to investigate the effect of C. cicadae on the expression of fibrosis biomarkers and the phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR)-mediated autophagy pathway in the renal tissues of mice. Results C. cicadae ameliorated renal lesions, the inflammatory response, and oxidative stress damage in MRL/lpr mice. C. cicadae treatment inhibited renal fibrosis (16.31 ± 4.16 vs. 31.25 ± 5.61) and downregulated the expression of the fibrosis biomarkers alpha-smooth muscle actin, fibronectin, and collagen I (COL I) in the kidneys of MRL/lpr mice. In addition, further research showed that the PI3K/mTOR-mediated autophagy pathway was involved in C. cicadae -mediated effects on renal fibrosis in MRL/lpr mice. Furthermore, the therapeutic effect of C. cicadae on repairing renal fibrosis and damage in MRL/lpr mice was abolished by the PI3K agonist 740 Y-P. Conclusions The findings of the present research showed that C. cicadae could alleviate inflammatory responses, oxidative stress, and fibrosis in the renal tissues of mice with LN by targeting the PI3K/mTOR-mediated autophagy pathway.
研究领域:
免疫学
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药理学
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肾脏病理学
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分子生物学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2023
·
IF 8.2
Zhengqi Zha,Xiaoning Wang,Guoqing Wang,Hongping Yin,Hang Wang
Acetic acid has been shown to be effective in chronic kidney disease (CKD). However, it is a low-molecular-weight compound that allows it to be absorbed in the upper digestive tract so that it cannot function in colon. To overcome these deficiencies, an acetate-releasing xylan derivative, xylan acetate ester (XylA), was synthesized and selected in this study for its potential in the treatment of CKD. IR, NMR and HPGPC were used to characterize the structure of XylA and its antinephritic effects was evaluated in vivo. The results showed that acetate was successfully grafted onto the C-2 and C-3 positions of xylan and with a molecular weight at 69157 Da. XylA treatments could relieve the symptoms of CKD in an adenine-induced chronic renal failure (CRF) model and an adriamycin-induced focal segmental glomerulosclerosis (FSGS) model in SD rats. Further study indicated that XylA could upregulate the short-chain fatty acids (SCFAs) in vitro and vivo . Nevertheless, the relative abundance of Phascolarctobacterium in colon was increased after XylA treatment. XylA could upregulate G-protein-coupled receptor 41 (GPR41) expression, inhibit glomerular cell apoptosis and promoting proliferation. Our study expands the application of xylan and provides a new idea for the treatment of CKD with acetic acid.
研究领域:
药学
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肾脏生理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Cell Death & Disease
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2020
·Vol. 11
·期 5
·1-19
·
IF 6.304
Tian Yuexin,Guo Huifang,Miao Xinyan,Xu Jie,Yang Ran,Zhao Lu,Liu Jinxi,Yang Lin,Gao Fan,Zhang Wei,Liu Qingjuan,Sun Shaoguang,Tian Yu,Li Hongbo,Huang Jie,Gu Cunyang,Liu Shuxia,Feng Xiaojuan
Podocyte injury is the main cause of proteinuria in lupus nephritis (LN). Nestin, an important cytoskeleton protein, is expressed stably in podocytes and is associated with podocyte injury. However, the role of nestin in the pathogenesis of proteinuria in LN remains unclear. The correlations among nestin, nephrin and proteinuria were analyzed in LN patients and MRL/lpr lupus-prone mice. The expression of nestin in mouse podocyte lines (MPCs) and MRL/lpr mice was knocked down to determine the role of nestin in podocyte injury. Inhibitors and RNAi method were used to explore the role of mitophagy and oxidative stress in nestin protection of podocyte from damage. There was a significantly negative correlation between nestin and proteinuria both in LN patients and MRL/lpr mice, whereas the expression of nephrin was positively correlated with nestin. Knockdown of nestin resulted in not only the decrease of nephrin, p-nephrin (Y1217) and mitophagy-associated proteins in cultured podocytes and the podocytes of MRL/lpr mice, but also mitochondrial dysfunction in podocytes stimulated with LN plasma. The expression and phosphorylation of nephrin was significantly decreased by reducing the level of mitophagy or production of reactive oxygen species (ROS) in cultured podocytes. Our findings suggested that nestin regulated the expression of nephrin through mitophagy and oxidative stress to protect the podocytes from injury in LN.
研究领域:
肾病学
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免疫学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Immunology
·
2020
·
IF 5.085
Wu Wen-Jun,Tan Ying,Liu Xiao-Ling,Yu Feng,Zhao Ming-Hui
To investigate the fine epitope(s) of anti-C1q A08 antibodies and their roles in complement activation in lupus nephritis, C1q A08 and related peptides with various amino acid sequences around A08 were synthesized. Anti-C1q A08 antibodies from 10 lupus nephritis patients were purified from plasmapheresis samples, and four monoclonal antibodies against C1q A08 were screened and identified from mouse hybridoma cells, to study the fine epitope(s) of C1q A08 using ELISA and Biolayer Interferometry (BLI). The biofunction of anti-C1q A08 antibodies for complement classical pathway activation was investigated by C3 activation assay. Anti-C1q A08 antibodies and anti-C1q antibodies were also detected in the sera of female BALB/C mice immunized by C1q A08 peptides. None of the anti-C1q A08 antibodies, which were affinity purified from the 10 lupus nephritis patients, could bind intact C1q coated on microtitre plates, neither could the anti-C1q antibodies bind to C1q A08 peptides coupled on resin, indicating that the human anti-C1q antibodies and anti-C1q A08 antibodies may recognize different epitopes of C1q. One of the four C1q A08 mAbs (32-4) bound to the six amino acids of N-terminus of C1q A08, while another C1q A08 mAb (17-9) bound to eight or 10 amino acids of C-terminus of A08. The third and fourth C1q A08 mAb (1A12 and 4B11) bound to the whole sequence of A08. Only 32-4 mAb bound to the intact C1q coating on an ELISA plate, whereas 17-9 mAb, 1A12 mAb, and 4B11 mAb could not. However, using a BLI assay, 17-9 mAb, 1A12 mAb, and 4B11 mAb, but not 32-4 mAb, could bind to intact C1q. Furthermore, 1A12 mAb and 4B11 mAb, but not 32-4 and 17-9 mAb, could inhibit the activation of complement classical pathway. Anti-C1q A08 antibodies were detected in all the female BALB/C mice in the experimental group but not in the control group. Two out of six in the experimental group developed anti-C1q antibodies. C1q A08 is a half-cryptic epitope of C1q involving N-terminal six amino acids of C1q A08, and this is important to the activation of a complement classical pathway, and some anti-C1q A08 antibodies were able to prevent this process. Epitope spreading of C1q occurred in the mice immunized with C1q A08 peptides.
研究领域:
免疫学
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风湿病学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
MOLECULES
·
2020
·Vol. 25
·期 3
·468
·
IF 3.267
Xiu E Feng,Ke Meng Cui,Qing Shan Li,Zi Cheng Wu,Fei Lei
Based on a foregoing gram-scale laboratory process, an efficient scale-up preparation process of 5,2′-dibromo-2,4′,5′-trihydroxydiphenylmethanone (LM49-API), a new acute pyelonephritis candidate drug, was developed and validated aiming to reduce by-products and achieve better impurity profiles. Meanwhile, the polymorph ofLM49-APIand process-related impurities were also investigated. Ultimately, the optimal reaction conditions were verified by evaluating the impurity profiles and their formation during the synthesis. Six process-related impurities were synthesized and identified, being useful for the quality control ofLM49-API. Its finalized preparation process was further validated at 329–410 g scale-up production in 53.4–57.1% overall yield with 99.95–99.98% high-performance liquid chromatography (HPLC) purity, and it is currently viable for commercial production.LM49-API-imCandLM49-API-imXwere identified as the main single impurities inLM49-API, with the content controlled to be less than 0.03%.Keywords:5,2′-dibromo-2,4′,5′-trihydroxydiphenylmethanone;process development;process-related impurity;acute pyelonephritis;polymorph
研究领域:
药物化学
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有机合成
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药物开发
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2022
·
IF 5.988
Zhang Cong,Song Yingying,Chen Liang,Chen Peng,Yuan Ming,Meng Yan,Wang Qi,Zheng Guohua,Qiu Zhenpeng
Urolithin A (UroA) is one of the primary intestinal metabolites of ellagitannins, showing translational potential as a nutritional intervention in humans. Mounting evidence suggests that fructose consumption contributes to the progression of chronic kidney disease (CKD) that manifests in hyperuricemic nephropathy, renal inflammation, and tubulointerstitial injury. Here, we investigated the efficacy of UroA in alleviating fructose-induced hyperuricemic nephropathy in mice. Uric acid-exposed human kidney-2 (HK-2) cells were utilized for in vitro mechanism validation. Histopathological staining, immunoblotting, and transmission electron microscope were performed for the mechanistic investigations. Our results revealed that UroA ameliorated fructose-induced hyperuricemic nephropathy in mice. The histopathologic assessment showed that UroA attenuated tubular hypertrophy and dilation, glomerular basement membrane thickening, and collagen deposition in the kidney of fructose-fed mice. Mechanistically, UroA treatment impaired STING-NLRP3 activation, resulting in reduced production of proinflammatory cytokines IL-1β, IL-6, and TNF-α. Notably, UroA exhibited a scavenging effect against reactive oxygen species (ROS) and restored fructose-impaired PINK1/Parkin-mediated mitophagy in nephropathic mice. Furthermore, the inhibitory effect of UroA in STING-NLRP3 activation was impaired after Parkin gene silencing in HK-2 cells. Together, this study suggests that UroA alleviates fructose-induced hyperuricemic nephropathy by promoting Parkin-dependent mitophagy, thereby suppressing STING-NLRP3 axis-mediated inflammatory response. Thus, dietary supplementation with UroA or ellagitannins-rich foods may serve as a promising intervention to prevent CKD progression.
研究领域:
药理学
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肾病学
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分子生物学
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营养学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2024
·Vol. 25
·期 24
·13399
·
IF 4.9
Wanyun Dang,Fangyang Li,Rong Gao,Cheng Zhang,Hongbo Cheng,Zhenhui Wu,Tingyu Yang,Jinchao Pan,Xianglin Tang,Yue Gao
Plateau hyperuricemia is a common disease in the plateau area, and the incidence is much higher than that in the plain area. Dioscin (DIO) and its active metabolite Diosgenin (DG) exert therapeutic effects on hyperuricemia through oxidative stress and inflammation. In this study, DIO and its active metabolite DG were taken as the research objects to explore their therapeutic effects on high-altitude hyperuricemia in rats. To evaluate the therapeutic effect of DIO on the rat model of high-altitude hyperuricemia, the evaluation indexes include blood biochemical indexes, renal histopathology, oil red O staining of the kidney, rat kidney index, and rat renal inflammatory factors. Transcriptomics was used to analyze the control group, model group, and drug-administered group to preliminarily explore the protective mechanism of DIO in rats with high-altitude hyperuricemia. An HK-2 high-altitude hyperuricemia cell injury model was established to verify the therapeutic mechanism of DIO in rats with high-altitude hyperuricemia. Western blot was used to detect the expression of related proteins in renal tissues and cell models. The results showed that DIO and its active metabolite DG regulate renal lipid metabolism through the EPHX2 gene, attenuate renal inflammatory reaction, and then promote the excretion of uric acid and reduce its reabsorption, which ultimately achieves the effect of treating plateau hyperuricemia.
研究领域:
药理学
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肾病学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2019
·
IF 4.18
Wen-Zhen Dang,Hui Li,Bing Jiang,Kutty Selva Nandakumar,Kai-Fei Liu,Li-Xin Liu,Xiao-Chen Yu,Hui-Jing Tan,Chun Zhou
Background Anti-malarial drug artesunate (ART), a semi-synthetic derivative of artemisnin, has immunosuppressive effects on several autoimmune diseases, including Systemic lupus erythematosus (SLE), Rheumatoid arthritis (RA), and Colitis . However, molecular mechanisms of ART, especially on follicular helper T cells (Tfh), central players in SLE pathology, are far from clear. Purpose The object for this work is to investigate the therapeutic effect of ART on lupus-prone MRL/ lpr mice and its regulatory function on Tfh cells . Study design and methods MRL/ lpr mice were used to explore therapeutic effects of ART on lupus-prone MRL/ lpr mice and its regulatory functions on Tfh cells. Then, experiments of renal function were accomplished using the biochemical kits. Effects of ART on histopathology of kidneys, inflammatory factors and autoantibodies were examined using H&E staining, ELISA and real-time PCR. Flow cytometry and western blot analysis were used to examine effects of ART on Tfh differentiation and Jak2–Stat3 signaling pathway . Results Upon oral administration , ART significantly prolonged the survival of MRL/ lpr mice, ameliorated the lupus nephritis symptoms, decreased the levels of anti-dsDNA antibodies deposited in the kidney, and the levels of pathogenic cytokines (IL-6, IFN-γ and IL-21). After ART treatment , T-cell compartment in the spleen of MRL/ lpr mice was restored in terms of reduction in the number of Tfh cells and in the maintenance of the ratio of Tfr to follicular regulatory T cells (Tfh). In addition, ART has significantly inhibited the phosphorylation levels of Jak2 and Stat3 in the MRL/ lpr mice. Conclusion ART showed therapeutic effects on lupus-prone MRL/ lpr mice by inhibiting the differentiation of Tfh cells as well as altering the activation status of Jak2–Stat3 signaling cascade.
研究领域:
免疫学
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药理学
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自身免疫疾病
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分子生物学
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）