Functional Metabolomics Analysis Elucidating the Metabolic Biomarker and Key Pathway Change Associated With the Chronic Glomerulonephritis and Revealing Action Mechanism of Rhein

Yu, Wei; Yang, Wenjun; Zhao, Mingyan; Meng, Xianglin

doi:10.3389/fphar.2020.554783

Cited by 14 publications

(11 citation statements)

References 83 publications

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“…Rhein is considered to be a highly effective natural component for the treatment of kidney-related diseases. According to the analysis of Yu et al for the metabonomics, rhein could treat CGN by regulating or participating in the following six important metabolic pathways: phenylalanine, tyrosine and tryptophan biosynthesis, tricarboxylic acid cycle (TCA cycle), alanine, aspartate and glutamate metabolism, and arginine and proline metabolism [ 21 ]. According to a systematic review and meta-analysis, rhein has beneficial effects on diabetic nephropathy animal models by reducing levels of transforming growth factor- β (TGF- β 1), renal fibrosis, metabolism, and oxidative stress status [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

Rhein Inhibits NF-κB Signaling Pathway to Alleviate Inflammatory Response and Oxidative Stress of Rats with Chronic Glomerulonephritis

Chen

Guo

et al. 2022

Applied Bionics and Biomechanics

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Objective. To explore the effect and mechanism of rhein on chronic glomerulonephritis (CGN). Method. Twenty-four eight-week-old male SD rats were randomly divided into following 4 groups (6 rats in each group): control group, CGN group, rhein group, and benazepril (Ben) group. And 5 mg/mL of cationization-bovine serum albumin (C-BSA) was mixed with an equal volume of Freund’s incomplete adjuvant for the preparation of 2.5 mg/mL of C-BSA solution. The rat model of CGN was established by injection of C-BSA for six weeks. Calculation of the renal index in rats was conducted. Biochemical detection was performed to measure the level of 24 h urinary protein, blood urea nitrogen (BUN), serum creatinine (SCr), and serum albumin (ALB) of the rats, as well as the level of malondiadehyde (MDA), superoxide (SOD), and glutathione peroxidase (GSH-Px) in the kidney tissue. Hematoxylin and eosin (H&E) staining was utilized to measure histological changes in the kidney of the rats. The level of TNF-α, IL-1β, IL-6, and ICAM-1 in rat kidney tissues was determined by enzyme-linked immunosorbent assay (ELISA). Western blot was applied to check the expression of NF-κB in the nucleus and cytoplasm as well as the expression of IκBα and p-IκBα in rat kidney tissues. Results. Rhein could decline urinary protein, restore blood biochemical parameters, and protect renal tissue in rats with CGN. Besides, rhein could inhibit the activity of the NF-κB signaling pathway in rats with CGN and could alleviate the inflammatory response and oxidative stress level at the same time. Conclusion. Rhein alleviates inflammatory responses and oxidative stress in rats with CGN. It also provides a theoretical basis and data support for the therapeutic drugs for CGN.

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Section: Discussionmentioning

confidence: 99%

Rhein Inhibits NF-κB Signaling Pathway to Alleviate Inflammatory Response and Oxidative Stress of Rats with Chronic Glomerulonephritis

Chen

Guo

et al. 2022

Applied Bionics and Biomechanics

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“…One such alternative treatment involves rhein (4,5‐dihydroxy‐9,10‐dioxoanthracene‐2‐carboxylic acid), a natural anthraquinone compound found in several herbal medicines, including rhubarb, aloe, and sennae leaf. Rhein has been recently reported to display therapeutic effects in several inflammatory conditions, such as skin wounding (W. Zhao et al, 2020), acute kidney injury (Bi et al, 2018), chronic glomerulonephritis (Yu et al, 2020), arthritis (Hu et al, 2019), and acute enteritis (Sha et al, 2019). In addition, modulation by rhein of gut microbiota and purine metabolism in the intestine to alleviate chronic colitis (Wu, Wei, et al, 2020), and protection of the epithelial barrier in cytokine‐stimulated intestinal epithelial cells have also been demonstrated (Zhuang, Zhong, Zhou, et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Rhein regulates redox‐mediated activation of NLRP3 inflammasomes in intestinal inflammation through macrophage‐activated crosstalk

Zhou

Gao

Vong

et al. 2022

British J Pharmacology

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Background and Purpose: Macrophage infiltration and activation is a critical step during acute colitis. Redox-mediated activation of NLRP3 inflammasomes in macrophages plays a critical role in mediating colonic inflammatory responses. Rhein isolated from the rhizome of rhubarb exhibits anti-inflammatory effects in various diseases. However, its role in regulating acute colonic inflammation is unexplored.Here, we investigated the protective mechanisms of rhein during acute gut inflammation and its regulation of macrophage activation. Experimental Approach: Inhibitory effects of rhein on NLRP3 inflammasomes were evaluated in activated macrophages and a mouse model of colitis. Expression of inflammatory mediators, inflammasome complex and redox-related signalling were analysed by ELISA, Western blots, immunofluorescence staining, and qRT-PCR. The phenotype of macrophages was assessed by flow cytometry. Colonic inflammation was evaluated by histological analysis. Key Results: Rhein significantly decreased IL-1β secretion via NLRP3 inflammasomes by disturbing their assembly in macrophages. Rhein also activated the Nrf2-HO1-NQO1 pathway and inhibited expression of Nox2 subunits and translocation to regulate redox balance. Moreover, rhein attenuated inflammatory responses by mediating macrophage polarization from M1 to M2 phenotype. NF-κB, AP-1, and MAPK signalling were also involved in improving inflammatory conditions by rhein. In mice with acute intestinal inflammation, rhein treatment attenuated clinical features and reduced macrophage infiltration into damaged tissue to alleviate colonic inflammation. Conclusion and Implications:Rhein regulated redox-mediated NLRP3 inflammasome activation to protect against acute colitis, by interfering with macrophage accumulation and polarization. These findings provide a promising strategy of novel compounds for regulating mucosal inflammation in gastrointestinal disorders.Abbreviations: AIM2, absent in melanoma 2; AP1, activator protein 1; Arg1, arginase 1; ASC, apoptosis-associated speck-like protein containing a C-terminal caspase-activation and recruitment (CARD) domain; BMDMs, bone marrow-derived macrophages; Chil3, chitinase-like 3; cLPs, colonic lamina propria cells; DCFH-DA, 2 0 7 0 -dichlorodihydrofluorescein diacetate; DSS, dextran sulphate sodium; GEO, gene expression omnibus; HO-1, haem oxygenase-1; IBD, inflammatory bowel disease; MPO, myeloperoxidase; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; NLRC4, NLR family CARD domain containing; NLRP3, NOD-like receptor family pyrin domain-containing 3; Nox, NADPH oxidase; NQO1, NAD(P)H dehydrogenase (quinone 1); Nrf2, nuclear factor-erythroid 2-related factor 2; PMA, phorbol 12-myristate 13-acetate.

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“…Compared with chrysophanol and emodin, rhein showed a strong inhibitory effect on renal fibrosis. Although rhein has been widely demonstrated to protect against renal fibrosis ( Zeng et al, 2014 ; Hu et al, 2019 ; He et al, 2020 ; Wu et al, 2020 ; Yu et al, 2020 ), only two previous studies have reported that rhein protected against renal fibrosis by inhibiting the NF-ƙB p65 protein expression ( Liu et al, 2021b ) and lincRNA-COX2/miR-150-5p/STAT1 axis ( Hu et al, 2020b ). Similarly, a number of publications have demonstrated that emodin retarded renal fibrosis by modulating several pathways, such as TGF-β/Smad, TGF-β/BMP-7, PI3K/Akt/GSK-3β, and Bax/caspase-3 signaling pathways ( Jing et al, 2017 ; Ma et al, 2018b ; Yang et al, 2020 ; Liu et al, 2021c ).…”

Section: Discussionmentioning

confidence: 99%

Shenkang Injection and Its Three Anthraquinones Ameliorates Renal Fibrosis by Simultaneous Targeting IƙB/NF-ƙB and Keap1/Nrf2 Signaling Pathways

Luo

Suo²,

Ren³

et al. 2021

Front. Pharmacol.

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Oxidative stress and inflammation are important and critical mediators in the development and progression of chronic kidney disease (CKD) and its complications. Shenkang injection (SKI) has been widely used to treat patients with CKD. Although the anti-oxidative and anti-inflammatory activity was involved in SKI against CKD, its bioactive components and underlying mechanism remain enigmatic. A rat model of adenine-induced chronic renal failure (CRF) is associated with, and largely driven by, oxidative stress and inflammation. Hence, we identified the anti-oxidative and anti-inflammatory components of SKI and further revealed their underlying mechanism in the adenine-induced CRF rats. Compared with control rats, the levels of creatinine, urea, uric acid, total cholesterol, triglyceride, and low-density lipoprotein cholesterol in serum were significantly increased in the adenine-induced CRF rats. However, treatment with SKI and its three anthraquinones including chrysophanol, emodin, and rhein could reverse these aberrant changes. They could significantly inhibit pro-fibrotic protein expressions including collagen I, α-SMA, fibronectin, and vimentin in the kidney tissues of the adenine-induced CRF rats. Of note, SKI and rhein showed the stronger inhibitory effect on these pro-fibrotic protein expressions than chrysophanol and emodin. Furthermore, they could improve dysregulation of IƙB/NF-ƙB and Keap1/Nrf2 signaling pathways. Chrysophanol and emodin showed the stronger inhibitory effect on the NF-κB p65 protein expression than SKI and rhein. Rhein showed the strongest inhibitory effect on p65 downstream target gene products including NAD(P)H oxidase subunits (p47phox, p67phox, and gp91phox) and COX-2, MCP-1, iNOS, and 12-LO in the kidney tissues. However, SKI and rhein showed the stronger inhibitory effect on the significantly downregulated anti-inflammatory and anti-oxidative protein expression nuclear Nrf2 and its target gene products including HO-1, catalase, GCLC, and NQO1 in the Keap1/Nrf2 signaling pathway than chrysophanol and emodin. This study first demonstrated that SKI and its major components protected against renal fibrosis by inhibiting oxidative stress and inflammation via simultaneous targeting IƙB/NF-ƙB and Keap1/Nrf2 signaling pathways, which illuminated the potential molecular mechanism of anti-oxidative and anti-inflammatory effects of SKI.

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Functional Metabolomics Analysis Elucidating the Metabolic Biomarker and Key Pathway Change Associated With the Chronic Glomerulonephritis and Revealing Action Mechanism of Rhein

Cited by 14 publications

References 83 publications

Rhein Inhibits NF-κB Signaling Pathway to Alleviate Inflammatory Response and Oxidative Stress of Rats with Chronic Glomerulonephritis

Rhein Inhibits NF-κB Signaling Pathway to Alleviate Inflammatory Response and Oxidative Stress of Rats with Chronic Glomerulonephritis

Rhein regulates redox‐mediated activation of NLRP3 inflammasomes in intestinal inflammation through macrophage‐activated crosstalk

Shenkang Injection and Its Three Anthraquinones Ameliorates Renal Fibrosis by Simultaneous Targeting IƙB/NF-ƙB and Keap1/Nrf2 Signaling Pathways

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