Indoxyl sulfate induces intestinal barrier injury through IRF1-DRP1 axis-mediated mitophagy impairment

Huang, Yinghui; Zhou, Jie; Wang, Shaobo; Xiong, Jiachuan; Chen, Yin; Liu, Yong; Xiao, Tangli; Li, Yang; He, Ting; Li, Yan; Bi, Xianjin; Yang, Kang; Han, Wenhao; Qiao, Yu; Yu, Yanli; Zhao, Jinghong

doi:10.7150/thno.45455

Cited by 81 publications

(81 citation statements)

References 56 publications

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“…This activation of the innate immune system causes inflammation. The above pathological factors eventually lead to intestinal epithelial cell dysfunction and destroy mucosal barrier integrity, thus aggravating reperfusion injury 1 , 6 , 33 , 34 . In animal experiments, exogenous ROS scavenger administration has been found to significantly reduce I/R-induced intestinal damage 35 , 36 , which suggests that interventions aimed at reducing ROS after intestinal I/R might be effective strategies for prevention of tissue injury.…”

Section: Discussionmentioning

confidence: 99%

circ-PRKCB acts as a ceRNA to regulate p66Shc-mediated oxidative stress in intestinal ischemia/reperfusion

Feng¹,

Wang²,

Zhao³

et al. 2020

Theranostics

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Background: Oxidative stress has emerged as an essential factor in the pathogenesis of intestinal ischemia/reperfusion (I/R) injury. The adaptor protein p66Shc is a key regulator of reactive oxygen species (ROS) generation and a mediator of I/R damage in the intestine, but the upstream mechanisms that directly regulate p66Shc expression during intestinal I/R remain largely unknown. Recent studies have suggested that noncoding RNAs, such as circular RNAs (circRNAs), are important players in physiological and pathological processes based on their versatile regulatory roles in gene expression. The aim of this study was to elucidate the contribution of p66Shc to oxidative damage in intestinal I/R and to investigate the regulation of p66Shc by circRNA sponges. Methods: Intestinal I/R was induced in mice via superior mesenteric artery (SMA) occlusion. A miR-339-5p agomir or circ-protein kinase C beta (PRKCB) siRNA was injected intravenously before I/R challenge. In addition, Caco-2 cells were subjected to hypoxia/reoxygenation (H/R) in vitro to simulate an in vivo I/R model. Results: In vitro , p66Shc deficiency significantly reduced H/R-induced ROS overproduction by attenuating mitochondrial superoxide anion (O 2 - ) levels, suppressing NADPH oxidase activity and enhancing antioxidant enzyme expression. Moreover, miR-339-5p was identified to directly regulate p66Shc expression in the intestine. Furthermore, we found that a circRNA transcribed from the PRKCB gene, named circ-PRKCB, acted as an endogenous miR-339-5p sponge to regulate p66Shc expression. circ-PRKCB silencing or miR-339-5p overexpression significantly downregulated p66Shc expression and attenuated oxidative stress levels and I/R injury in vivo and in vitro . Notably, the increased circ-PRKCB levels and decreased miR-339-5p levels associated with murine intestinal I/R were consistent with those in patients with intestinal infarction. Conclusions: Our findings reveal a crucial role for the circ-PRKCB/miR-339-5p/p66Shc signaling pathway in regulating oxidative stress in the I/R intestine. This pathway may be a potential therapeutic target for intestinal I/R injury.

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Section: Discussionmentioning

confidence: 99%

circ-PRKCB acts as a ceRNA to regulate p66Shc-mediated oxidative stress in intestinal ischemia/reperfusion

Feng¹,

Wang²,

Zhao³

et al. 2020

Theranostics

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“…In addition to the renal system, IS affects the cardiovascular system and central nervous system ( Gao and Liu, 2017 ; Hung et al., 2017 ). Many studies have found that IS promotes inflammation, oxidative damage, and fibrosis and induces gut barrier ( Huang et al., 2020 ) and endothelial cell dysfunction. Our study showed that IS was elevated after stroke, and lactulose significantly decreased its accumulation.…”

Section: Discussionmentioning

confidence: 99%

Lactulose Improves Neurological Outcomes by Repressing Harmful Bacteria and Regulating Inflammatory Reactions in Mice After Stroke

Yuan

Xin

Han

et al. 2021

Front. Cell. Infect. Microbiol.

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Background and ObjectiveGut microbiota dysbiosis following stroke affects the recovery of neurological function. Administration of prebiotics to counteract post-stroke dysbiosis may be a potential therapeutic strategy to improve neurological function. We aim to observe the effect of lactulose on neurological function outcomes, gut microbiota composition, and plasma metabolites in mice after stroke.MethodsMale C57BL/6 mice (20–25 g) were randomly divided into three groups: healthy control, photothrombotic stroke + triple-distilled water, and photothrombotic stroke + lactulose. After 14 consecutive days of lactulose administration, feces, plasma, and organs were collected. 16S rDNA sequencing, plasma untargeted metabolomics, qPCR, flow cytometry and Elisa were performed.ResultsLactulose supplementation significantly improved the functional outcome of stroke, downregulated inflammatory reaction, and increased anti-inflammatory factors in both the brain and gut. In addition, lactulose supplementation repaired intestinal barrier injury, improved gut microbiota dysbiosis, and partially amended metabolic disorder after stroke.ConclusionLactulose promotes functional outcomes after stroke in mice, which may be attributable to repressing harmful bacteria, and metabolic disorder, repairing gut barrier disruption, and reducing inflammatory reactions after stroke.

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“…In this work, we discovered that children with CD have higher excretion of indoxyl sulfate and its oxidized metabolite, hydroxyindoxyl sulfate that was identified by MS/MS for the first time, along with corresponding lower kynurenine as compared to age-matched UC cases ( Figure 2 , Table 2 ). Elevated levels of indoxyl sulfate and other indole/aryl metabolites function as proinflammatory uremic toxins in circulation, which may contribute to epithelial barrier injury [ 30 ] in IBD patients with underlying gut dysbiosis. Similarly, phenylacetylglutamine also had higher excretion in patients with CD relative to UC.…”

Section: Discussionmentioning

confidence: 99%

Urinary Metabolites Enable Differential Diagnosis and Therapeutic Monitoring of Pediatric Inflammatory Bowel Disease

et al. 2021

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Rates of pediatric Crohn’s disease (CD) and ulcerative colitis (UC) are increasing globally. Differentiation of these inflammatory bowel disease (IBD) subtypes however can be challenging when relying on invasive endoscopic approaches. We sought to identify urinary metabolic signatures of pediatric IBD at diagnosis, and during induction treatment. Nontargeted metabolite profiling of urine samples from CD (n = 18) and UC (n = 8) in a pediatric retrospective cohort study was performed using multisegment injection-capillary electrophoresis-mass spectrometry. Over 122 urinary metabolites were reliably measured from pediatric IBD patients, and unknown metabolites were identified by tandem mass spectrometry. Dynamic changes in sum-normalized urinary metabolites were also monitored following exclusive enteral nutrition (EEN) or corticosteroid therapy (CS) in repeat urine samples collected over 8 weeks. Higher urinary excretion of indoxyl sulfate, hydroxyindoxyl sulfate, phenylacetylglutamine, and sialic acid were measured in CD as compared to UC patients, but lower threonine, serine, kynurenine, and hypoxanthine (p < 0.05). Excellent discrimination of CD from UC was achieved based on the urinary serine:indoxylsulfate ratio (AUC = 0.972; p = 3.21 × 10−5). Urinary octanoyl glucuronide, pantothenic acid, and pyridoxic acid were also identified as specific dietary biomarkers of EEN in pediatric IBD patients who achieved clinical remission. This work may complement or replace existing strategies in the diagnosis and early management of children with IBD.

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Indoxyl sulfate induces intestinal barrier injury through IRF1-DRP1 axis-mediated mitophagy impairment

Cited by 81 publications

References 56 publications

circ-PRKCB acts as a ceRNA to regulate p66Shc-mediated oxidative stress in intestinal ischemia/reperfusion

circ-PRKCB acts as a ceRNA to regulate p66Shc-mediated oxidative stress in intestinal ischemia/reperfusion

Lactulose Improves Neurological Outcomes by Repressing Harmful Bacteria and Regulating Inflammatory Reactions in Mice After Stroke

Urinary Metabolites Enable Differential Diagnosis and Therapeutic Monitoring of Pediatric Inflammatory Bowel Disease

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