Citrulline, A Potential Biomarker of Radiation-Induced Small Intestine Damage

Ye, Fei; Ning, Jing; Fardous, Zeenath; Katsube, Takanori; Li, Qiang; Wang, Bing

doi:10.1177/1559325820962341

Cited by 12 publications

(10 citation statements)

References 103 publications

(117 reference statements)

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“…Citrulline is a non-essential amino acid synthesized from glutamine, and plays a role associated with inflammatory disease (137)(138)(139)(140)(141)(142). In several organ exclusion experiments, it has been observed that most citrulline is synthesized in the intestinal epithelium, and subsequently enters into the blood circulation; thus, the intestinal epithelium is the main source of circulating citrulline under physiological conditions (138,(143)(144)(145).…”

Section: Citrullinementioning

confidence: 99%

Relevance of biomarkers indicating gut damage and microbial translocation in people living with HIV

et al. 2023

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The intestinal barrier has the daunting task of allowing nutrient absorption while limiting the entry of microbial products into the systemic circulation. HIV infection disrupts the intestinal barrier and increases intestinal permeability, leading to microbial product translocation. Convergent evidence has shown that gut damage and an enhanced level of microbial translocation contribute to the enhanced immune activation, the risk of non-AIDS comorbidity, and mortality in people living with HIV (PLWH). Gut biopsy procedures are invasive, and are not appropriate or feasible in large populations, even though they are the gold standard for intestinal barrier investigation. Thus, validated biomarkers that measure the degree of intestinal barrier damage and microbial translocation are needed in PLWH. Hematological biomarkers represent an objective indication of specific medical conditions and/or their severity, and should be able to be measured accurately and reproducibly via easily available and standardized blood tests. Several plasma biomarkers of intestinal damage, i.e., intestinal fatty acid-binding protein (I-FABP), zonulin, and regenerating islet-derived protein-3α (REG3α), and biomarkers of microbial translocation, such as lipopolysaccharide (LPS) and (1,3)-β-D-Glucan (BDG) have been used as markers of risk for developing non-AIDS comorbidities in cross sectional analyses and clinical trials, including those aiming at repair of gut damage. In this review, we critically discuss the value of different biomarkers for the estimation of gut permeability levels, paving the way towards developing validated diagnostic and therapeutic strategies to repair gut epithelial damage and to improve overall disease outcomes in PLWH.

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Section: Citrullinementioning

confidence: 99%

Relevance of biomarkers indicating gut damage and microbial translocation in people living with HIV

et al. 2023

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“…Citrulline is a nitrogen end-product of glutamine metabolism in small-bowel enterocytes, and plasma citrulline has been identified as a biomarker of radiation-induced gut damage[ 34 ]. To assess gut damage, mice were subjected to 14.5-Gy PBI and at 24 h later, they were treated daily with 1 μg/kg BW tag-free rhMFG-E8.…”

Section: Resultsmentioning

confidence: 99%

“…The serum levels of citrulline from PBI samples were measured using commercially available enzyme-linked immunosorbent assay (ELISA) kits (Mouse Citrulline ELISA Kit, MyBioSource, cat # MBS2602136). Plasma citrulline has been identified as a biomarker of radiation-induced gut damage [ 34 ]. Jejunal segments were paraffin-embedded, sectioned, and stained with H&E. Gut histological damage score for PBI samples was quantified using RIIMS, a detailed 7-category scoring system previously described [ 11 ].…”

Section: Methodsmentioning

confidence: 99%

Development of human cell-expressed tag-free rhMFG-E8 as a radiation mitigator and a therapeutic for acute kidney injury

Chaung

Zhang

et al. 2023

Preprint

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Background Human milk fat globule epidermal growth factor-factor VIII (MFG-E8) functions as a bridging molecule to promote the removal of dying cells by professional phagocytes. E. coli-expressed histidine-tagged recombinant human MFG-E8 (rhMFG-E8) is protective in various disease conditions. However, due to improper recombinant protein glycosylation, misfolding and possible antigenicity, E. coliexpressed histidine-tagged rhMFG-E8 is unsuitable for human therapy. Therefore, we hypothesize that human cell-expressed, tag-free rhMFG-E8 can be developed as a safe and effective novel biologic to treat inflammatory diseases such as radiation injury and acute kidney injury (AKI). Methods We produced a new tag-free rhMFG-E8 protein by cloning the human MFG-E8 full-length coding sequence without any fusion tag into a mammalian vector and expressed it in HEK293-derived cells. The construct includes the leader sequence of cystatin S to maximize secretion of rhMFG-E8 into the culture medium. After purification and confirmation of the protein identity, we first evaluated its biological activity in vitro. We then determined its efficacy in vivo utilizing two experimental rodent models of organ injury: partial body irradiation (PBI) and ischemia/reperfusion-induced AKI. Results HEK293 cell supernatant containing tag-free rhMFG-E8 protein was concentrated, purified, and rhMFG-E8 was verified by SDS-PAGE analysis and mass spectrometry. The biological activity of human cell-expressed tag-free rhMFG-E8 was superior to that of E. coli-expressed His-tagged rhMFG-E8. Toxicity, stability, and pharmacokinetic studies indicate that tag-free rhMFG-E8 is safe, highly stable after lyophilization and long-term storage, and with an adequate half-life for therapeutic applications. In the PBI model, a dose-dependent improvement of the 30-day survival rate was observed after tag-free rhMFG-E8 treatment with a 30-day survival of 89%, which was significantly higher than the 25% survival in the vehicle group. The dose modification factor (DMF) of tag-free rhMFG-E8 was 1.073. Tag-free rhMFG-E8 also attenuated gastrointestinal damage after PBI. In the model of AKI, tag-free rhMFG-E8 treatment significantly attenuated kidney injury and inflammation, and improved the 10-day survival. Conclusion Our new human cell-expressed tag-free rhMFG-E8 can be further developed as a safe and effective therapy to treat victims of severe acute radiation injury and patients with acute kidney injury.

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“…Decreased circulating levels of citrulline may imply that enterocytes are being damaged, thus compromising the amino acid synthesis and reducing its release in the blood stream. Such a relation is explored in human health to assess the cytotoxic effects of chemo- and radiotherapy on the gut mucosa, which result in mucositis [ 172 , 173 , 174 , 175 ]. Citrulline circulating levels have also responded to intestinal cytotoxicity in dogs and rats, but this is still controversial in these species [ 176 , 177 , 178 , 179 ].…”

Section: Structural and Inflammatory Biomarkersmentioning

confidence: 99%

Morphological Assessment and Biomarkers of Low-Grade, Chronic Intestinal Inflammation in Production Animals

Soares¹,

Belote²,

Santín³

et al. 2022

Animals

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The complex interaction between the intestinal mucosa, the gut microbiota, and the diet balances the host physiological homeostasis and is fundamental for the maximal genetic potential of production animals. However, factors such as chemical and physical characteristics of the diet and/or environmental stressors can continuously affect this balance, potentially inducing a state of chronic low-grade inflammation in the gut, where inflammatory parameters are present and demanding energy, but not in enough intensity to provoke clinical manifestations. It’s vital to expand the understanding of inflammation dynamics and of how they compromise the function activity and microscopic morphology of the intestinal mucosa. These morphometric alterations are associated with the release of structural and functional cellular components into the feces and the blood stream creating measurable biomarkers to track this condition. Moreover, the identification of novel, immunometabolic biomarkers can provide dynamic and predictors of low-grade chronic inflammation, but also provide indicators of successful nutritional or feed additive intervention strategies. The objective of this paper is to review the mechanisms of low-grade inflammation, its effects on animal production and sustainability, and the biomarkers that could provide early diagnosis of this process and support studies of useful interventional strategies.

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Citrulline, A Potential Biomarker of Radiation-Induced Small Intestine Damage

Cited by 12 publications

References 103 publications

Relevance of biomarkers indicating gut damage and microbial translocation in people living with HIV

Relevance of biomarkers indicating gut damage and microbial translocation in people living with HIV

Development of human cell-expressed tag-free rhMFG-E8 as a radiation mitigator and a therapeutic for acute kidney injury

Morphological Assessment and Biomarkers of Low-Grade, Chronic Intestinal Inflammation in Production Animals

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