Serine alleviates oxidative stress via supporting glutathione synthesis and methionine cycle in mice

Zhou, Xin; He, Liuqin; Wu, C.L.; Zhang, Yumei; Wu, Xin; Yin, Yulong

doi:10.1002/mnfr.201700262

Cited by 133 publications

(92 citation statements)

References 45 publications

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“…Moreover, cancer cells cultured in the serine‐deficient medium had reduced glutathione content and were vulnerable to peroxide treatment . Furthermore, our previous studies suggested that serine supplementation could alleviate oxidative stress in different rodent models . Either exogenous or endogenous serine might be important for the synthesis of glutathione and for the cells to counteract oxidative stress, although direct evidence is still lacking.…”

Section: Introductionmentioning

confidence: 99%

Serine is required for the maintenance of redox balance and proliferation in the intestine under oxidative stress

Long

Zhou

et al. 2020

FASEB j.

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Serine has critical roles in maintaining cell growth and redox balance in cancer cells. However, the role of exogenous serine played in oxidative response and proliferation in normal mammalian intestine need to be further elucidated. We used a mouse model and intestinal porcine epithelial cells (IPEC‐J2) to reveal that exogenous serine deficiency did not lead to redox imbalance and inhibition of proliferation in the intestine. However, serine deficiency exacerbated oxidative stress, mitochondrial dysfunction, apoptosis, and inhibition of proliferation in IPEC‐J2 cells challenged by hydrogen peroxide, while serine supplementation rescued redox imbalance and those proliferation defects. Importantly, serine supplementation restored the glutathione content and decreased the accumulation of reactive oxygen species, while no such effects were observed when glutathione synthesis was inhibited. Additionally, serine supplementation increased nuclear nrf2 expression in IPEC‐J2 cells. These results suggested that serine alleviates oxidative stress through supporting glutathione synthesis and activating nrf2 signaling. We further found that serine supplementation activated the mTOR pathway, while inhibition of mTOR diminished the effects of serine on promoting proliferation, suggesting critical roles of the mTOR pathway in this context. Taken together, our study underlines the importance of serine in the maintenance of redox status and proliferation in the intestine and reveals a novel potential mechanism that mediates these effects.

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Section: Introductionmentioning

confidence: 99%

Serine is required for the maintenance of redox balance and proliferation in the intestine under oxidative stress

Long

Zhou

et al. 2020

FASEB j.

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“…Research examining the impacts of dietary serine supplementation on humans and rodents showed no adverse effects [4]. Our recent studies with mice showed that serine, as a precursor of glutathione, could alleviate hepatic oxidative stress by regulating the expression of glutathionesynthesis-related genes and increasing glutathione concentration [6,7]. In addition, serine supplementation has been reported to be beneficial for intestinal health in a mouse model with intestinal inflammation and barrier damage induced by lipopolysaccharide (LPS) [8].…”

Section: Introductionmentioning

confidence: 99%

Effects of Dietary Serine Supplementation on Intestinal Integrity, Inflammation and Oxidative Status in Early-Weaned Piglets

Zhou

Zhang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Early weaning often causes gut dysfunction. Since serine alleviates oxidative stress and inflammatory response which are accompany with early weaning, we conducted the study to explore whether serine improves intestinal function in early-weaned piglets. Methods: Twenty-eight weaned piglets (aged 21 d) were fed either a basal diet or a basal diet plus 0.2% serine. We determined the effects of dietary serine supplementation on intestinal morphology by hematoxylin and eosin staining, expression of tight junction proteins (TJPs) by immunoblotting and immunofluorescence, expression of inflammatory cytokines and apoptosis markers by RT-qPCR and the level of antioxidant enzymes with ELISA kits in early-weaned piglets. Results: Serine supplementation increased daily body weight gain while decreasing diarrhea incidence. Both the jejunum and ileum of serine-supplemented piglets showed regularly arranged villi and microvilli. Moreover, dietary serine increased TJP expression, and alleviated apoptosis, inflammation, and oxidative stress in the intestine of early-weaned piglets. Conclusion: Our findings suggest that serine has the potential for use as a feed additive to prevent gut dysfunction caused by weaning.

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“…NADH production via one-carbon metabolism is driven by serine, which can be generated through the upstream serine biosynthesis pathway in the cytosol ( PHGDH , PSAT1 , PSPH )( Figure 4B ). While enzymes of serine biosynthesis are known to be transcriptionally induced in various stresses (Zhao et al, 2016;Zhou et al, 2017) , we find additional upregulation of ribosome binding and therefore translation for these genes ( Figure 4B; Figure S7 ). We also find such concordant increase in transcription and translation for the mitochondrial one-carbon metabolism enzymes, but not for their cytosolic homologs, supporting our interpretation.…”

Section: Translation Regulation Modulates Energy Metabolism During Ermentioning

confidence: 53%

Quantifying multi-layered expression regulation in response to stress of the endoplasmic reticulum

Rendleman

Cheng

Maity

et al. 2018

Preprint

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The mammalian response to endoplasmic reticulum (ER) stress dynamically affects all layers of gene expression regulation. We quantified transcript and protein abundance along with footprints of ribosomes and non-ribosomal proteins for thousands of genes in cervical cancer cells responding to treatment with tunicamycin or hydrogen peroxide over an eight hour time course. We identify shared and stress-specific significant regulatory events at the transcriptional and post-transcriptional level and at different phases of the experiment. ER stress regulators increase transcription and translation at different times supporting an adaptive response. ER stress also induces translation of genes from serine biosynthesis and one-carbon metabolism indicating a shift in energy production. Discordant regulation of DNA repair genes suggests transcriptional priming in which delayed translation fine-tunes the early change in the transcriptome. Finally, case studies on stress-dependent alternative splicing and protein-mRNA binding demonstrate the ability of this resource to generate hypotheses for new regulatory mechanisms.have substantial contributions to the ER stress response, but show different temporal patterns (Kershaw et al., 2015;Liu et al., 2017;Quirós et al., 2017 ;Cheng et al., 2015 ;Guan et al., 2014) .Here, we provide one of the most comprehensive assessments of the gene expression response to ER stress available to date. We collected replicate samples at four time points (0, 1, 4, and 8 hours) from human cervical cancer cells treated with tunicamycin. Using RNA-seq and mass spectrometry, we determined the complete RNA and protein concentrations for >7,000 genes in the core dataset and for >14,000 genes in the extended data. Further, using ribosome footprinting and protein-occupancy profiling, we mapped the binding of ribosomes and non-ribosomal proteins to mRNA, which informs on translation as well as several aspects of RNA processing, respectively. Finally, we applied the same technologies to cells treated with hydrogen peroxide to elicit oxidative stress. ER stress and the UPR are tightly linked to the oxidative stress response, largely due to reactive oxygen species (ROS) produced during protein folding in the ER (Malhotra and Kaufman, 2007) . In addition, eIF2α phosphorylation and translation inhibition are part of Integrated Stress Response, which is conserved across eukaryotes and triggered by a variety of stresses (Dickhout et al., 2012;Harding et al., 2003;Pakos-Zebrucka et al., 2016) . As the data rely on the coordinated change of two molecule types, e.g. a change in ribosome-bound mRNAs depends both on the number of translating ribosomes as well as the mRNA abundance, we have adapted our Protein Expression Control Analysis tool (PECA) (Teo et al., 2014(Teo et al., , 2018 to deconvolute the measurements and extract significant regulatory events per gene, per time point, and per regulatory level. Therefore, the presented data explores both shared and stress-specific regulation, it describes both the early and...

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Serine alleviates oxidative stress via supporting glutathione synthesis and methionine cycle in mice

Abstract: Our results indicated that serine supplementation alleviated oxidative stress via supporting glutathione synthesis and methionine cycle, mostly by condensing with homocysteine to synthesize cysteine and providing one-carbon units for homocysteine remethylation.

Cited by 133 publications

References 45 publications

Serine is required for the maintenance of redox balance and proliferation in the intestine under oxidative stress

Serine is required for the maintenance of redox balance and proliferation in the intestine under oxidative stress

Effects of Dietary Serine Supplementation on Intestinal Integrity, Inflammation and Oxidative Status in Early-Weaned Piglets

Quantifying multi-layered expression regulation in response to stress of the endoplasmic reticulum

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