N 6 -methyladenine (m 6 A) is the most prevalent type of internal RNA methylation in eukaryotic mRNA and plays critical roles in regulating gene expression for fundamental cellular processes and diverse physiological functions. Recent evidence indicates that m 6 A methylation regulates physiology and metabolism, and m 6 A has been increasingly implicated in a variety of human diseases, including obesity, diabetes, metabolic syndrome and cancer. Conversely, nutrition and diet can modulate or reverse m 6 A methylation patterns on gene expression. In this review, we summarize the recent progress in the study of the m 6 A methylation mechanisms and highlight the crosstalk between m 6 A modification, nutritional physiology and metabolism. KEYWORDS epitranscriptomic, M 6 A RNA methylation, metabolism, nutrition 1 | INTRODUCTION More than 100 types of chemical modifications have been discovered in cellular RNAs. 1 Reversible RNA modifications are an emerging layer of posttranscriptional gene regulation, 2,3 which exerts a large number of physiological processes and biological functions. 4,5 As a novel epitranscriptomic marker, the dynamic and reversible chemical N 6methyladenine (m 6 A) modification is the most abundant internal modification in mRNA. In mammals, plants and some prokaryotes, m 6 A is widely involved in mRNA metabolism, including mRNA stability, 6 mRNA splicing, 7,8 RNA nucleation, 9 RNA-protein interactions 10 and mRNA translation. 11The m 6 A modification plays an important role in nutritional physiology and metabolism, such as controlling circadian rhythms, 12,13 lipid accumulation 14 and adipogenesis. 15,16 The dysregulation of m 6 A patterns causes abnormal gene expression and functions, aberrant cell differentiation and cellular homeostasis imbalance, leading to the occurrence of certain inflammatory states, metabolic diseases and cancer. 9,17,18 Therefore, the effects of m 6 A RNA methylation on physiology and metabolism have become a research hotspot in the RNA Abbreviations: m 6 A, N 6 -methyladenine; 3'-UTRs, 3'untranslated regions; CDS, coding sequence; MTC, methyltransferase cpmplex; METTL3, methyltransferase-like 3; METTL14, methyltransferase-like 14; WTAP, Wilms' tumour 1-associating protein; ZC3H13, zinc finger CCCH-type containing 13; RBM15/15B, RNA binding motif protein 15/15B; FTO, fat mass and obesity-associated protein; ALKBH5, AlkB homolog 5; YTHDF1/2/3, YTH domain family 1/2/3; YTHDC1/2, YTH domain containing 1/2; SAM, S-adenosylmethionine; hm 6 A, N 6hydroxymethyladenosine; f 6 A, N 6 -formyladenosine; A, adenosine; m 6 A m , N 6 ,2'-O-dimethyladenosine; DCP2, decapping mRNA 2; snRNA, small nuclear RNA; eIF3, eukaryotic initiation factor 3; SRSF3, serine/arginine-rich splicing factor 3; SRSF10, serine/arginine-rich splicing factor 10; HNRNPA2B1, heterogenous nuclear ribonucleoprotein A2B1; HNRNPC, heterogenous nuclear ribonucleoprotein C; DGCR8, DiGeorge syndrome critical region gene 8; IGF2BP1/2/3, insulin-like growth factor 2 mRNA-binding protein 1/2/3; T2DM, type 2 diabetes melli...

Human infants or piglets are vulnerable to intestinal microbe-caused disorders and inflammation due to their rapidly changing gut microbiota and immaturity of their immune systems at weaning. Resveratrol and curcumin have significant anti-inflammatory, bacteria-regulating and immune-promoting effects. The purpose of this study was to investigate whether dietary supplementation with resveratrol and curcumin can change the intestinal microbiota and alleviate intestinal inflammation induced by weaning in piglets. One hundred eighty piglets weaned at 21 ± 2 d were fed a control diet (CON group) or supplemented diet (300 mg/kg of antibiotics, ANT group; 300 mg/kg of resveratrol and curcumin, respectively, HRC group; 100 mg/kg of resveratrol and curcumin, respectively, LRC group; 300 mg/kg of resveratrol, RES group; 300 mg/kg of curcumin, CUR group) for 28 days. The results showed that compared with the CON group, curcumin alone and antibiotics decreased the copy numbers of Escherichia coli. Both curcumin and resveratrol down-regulated the level of Toll-like-receptor 4 mRNA and protein expression in the intestine to inhibit the release of critical inflammation molecules (interleukin-1β, tumor necrosis factor-α), and increase the secretion of immunoglobulin. Our results suggested that curcumin and resveratrol can regulate weaned piglet gut microbiota, down-regulate the TLR4 signaling pathway, alleviate intestinal inflammation, and ultimately increase intestinal immune function.

The purpose of this study was to explore the effects of curcumin on IUGR jejunum damage. A total of 24 IUGR and 12 normal-birth weight (NBW) female crossbred (Duroc × Landrace × Large White) piglets were randomly assigned into three groups at weaning (26 days): IUGR group, NBW group, and IUGR + CUR group, which were fed diets containing 0 mg/kg (NBW), 0 mg/kg (IUGR) and 200 mg/kg (IUGR + CUR) curcumin from 26 to 115 days of age. Results showed that dietary supplementation with 200 mg/kg curcumin significantly increased the total superoxide dismutase (T-SOD) activity and decreased the malondialdehyde (MDA) content in the jejunum of IUGR pigs (p < 0.05). Results of real-time PCR showed that the IUGR + CUR group significantly increased the gene expression of NF-E2-related factor 2 (Nrf2) (p < 0.05), and increased the glutamate-cysteine ligase catalytic subunit (GCLC), superoxide dismutase 1 (SOD1), glutamate-cysteine ligase modifier subunit (GCLM), and NAD(P)H quinone dehydrogenase 1 (NQO1) mRNA expression compared with the IUGR group (p < 0.05). Western blot results showed that dietary supplementation with 200 mg/kg curcumin significantly increased the protein levels of Nrf2 and NQO1. Compared with the IUGR group, pigs in IUGR + CUR group showed significantly decreased the levels of tumor necrosis factor-α (TNFα), interleukin-6 (IL-6), and interferon gamma (IFNγ) (p < 0.05), and increased the interleukin-2 (IL-2) level (p < 0.05). Dietary supplementation with 200 mg/kg curcumin significantly reduced cysteinyl aspartate specific proteinase 3 (caspase3), BCL2-associated X protein (bax), B-cellCLL/lymphoma 2 (bcl2), and heat-shock protein 70 (hsp70) mRNA expression, and increased occludin (ocln) mRNA expression (p < 0.05). In conclusion, dietary supplementation with 200 mg/kg curcumin can alleviate jejunum damage in IUGR growing pigs, through Nrf2/Keap1 pathway.

Curcumin has improved effects on antioxidant capacity via multiple mechanisms. Intrauterine growth retardation (IUGR) has had adverse influences on human health. IUGR is always associated with elevated oxidative stress and deficiencies in antioxidant defense. Therefore, we chose IUGR piglets as a model to investigate the effects of IUGR on antioxidant capacity of newborn and weaned piglets and determine how these alterations were regulated after supplementation with curcumin in weaned IUGR piglets. In experiment 1, eight normal-birth-weight (NBW) and eight IUGR newborn piglets were selected to determine the effect of IUGR on the antioxidant capacity of neonatal piglets. In experiment 2, thirty-two weaned piglets from four experimental groups: NBW, NC (curcumin supplementation), IUGR, IC (curcumin supplementation) were selected. The results showed that both IUGR newborn and weaned piglets exhibited oxidative damage and lower antioxidant enzymes activities in the liver compared with the NBW piglets. Dietary curcumin supplementation increased body-weight gain, feed intake, activities of antioxidant enzymes, and the expressions of nuclear factor, erythroid 2-like 2 (Nrf2) and heme oxygenase-1 (Hmox1) proteins in the liver of weaned piglets with IUGR. In conclusion, IUGR decreased the antioxidant capacity of newborn and weaned piglets. Curcumin could efficiently improve the growth, increase hepatic antioxidant capacity, and upregulate Nrf2 and Hmox1 levels in the liver of IUGR weaned piglets.

N6-Methyladenosine (m6A) is the most prevalent modification on eukaryotic messenger RNA (mRNA). Resveratrol and curcumin, which can exert many health-protective effects, may have a relationship with m6A RNA methylation. We hypothesized that the combination of resveratrol and curcumin could affect growth performance, intestinal mucosal integrity, m6A RNA methylation, and gene expression in weaning piglets. One hundred and eighty piglets weaned at 28 ± 2 days were fed a control diet or supplementary diets (300 mg/kg of antibiotics; 300 mg/kg of each resveratrol and curcumin; 100 mg/kg of each resveratrol and curcumin; 300 mg/kg of resveratrol; 300 mg/kg of curcumin) for 28 days. The results showed that the combination of resveratrol and curcumin improved growth performance and enhanced intestinal mucosal integrity and functions in weaning piglets. Resveratrol and curcumin also increased intestinal antioxidative capacity and mRNA expression of tight junction proteins. Furthermore, resveratrol and curcumin decreased the content of m6A and decreased the enrichment of m6A on the transcripts of tight junction proteins and on heme oxygenase-1 in the intestine. Our findings indicated that the combination of resveratrol and curcumin increased growth performance, enhanced intestine function, and protected piglet health, which may be associated with changes in m6A methylation and gene expression, suggesting that curcumin and resveratrol may be a potential natural alternative to antibiotics.