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Behavioral evidence showed decreased cognitive flexibility in older adults. However, task-based network mechanisms of cognitive flexibility in aging (CFA) remain unclear. Here, we provided the first task-state network evidence that CFA was associated with inadequate preparation for switching trials by revealing age-related changes in functional integration. We examined functional integration in a letter–number switch task that distinguished between the cue and target stages. Both young and older adults showed decreased functional integration from the cue stage to the target stage, indicating that control-related processes were executed as the task progressed. However, compared to young adults, older adults showed less cue-to-target reduction in functional integration, which was primarily driven by higher network integration in the target stage. Moreover, less cue-to-target reductions were correlated with age-related decreases in task performance in the switch task. To sum up, compared to young adults, older adults pre-executed less control-related processes in the cue stage and more control-related processes in the target stage. Therefore, the decline in cognitive flexibility in older adults was associated with inadequate preparation for the impending demands of cognitive switching. This study offered novel insights into network mechanisms underlying CFA. Furthermore, we highlighted that training the function of brain networks, in conjunction with providing more preparation time for older adults, may be beneficial to their cognitive flexibility.

Schizophrenia often occurs in youth, and psychosis risk syndrome (PRS) occurs before the onset of psychosis. Assessing the neuropsychological abnormalities of PRS individuals can help in early identification and active intervention of mental illness. Auditory P300 amplitude defect is an important manifestation of attention processing abnormality in PRS, but it is still unclear whether there are abnormalities in the attention processing of rhythmic compound tone stimuli in PRS individuals, and whether the P300 amplitude induced by these stimuli is specific to PRS individuals and related to their clinical outcomes.

Oleum cinnamomi(OCM, cinnamon oil), which is produced by aromatic cinnamon plants, is increasingly used as a feed additive to animal diets. OCM is a natural product rich in polyphenolic compounds that exhibit strong antioxidative property. However, the direct addition of OCM to the feed is questionable due to several limiting physical–chemical factors such as the high hydrophobicity, volatility, odor, fast decomposition, and poor availability in the lower gastrointestinal tract of animals. Therefore, the coated form of OCM (cOCM) is one of the ways to solve these concerns. We have demonstrated that dietary cOCM supplementation did not improve the growth performance of broiler chickens, but it showed beneficial effects on immunity and intestinal integrity. In the current study, we further investigated the intestinal cinnamaldehyde release and antioxidative capacity of chickens fed cOCM-supplemented diets. As cinnamaldehyde is a major constituent of OCM, we evaluated the release of cOCM in the intestine of birds by determining the contents of cinnamaldehyde in the digesta of small intestine and cecum. The increased availability of OCM in the lower intestine supplied a foundation for exerting its antioxidative effects. The activities of antioxidative enzymes were increased and superoxide levels were decreased in the plasma and intestinal mucosa of birds fed cOCM-supplemented diets. The improvement of antioxidative capacity was achieved by modulating the gene expression of nuclear factor erythroid 2-related factor 2 and downstream antioxidative enzymes.

Glässer’s disease, caused by Haemophilus parasuis, is a chronic disease related to an inflammatory immune response. Baicalin exerts important biological functions. In this study, we explored the protective efficacy of treatment with baicalin and the potential mechanism of activation of the MAPK signaling pathway in porcine aortic vascular endothelial cells (PAVECs) induced by H. parasuis. H. parasuisstimulated expression of receptor for advanced glycation end products, induced a significant increase in the level of protein kinase-α and protein kinase-δ phosphorylation, and significantly up-regulated ERK, c-Jun N-terminal kinase, and p38 phosphorylation in PAVECs. H. parasuisalso up-regulated the levels of apoptotic genes (Bax, C-myc, and Fasl) and the expression levels of c-Jun and c-Fos, and induced S-phase arrest in PAVECs. However, treatment with baicalin inhibited expression of RAGE, suppressed H. parasuis-induced protein kinase-α and protein kinase-δ phosphorylation, reduced ERK, c-Jun N-terminal kinase, and p38 phosphorylation, down-regulated apoptotic genes (Bax, C-myc, and Fasl), attenuated phospho-c-Jun production from the extracellular to the nuclei, and reversed S-phase arrest in PAVECs. In conclusion, baicalin treatment inhibited the MAPK signaling pathway, thereby achieving its anti-inflammatory responses, which provides a new strategy to control H. parasuisinfection.

Here, the potential mechanisms of the protective effects of fish oil against LPS-induced liver injury in a piglet model were investigated by using RNA sequencing. Twenty-four piglets were used in a 2 × 2 factorial design, and the main factors included diet (5% corn oil or 5% fish oil) and immunological challenge (LPS or saline, on d 19). All piglets were slaughtered at 4 h after challenge, and liver samples were collected. Fish oil improved liver morphology and reduced TNF-α, IL-1β and IL-6 productions after LPS challenge. RNA sequencing analysis showed fish oil had significant effect on the expressions of genes involved in immune response during LPS-induced inflammation. Selected gene expression changes were validated using quantitative RT-PCR. Fish oil reduced the expressions of pro-inflammatory genes IL1R1, IL1RAP, CEBPBand CRP, and increased that of anti-inflammatory genes IL-18BP, NFKBIA, IFIT1, IFIT2and ATF3. Moreover, fish oil restored the expressions of some lipid metabolism-related genes, such as ACAA1, ACACA, ACADSand ACADM, which were only decreased in pigs fed a corn oil diet after LPS challenge. Our RNA sequencing reveals novel gene-nutrient interactions following fish oil supplementation and evoked inflammation, which add to the current understanding of the benefits of n-3 polyunsaturated fatty acids against liver injury.

Arginine (Arg) has traditionally not been considered as a deficient nutrient in diets for gestating or lactating swine due to the assumption that these animals can synthesize sufficient amounts of Arg to meet their physiological needs. The lack of full knowledge about Arg nutrition has contributed to suboptimal efficiency of pork production. Over the past 25 yr, there has been growing interest in Arg metabolism in the pig, which is an agriculturally important species and a useful model for studying human biology. Arginine is a highly abundant amino acid in tissues of pigs, a major amino acid in allantoic fluid, and a key regulator of gene expression, cell signaling, and antioxidative reactions. Emerging evidence suggests that dietary supplementation with 0.5% to 1% Arg maintains gut health and prevents intestinal dysfunction in weanling piglets, while enhancing their growth performance and survival. Also, the inclusion of 1% Arg in diets is required to maximize skeletal muscle accretion and feed efficiency in growing pigs, whereas dietary supplementation with 1% Arg reduces muscle loss in endotoxin-challenged pigs. Furthermore, supplementing 0.83% Arg to corn- and soybean meal–based diets promotes embryonic/fetal survival in swine and milk production by lactating sows. Thus, an adequate amount of dietary Arg as a quantitatively major nutrient is necessary to support maximum growth, lactation, and reproduction performance of swine. These results also have important implications for improving the nutrition and health of humans and other animals.

Traditionally, antibiotics are included in animal feed at subtherapeutic levels for growth promotion and disease prevention. However, recent links between in-feed antibiotics and a rise in antibiotic-resistant pathogens have led to a ban of all antibiotics in livestock production by the European Union in January 2006 and a removal of medically important antibiotics in animal feeds in the United States in January 2017. An urgent need arises for antibiotic alternatives capable of maintaining animal health and productivity without triggering antimicrobial resistance. Host defense peptides (HDP) are a critical component of the animal innate immune system with direct antimicrobial and immunomodulatory activities. While in-feed supplementation of recombinant or synthetic HDP appears to be effective in maintaining animal performance and alleviating clinical symptoms in the context of disease, dietary modulation of the synthesis of endogenous host defense peptides has emerged as a cost-effective, antibiotic-alternative approach to disease control and prevention. Several different classes of small-molecule compounds have been found capable of promoting HDP synthesis. Among the most efficacious compounds are butyrate and vitamin D. Moreover, butyrate and vitamin D synergize with each other in enhancing HDP synthesis. This review will focus on the regulation of HDP synthesis by butyrate and vitamin D in humans, chickens, pigs, and cattle and argue for potential application of HDP-inducing compounds in antibiotic-free livestock production.

Stress causes intestinal inflammation and barrier dysfunction. Corticotrophin-releasing factor (CRF)/CRF receptor (CRFR) signaling pathway has been shown to be important for stress-induced intestinal mucosal alteration. L-Asparagine (ASN) is a powerful stimulator of ornithine decarboxylase and cell proliferation in a variety of cell types, including colonic cells. In the present study, we investigated whether dietary ASN supplementation could alleviate the damage of intestinal barrier function caused by LPS through modulation of CRF/CRFR signaling pathway. Twenty-four weaned pigs were randomly divided into one of four treatments: (1) non-challenged control; (2) Escherichia coliLPS challenged control; (3) LPS + 0.5% ASN; (4) LPS + 1.0% ASN. LPS stress induced villous atrophy, intestinal morphology disruption and decreased claudin-1 expression. ASN supplementation increased intestinal claudin-1 protein expression and alleviated villous atrophy and intestinal morphology impairment caused by LPS stress. In addition, ASN supplementation increased the number of intestinal intraepithelial lymphocytes and reversed the elevations of intestinal mast cell number and neutrophil number induced by LPS stress. Moreover, ASN decreased the mRNA expression of intestinal CRF, glucocorticoid receptors and tryptase. These results indicate that ASN attenuates intestinal barrier dysfunction induced by LPS stress, and regulates CRF/CRFR1 signaling pathway and mast cell activation.

Infection and inflammation can result in the rapid loss of muscle mass and myofibrillar proteins (muscle atrophy). In addition, aspartate (Asp) is necessary for protein synthesis in mammalian cells. We hypothesized that Asp could attenuate LPS-induced muscle atrophy in a piglet model. Twenty-four weaning piglets were allotted to four treatments, including non-challenged control, LPS challenged control, LPS+0.5% Asp and LPS+1.0% Asp. On d 21, the piglets were injected with i.p. injection of LPS (100 ug/kg BM) or saline. At 4 h post-injection, blood, gastrocnemius and longissimus dorsi muscles samples were collected for biochemical and molecular analyses. Asp decreased the concentrations of cortisol and glucagon in plasma. In addition, Asp increased protein and RNA contents in muscles, and decreased mRNA expression of muscle atrophy F-box (MAFbx) and muscle RING finger 1 (MuRF1). Moreover, Asp decreased phosphorylation of AMPKα but increased phosphorylation of Akt and Forkhead Box O (FOXO) 1 in the muscles. Our results indicate that Asp suppresses LPS-induced MAFbx and MuRF1 expression via activation of Akt signaling, and inhibition of AMPKα and FOXO1 signaling.

Amino acids (AAs) are defined as organic compounds containing both amino and acid groups (1). Proteinogenic AAs are AAs that serve as substrates for protein synthesis in animal cells, and occur naturally as L-AAs except for glycine. Free AAs (those AAs that are not constituents of peptides or polymers) in physiologic fluid exist primarily in an L-isoform, but some of them may be present in a D-isoform. Based on his findings in 1912 that adult dogs exhibited a negative nitrogen balance when fed a tryptophan-free diet but maintained a positive nitrogen balance when fed a proline-free diet, Abderhalden (2) classified AAs as nutritionally essential (EAAs) or nonessential (NEAAs). Beginning in 1924, WC Rose and coworkers (3) published a series of landmark papers on AA nutrition and metabolism in rats and humans that further defined AAs as EAAs or NEAAs based on nitrogen balance or growth. We published an essay on NEAAs in 2017 (4), and EAAs are the focus of the present article.

In this study, the anti-inflammatory effects and mechanisms of baicalin on LPS-induced NLRP3 inflammatory pathway were investigated in piglet mononuclear phagocytes (control, LPS stimulation, LPS stimulation + 12.5 µg/ml baicalin, LPS stimulation + 25 µg/ml baicalin, LPS stimulation + 50 µg/ml baicalin and LPS stimulation + 100 µg/ml baicalin). The levels of reactive oxygen species (ROS), the secretion levels of IL-1β, IL-18 and TNF-α, mRNA expression levels of IL-1β, IL-18, TNF-α and NLRP3, as well as the protein levels of cleaved caspase-1 p20 were significantly increased after LPS-challenge in vitro. However, LPS stimulation did not influence apoptosis-associated speck-like protein and caspase-1 mRNA levels, which are also components of the NLRP3 inflammasome. Baicalin at 50 µg/ml and 100 µg/ml could inhibit the production of ROS, TNF-α, IL-1β and IL-18, and down-regulate mRNA expression of IL-1β, IL-18, TNF-α and NLRP3, as well as expression of cleaved caspase-1 p20. These results showed that the anti-inflammatory effects of baicalin occurred via the regulation of the release of ROS and mRNA expression of NLRP3. The anti-inflammatory activity of baicalin could be related to the suppression of NLRP3 inflammasome pathway under LPS stimulation.

Amino acids (AAs) are building blocks of protein. Eight AAs (Ala, Asn, Asp, Glu, Gln, Gly, Pro, and Ser) are formed by all animals, whereas de novo synthesis of Arg occurs in a species-specific manner in most mammals (e.g., humans, pigs, and rats). Synthesizable AAs were traditionally classified as nutritionally nonessential for animals, because they were thought to be formed in sufficient amounts. However, this assumption is not supported by evidence showing that 1) rats grow slowly when their diets do not contain Arg, Glu, or Gln despite adequate provision of all other proteinogenous AAs; 2) pigs cannot achieve maximum growth, lactation, or reproduction performance when fed corn- and soybean meal-based diets meeting National Research Council–recommended requirements of protein and AAs without supplemental Arg, Glu, Gln, Gly, or Pro; 3) chickens exhibit increases in lean tissue gain and feed efficiency when their diets are supplemented with Glu, Gln, Gly, and Pro; 4) lactating cows cannot obtain maximum milk protein production without a postruminal supply of Gln or Pro; 5) fish cannot achieve maximum growth when diets do not contain Gln or Pro; and 6) men fail to sustain spermatogenesis when fed an Arg-deficient diet. Quantitative analysis of nitrogen metabolism showed that AA synthesis in animals is constrained by both precursor availability and enzyme activity. Taken together, these findings support the conclusion that the endogenous synthesis of AAs limits growth, lactation, and reproduction in animals. This new knowledge can guide the optimization of human nutrition for improving health and well-being.

The intestinal epithelium (IE) forms an indispensible barrier and interface between the intestinal interstitium and the luminal environment. The IE regulates water, ion and nutrient transport while providing a barrier against toxins, pathogens (bacteria, fungi and virus) and antigens. The apical intercellular tight junctions (TJ) are responsible for the paracellular barrier function and regulate trans-epithelial flux of ions and solutes between adjacent cells. Increased intestinal permeability caused by defects in the IE TJ barrier is considered an important pathogenic factor for the development of intestinal inflammation, diarrhea and malnutrition in humans and animals. In fact, defects in the IE TJ barrier allow increased antigenic penetration, resulting in an amplified inflammatory response in inflammatory bowel disease (IBD), necrotizing enterocolitis and ischemia-reperfusion injury. Conversely, the beneficial enhancement of the intestinal TJ barrier has been shown to resolve intestinal inflammation and apoptosis in both animal models of IBD and human IBD. Autophagy (self-eating mechanism) is an intracellular lysosome-dependent degradation and recycling pathway essential for cell survival and homeostasis. Dysregulated autophagy has been shown to be directly associated with many pathological processes, including IBD. Importantly, the crosstalk between IE TJ and autophagy has been revealed recently. We showed that autophagy enhanced IE TJ barrier function by increasing transepithelial resistance and reducing the paracellular permeability of small solutes and ions, which is, in part, by targeting claudin-2, a cation-selective, pore-forming, transmembrane TJ protein, for lysosome (autophagy)-mediated degradation. Interestingly, previous studies have shown that the inflamed intestinal mucosa in patients with active IBD has increased claudin-2 expression. In addition, inflammatory cytokines (for example, tumor necrosis factor-α, interleukin-6, interleukin-13, and interleukin-17) whose levels are increased in IBD patients cause an increase in claudin-2 expression and a claudin-2-dependent increase in TJ permeability. Thus, the role of claudin-2 in intestinal pathological processes has been attributed, in part, to the increase of intestinal TJ permeability. Claudin-2 represents a new therapeutic target in treating IBD, diarrhea and malnutrition in animals and humans.

Acetaminophen (AAP) and N-acetylcysteine (NAC) have been found to have anti-inflammatory effects via the TLR–NF-κB pathway in LPS-challenged piglets. However, the action mechanisms employed by AAP and NAC have yet to be completely understood. This study investigated the anti-inflammatory effects and mechanisms of AAP and NAC on LPS-induced inflammatory responses via the NLRP3 inflammasome pathway in piglet mononuclear phagocytes. The results show that mRNA expression levels of IL-1β, IL-18 and NLRP3, as well as the protein level of cleaved caspase-1, are significantly increased after LPS challenge in vitro. LPS stimulation did not change ASC and caspase-1 mRNA levels, which were components of NLRP3 inflammasome complex. AAP (0.5–1.0 mM) and NAC (0.5–1.0 mM) used individually or in combination could down-regulate protein expression of cleaved caspase-1 and mRNA expression of IL-1β, IL-18 and NLRP3. NAC could significantly enhance the above inhibition actions of AAP. The combined use of AAP plus NAC had better inhibition action on the NLRP3 inflammasome pathway. These results indicate that the anti-inflammatory effects of AAP and NAC occur via the regulation on mRNA expression of NLRP3 and activation of caspase-1. The anti-inflammatory activity of AAP and NAC could be related to the suppression of NLRP3 inflammasome pathway under LPS stimulation.

AbstractSalmonellaTyphimurium is a foodborne pathogen and commonly present on pig farms. Probiotics have shown potential as a means of reducing Salmonellashedding in pigs. Three experimental challenge trials were conducted to investigate the potential application of newly isolated Lactobacillusisolates for controlling Salmonellainfection in pigs. In each trial, 16 Yorkshire piglets (28-d old) were randomly allocated to 1 of 4 dietary treatments: (1) basal diet (BD), (2) naturally fermented (NF) feed, (3) Lactobacillus zeae–fermented (LZ-F) feed, and 4) Lactobacillus casei-fermented (LC-F) feed. All pigs consumed their assigned diets for 3 d prior to the challenge of SalmonellaTyphimurium DT104 (approximately 6 log colony-forming units/pig) through gavage. Pediococcus pentosaceus, L. zeae, and L. caseiwere most abundant in NF, LZ-F, and LC-F feed, respectively. After the challenge, pigs on fermented feed had lower rectal temperature, diarrhea scores, serum haptoglobin concentrations, and intestinal Salmonellacounts than the control group (BD) (p≤0.01). Salmonellaspp. were detected in both ileocecal lymph nodes (ICLN) and spleens from all pigs on BD, NF, and LC-F, but only 50% of spleens from pigs on LZ-F. Pigs had a dynamic spatial and temporal immune response to Salmonellainfection and dietary treatments, as indicated by up- and downregulation in gene expression of inflammatory cytokines (interleukin (IL)-1β, IL-6, IL-10, interferon-γ, and tumor necrosis factor) in the ileum, ICLN, and spleen. The alternation in cytokine expression by fermented feed, particularly LZ-F, appeared to benefit pigs in combating Salmonellainfection.

This study evaluated whether fish oil exerted a hepatoprotective effect in a LPS-induced liver injury model via regulation of TLR4 and nucleotide-binding oligomerization domain protein (NOD) signaling pathways. Twenty-four piglets were used in a 2 × 2 factorial design, and the main factors included diet (5% corn oil or 5% fish oil) and immunological challenge (LPS or saline). Fish oil resulted in enrichment of eicosapentaenoic acid, docosahexaenoic acid and total (n-3) polyunsaturated fatty acids in liver. Less severe liver injury was observed in pigs fed fish oil, as evidenced by improved serum biochemical parameters and less severe histological liver damage. In addition, higher expression of liver tight junction proteins, and lower hepatocyte proliferation and higher hepatocyte apoptosis were observed in pigs fed fish oil. The improved liver integrity in pigs fed fish oil was concurrent with reduced hepatic mRNA expression of TLR4, myeloid differentiation factor 88, IL-1 receptor-associated kinase 1 and TNF-α receptor-associated factor 6, and NOD1, NOD2 and receptor-interacting serine/threonine-protein kinase 2, as well as reduced hepatic protein expression of NF-κB p65, leading to reduced hepatic pro-inflammatory mediators. These results indicate that fish oil improves liver integrity partially via inhibition of TLR4 and NOD signaling pathways under an inflammatory condition.

This study was conducted to evaluate whether dietary supplementation with L-arginine (Arg) could attenuate Escherichia coli LPS-induced liver injury through the TLR4 signaling pathway in weaned pigs. Eighteen weaned pigs were allotted to three treatments: non-challenged control, LPS challenged control and LPS + 0.5% Arg. On d 18, pigs were injected with LPS at 100 µg/kg of body weight (BW) or sterile saline. Blood samples were obtained at 4 h post-injection. Pigs were then sacrificed for the collection of liver samples. Arg supplementation (0.5%) alleviated liver morphological impairment, including hepatocyte caryolysis, karyopycnosis and fibroblast proliferation induced by LPS challenge; it mitigated the increase of serum aspartate aminotransferase and alkaline phosphatase activities induced by LPS (P < 0.05); it prevented the increase of hepatic TNF-α, malondialdehyde contents and mast cell number induced by LPS administration (P < 0.05); and it attenuated the elevation of hepatic NF-κB and TLR4-positive cell percentages (P < 0.05). These results indicate that Arg supplementation has beneficial effects in attenuating hepatic morphological and functional injury induced by LPS challenge in piglets. Additionally, it is possible that the protective effects of Arg on the liver are associated with a decreased release of liver pro-inflammatory cytokines and free radicals through inhibiting TLR4 signaling.

Our previous study demonstrated mRNA and protein expression of peroxisome proliferator-activated receptor-g (PPAR-g) in the immune system of weaned pigs. In this report, to test the hypothesis that activation of PPAR-g in immune system modulates inflammatory response, and adrenal and somatotropic responses associated with immune challenge, we administered intraperitoneally PPAR-g agonist and/or antagonist in weaned pigs subjected to Escherichia coli lipopolysaccharide (LPS) challenge. Unexpectedly, we found that a single injection of the PPAR-g agonist rosiglitazone (given at 3 mg/kg body weight 30 min before LPS injection) failed to block pro-inflammatory cytokine production induced by LPS injection. Rather, plasma levels of tumor necrosis factor-a (TNF-a) and interleukin-6 (IL-6), mRNA abundance of TNF-a in thymus, spleen, mesenteric lymph node and peripheral white blood cells, mRNA abundance of IL-6 in thymus, protein levels of TNF-a in spleen and mesenteric lymph node, and protein levels of IL-6 in spleen and mesenteric lymph node, were elevated beyond the levels in control pigs injected with LPS. Furthermore, rosiglitazone potentiated the increase of plasma cortisol and prostaglandin E2concentrations, and the decrease of plasma insulin-like growth factor-1 concentration induced by LPS injection. Co-administration of the PPAR-g antagonist bisphenol A diglycidyl ether (given 30 mg/kg body weight) 30 min prior to treatment with rosiglitazone antagonized the effect of the PPAR-g agonist, indicating a PPAR-g-dependent effect. Our data indicate that ligand-induced activation of PPAR-g does not ameliorate but enhances pro-inflammatory cytokine production, and further potentiates the adrenal and somatotropic changes in weaned pigs subjected to E. coli LPS challenge, which suggests that PPAR-g activation may not be useful, but potentially harmful, in the treatment of immune challenge in livestock. Our results raise doubts about the prevalently accepted anti-inflammatory role for PPAR-g activation.