Stress-Induced Metabolic Disorder in Peripheral CD4+ T Cells Leads to Anxiety-like Behavior.

Physical or mental stress leads to neuroplasticity in the brain and increases the risk of depression and anxiety. Stress exposure causes the dysfunction of peripheral T lymphocytes. However, the pathological role and underlying regulatory mechanism of peripheral T lymphocytes in mood disorders have not been well established. Here, we show that the lack of CD4+ T cells protects mice from stress-induced anxiety-like behavior. Physical stress-induced leukotriene B4 triggers severe mitochondrial fission in CD4+ T cells, which further leads to a variety of behavioral abnormalities including anxiety, depression, and social disorders. Metabolomic profiles and single-cell transcriptome reveal that CD4+ T cell-derived xanthine acts on oligodendrocytes in the left amygdala via adenosine receptor A1. Mitochondrial fission promotes the de novo synthesis of purine via interferon regulatory factor 1 accumulation in CD4+ T cells. Our study implicates a critical link between a purine metabolic disorder in CD4+ T cells and stress-driven anxiety-like behavior.

Multiomics analyses reveal a critical role of selenium in controlling T cell differentiation in Crohn's disease.

Inflammatory bowel disease (IBD) mainly includes Crohn's disease (CD) and ulcerative colitis (UC). Immune disorders play an essential role in the pathogenesis of these two IBDs, but the differences in the immune microenvironment of the colon and their underlying mechanisms remain poorly investigated. Here we examined the immunological features and metabolic microenvironment of untreated individuals with IBD by multiomics analyses. Modulation of CD-specific metabolites, particularly reduced selenium, can obviously shape type 1 T helper (Th1) cell differentiation, which is specifically enriched in CD. Selenium supplementation suppressed the symptoms and onset of CD and Th1 cell differentiation via selenoprotein W (SELW)-mediated cellular reactive oxygen species scavenging. SELW promoted purine salvage pathways and inhibited one-carbon metabolism by recruiting an E3 ubiquitin ligase, tripartite motif-containing protein 21, which controlled the stability of serine hydroxymethyltransferase 2. Our work highlights selenium as an essential regulator of T cell responses and potential therapeutic targets in CD.

Efficacy of Internet-Based Cognitive Behavioral Therapy for Subthreshold Depression Among Older Adults in Institutional Long-Term Care Settings: Pragmatic Randomized Controlled Trial.

BACKGROUND: Subthreshold depression (sD) is prevalent in older populations in long-term care (LTC) settings, but psychological therapy in LTC settings in China is not readily available. Thus, internet-based cognitive behavioral therapy (ICBT) may be suitable for this population, but research on the efficacy of ICBT for older adults with sD, especially those living in LTC settings, is limited. OBJECTIVE: This study aimed to evaluate the efficacy and acceptability of ICBT treatment for sD among LTC residents in China. We also examined whether ICBT is as effective as group-based cognitive behavioral therapy (CBT) for treating sD in this population. METHODS: We conducted a pragmatic randomized controlled trial, which included 18 LTC institutions. A total of 354 participants were randomized to ICBT, group-based CBT, or a waiting list and were followed up for 12 months. The primary outcome was self-reported depressive symptoms on the Center for Epidemiological Studies Depression Scale (CES-D). Secondary outcomes were the scores of the Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder 7-Item (GAD-7), and Geriatric Depression Scale (GDS). A mixed-effects model was used to assess the efficacy of ICBT. RESULTS: The ICBT group showed a significant improvement in self-reported depressive symptoms, which was maintained at the 12-month follow-up (all P<.001). The ICBT group exhibited a significantly larger reduction in the scores of the CES-D (Cohen d=0.07, 95% CI 0.04-0.09; P=.01), PHQ-9 (d=0.30, 95% CI 0.28-0.33; P<.001), GDS (d=0.10, 95% CI 0.08-0.13; P<.001), and GAD-7 (d=0.19, 95% CI 0.17-0.22; P<.001) compared with a waiting list at postintervention. ICBT had significantly stronger effects than CBT on the PHQ-9 and GAD-7 at postintervention (d=0.15, 95% CI 0.13-0.17; P<.001 and d=0.21, 95% CI 0.19-0.23; P<.001, respectively), 6-month follow-up (d=0.18, 95% CI 0.16-0.21; P<.001 and d=0.18, 95% CI 0.15-0.21; P<.001, respectively), and 12-month follow-up (d=0.15, 95% CI 0.11-0.19; P<.001 and d=0.18, 95% CI 0.14-0.21; P<.001, respectively). CONCLUSIONS: ICBT is a relatively effective and acceptable intervention for reducing depressive symptoms among Chinese LTC residents with sD. These findings indicate the usefulness of ICBT application for sD in LTC settings. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2000030697; https://www.chictr.org.cn/showproj.aspx?proj=50781.

Maternal folic acid and vitamin B12 supplementation during medium to late gestation promotes fetal development via improving placental antioxidant capacity, angiogenesis and amino acid transport.

BACKGROUND: Folic acid and vitamin B12 (FV), being B vitamins, not only facilitate the remethylation of homocysteine (Hcy) but also contribute to embryonic development. This study aimed to assess the impact of FV supplementation during late pregnancy on sows' reproductive performance, amino acid metabolism, placental angiogenesis, and related parameters. Twenty primiparous sows at day 60 of gestation were randomly allocated to two groups: a basal diet (CON) group and a group receiving a basal diet supplemented with folic acid at 20 ppm and vitamin B12 at 125 ppb. RESULTS: The findings revealed that dietary FV supplementation significantly reduced the incidence of intrauterine growth retardation compared to the CON group (P < 0.05). Furthermore, it led to a decrease in the Hcy levels in umbilical cord serum (P < 0.05) and activation of the placental mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway (P < 0.05). Additionally, FV supplementation lowered placental malondialdehyde levels (P < 0.05) and increased the expression of placental thioredoxin (P = 0.05). Moreover, maternal FV supplementation notably elevated placental vascular density (P < 0.05) and the expression of sodium-coupled neutral amino acid transporter 2 (SNAT2) (P < 0.05), as well as amino acid concentrations in umbilical cord blood (P < 0.05). CONCLUSION: Maternal FV supplementation during medium to late gestation reduced Hcy levels in umbilical cord blood and positively impacted fetal development. This improvement was closely associated with increased placental antioxidant capacity and vascular density, as well as activation of the placental mTORC1-SNAT2 signaling pathway. © 2023 Society of Chemical Industry.

Probiotic Lactobacillus rhamnosus GG improves insulin sensitivity and offspring survival via modulation of gut microbiota and serum metabolite in a sow model.

BACKGROUND: Sows commonly experience insulin resistance in late gestation and lactation, causing lower feed intake and milk production, which can lead to higher mortality rates in newborn piglets. The probiotic Lactobacillus rhamnosus GG (LGG) is known to improve insulin resistance. However, whether supplementing LGG can improve insulin sensitivity in sows and enhance lactation performance, particularly the early survival of offspring remains unclear. Hence, we explored the effects and mechanisms of supplementing LGG during late gestation and lactation on sow insulin sensitivity, lactation performance, and offspring survival. In total, 20 sows were randomly allocated to an LGG (n = 10) and control group (n = 10). RESULTS: In sows, LGG supplementation significantly improved insulin sensitivity during late gestation and lactation, increased feed intake, milk production and colostrum lactose levels in early lactation, and enhanced newborn piglet survival. Moreover, LGG treatment significantly reshaped the gut microbiota in sows, notably increasing microbiota diversity and enriching the relative abundance of insulin sensitivity-associated probiotics such as Lactobacillus, Bifidobacterium, and Bacteroides. Serum metabolite and amino acid profiling in late-gestation sows also revealed decreased branched-chain amino acid and kynurenine serum levels following LGG supplementation. Further analyses highlighted a correlation between mitigated insulin resistance in late pregnancy and lactation by LGG and gut microbiota reshaping and changes in serum amino acid metabolism. Furthermore, maternal LGG enhanced immunity in newborn piglets, reduced inflammation, and facilitated the establishment of a gut microbiota. CONCLUSIONS: We provide the first evidence that LGG mitigates insulin resistance in sows and enhances offspring survival by modulating the gut microbiota and amino acid metabolism.

Zearalenone Decreases Food Intake by Disrupting the Gut-Liver-Hypothalamus Axis Signaling via Bile Acids.

Zearalenone (ZEN) is a mycotoxin that is harmful to humans and animals. In this study, female and male rats were exposed to ZEN, and the results showed that ZEN reduced the farnesoid X receptor (FXR) expression levels in the liver and disrupted the enterohepatic circulation of bile acids (BAs). A decrease in food intake induced by ZEN was negatively correlated with an increase in the level of total BAs. BA-targeted metabolomics revealed that ZEN increased glycochenodeoxycholic acid levels and decreased the ratio of conjugated BAs to unconjugated BAs, which further increased the hypothalamic FXR expression levels. Preventing the increase in total BA levels induced by ZEN via Lactobacillus rhamnosus GG intervention restored the appetite. In conclusion, ZEN disrupted the enterohepatic circulation of BAs to decrease the level of food intake. This study reveals a possible mechanism by which ZEN affects food intake and provides a new approach to decrease the toxic effects of ZEN.

Butyrate Prevents the Pathogenic Anemia-Inflammation Circuit by Facilitating Macrophage Iron Export.

Most patients with inflammatory bowel disease (IBD) develop anemia, which is attributed to the dysregulation of iron metabolism. Reciprocally, impaired iron homeostasis also aggravates inflammation. How this iron-mediated, pathogenic anemia-inflammation crosstalk is regulated in the gut remains elusive. Herein, it is for the first time revealed that anemic IBD patients exhibit impaired production of short-chain fatty acids (SCFAs), particularly butyrate. Butyrate supplementation restores iron metabolism in multiple anemia models. Mechanistically, butyrate upregulates ferroportin (FPN) expression in macrophages by reducing the enrichment of histone deacetylase (HDAC) at the Slc40a1 promoter, thereby facilitating iron export. By preventing iron sequestration, butyrate not only mitigates colitis-induced anemia but also reduces TNF-α production in macrophages. Consistently, macrophage-conditional FPN knockout mice exhibit more severe anemia and inflammation. Finally, it is revealed that macrophage iron overload impairs the therapeutic effectiveness of anti-TNF-α antibodies in colitis, which can be reversed by butyrate supplementation. Hence, this study uncovers the pivotal role of butyrate in preventing the pathogenic circuit between anemia and inflammation.

Effects of Organic Chromium Yeast on Performance, Meat Quality, and Serum Parameters of Grow-Finish Pigs.

Trivalent chromium (Cr) is an essential trace element for humans and animals. This study was conducted to investigate the effects of chromium(III) yeast (CrYst) on growth performance, carcass characteristics, meat traits, antioxidant status, immune traits, and serum biochemical parameters of grow-finish pigs. A total of 72 commercial hybrid barrows (Duroc × Landrace × Large White) of approximately 50 kg body weight were allocated into two dietary treatments randomly, which received a corn-soybean meal basal diet or a basal diet supplemented with 100 mg CrYst/kg. The trial duration was 11 weeks divided into three periods from body weights of 50-75 kg, 75-100 kg, and 100-110 kg, respectively. The results revealed that supplemental CrYst did not affect growth performance. Organic CrYst supplementation significantly decreased the backfat depth and increased the meat tenderness score and juiciness score values in pigs (P < 0.05), while other carcass traits and meat traits indexes were unaffected. CrYst addition significantly decreased serum malondialdehyde (MDA) content of pigs in the whole growth phase; significantly increased the serum levels of immunoglobulin G (IgG), total antioxidant capacity (T-AOC), glutathione peroxidase (GSH-Px), and reduced glutathione (GSH) in growing pigs; and also increased the serum IgG, IgM, and GSH concentrations in pigs during the finishing phase (P < 0.05). Additionally, diets supplemented with CrYst significantly decreased the serum high-density lipoprotein cholesterol (HDL-C) content in growing pigs and significantly increased the serum LDL-C level at the fattening period (P < 0.05), whereas no significant differences were observed for the other serum biochemical indexes compared to the control pigs. In conclusion, CrYst supplementation could reduce lipid peroxidation and backfat thickness and improve the meat tenderness and juiciness, immune traits, and antioxidant status of pigs.

Supplementation of a Multi-Carbohydrase and Phytase Complex in Diets Regardless of Nutritional Levels, Improved Nutrients Digestibility, Growth Performance, and Bone Mineralization of Growing-Finishing Pigs.

This study was conducted to investigate the effects of dietary multi-enzyme (multi-carbohydrase and phytase complex, MCPC) supplementation on digestibility, growth performance, bone mineralization, and carcass yield and traits in growing-finishing pigs fed diets with adequate or deficient net energy (NE), amino acids (AA), calcium (Ca) and phosphorus (P) levels. A total of 576 crossbred [Duroc × (Landrace × Yorkshire)] barrows (~25 kg) were fed one of the six diets till live weight approached 130 kg. Basal diets included a positive control (PC), negative control 1 (NC1) and 2 (NC2), while another three diets were prepared by adding MCPC to the three basal diets. The final body weight was lower (p < 0.05) in NC2 than in NC1 and PC treatments, while overall feed intake and feed-gain ratio were higher (p < 0.05) in NC1 and NC2 than in PC treatment. The NC2 treatment showed lower (p < 0.05) carcass weight but higher (p < 0.05) lean meat percentage than the PC treatment. The apparent ileal digestibility (AID) of gross energy (GE), crude protein (CP) and AA was decreased (p < 0.05) or tended (p < 0.10) to decrease in NC1 and/or NC2 diets compared with a PC diet. MCPC supplementation improved (p < 0.05) AID of Ca, P and AA (Lys, Leu, Val, Phe, Gly, Tyr and Pro), apparent total-tract digestibility (ATTD) of GE, CP, bone strength, Ca, and P retention. In conclusion, MCPC supplementation improved nutrient digestibility, bone mineralization, and growth performance of fattening pigs, regardless of the nutritional level of the basal diet.

Bio-Based Hydrogel and Aerogel Composites Prepared by Combining Cellulose Solutions and Waterborne Polyurethane.

Hydrogel composites can be prepared from cellulose-based materials and other gel materials, thus combining the advantages of both kinds of material. The aerogel, porous material formed after removing the water in the hydrogel, can maintain the network structure. Hydrogel and aerogel have high application potential. However, low mechanical strength and weight loss of cellulose hydrogel due to the water dehydration/absorption limit the feasibility of repeated use. In this study, cellulose hydrogels were prepared using microcrystalline cellulose (MC), carboxymethyl cellulose (CMC), and hydroxyethyl cellulose (HEC) as raw materials. Waterborne polyurethane (WPU) was added during the preparation process to form cellulose/WPU composite hydrogel and aerogel. The influence of the cellulose type and WPU addition ratio on the performance of hydrogel and aerogel were investigated. The results show that the introduction of WPU can help strengthen and stabilize the structure of cellulose hydrogel, reduce weight loss caused by water absorption and dehydration, and improve its reusability. The mixing of cellulose and WPU at a weight ratio of 90/10 is the best ratio to make the cellulose/WPU composite aerogel with the highest water swelling capacity and heat resistance.

The effect of Bacillus cereus LV-1 on the crystallization and polymorphs of calcium carbonate.

The study of CaCO3 polymorphism is of great significance for understanding the mechanism of carbonate mineralization induced by bacteria and the genesis of carbonate rock throughout geological history. To investigate the effect of bacteria and shear force on CaCO3 precipitation and polymorphs, biomineralization experiments with Bacillus cereus strain LV-1 were conducted under the standing and shaking conditions. The results show that LV-1 induced the formation of calcite and vaterite under the standing and shaking conditions, respectively. However, the results of mineralization in the media and the CaCl2 solution under both kinetic conditions suggest the shear force does not affect the polymorphs of calcium carbonate in abiotic systems. Further, mineralization experiments with bacterial cells and extracellular polymeric substances (EPS) were performed under the standing conditions. The results reveal that bacterial cells, bound EPS (BEPS), and soluble EPS (SEPS) are favorable to the formation of spherical, imperfect rhombohedral, and perfect rhombohedral minerals, respectively. The increase in the pH value and saturation index (SI) caused by LV-1 metabolism under the shear force played key roles in controlling vaterite precipitation, whereas bacterial cells and EPS do not play roles in promoting vaterite formation. Furthermore, we suggest that vaterite formed if pH > 8.5 and SIACC > 0.8, while calcite formed if pH was between 8.0-9.0 and SIACC < 0.8. Bacterial cells and BEPS are the main factors affecting CaCO3 morphologies in the mineralization process of LV-1. This may provide a deeper insight into the regulation mechanism of the polymorphs and morphologies during bacterially induced carbonate mineralization.

The combination sequence effect on nitrogen removal pathway in hybrid constructed wetlands treating raw sewage from multiple perspectives.

The combination sequence of traditional hybrid constructed wetlands (HCWs) affects the removal of nitrogen in raw sewage, but the effect of the combination sequence on nitrogen removal pathway have seldom been reported, especially the specific conditions allowing anammox to occur. Three-stage HCWs, namely vertical flow (VF), horizontal flow (HF) and surface flow (SF) constructed wetlands, were arranged in six different sequences to investigate nitrogen removal efficiencies and microbial removal pathways using metagenomic and stable isotope analyses. Results showed that the combination sequence significantly affected nitrogen removal pathways in HCWs. We found the best removal of total nitrogen (~50%) and ammonium (NH4+-N, ~99%) in HCWs with a VFCW in the 1st stage. Metagenomic results and stable isotope analyses further indicated that simultaneous nitrification and heterotrophic denitrification were the main pathways in unsaturated VFCW, which depended on the energy substance and electron donor supplied by chemical oxygen demand (CODCr) in raw sewage. Nitrifier, anammox bacteria and autotrophic denitrifies prevailed in the subsequent saturated CWs, which tend to nitrogen loss by partial nitrification and anammox in HFCW when fed with NH4+-N wastewater with low CODCr. Providing NH4+-N and oxygen in low CODCr wastewater was the essential step to facilitate anammox process in HFCW. It implied that the problem of poor nitrogen removal due to carbon limitation could be overcome by optimizing conditions in anammox's favor.

Dietary supplementation with a mixture of herbal extracts during late gestation and lactation improves performance of sows and nursing piglets through regulation of maternal metabolism and transmission of antibodies.

The dietary inclusion of phytogenic feed additives to improve the performance and health of sows is considered to be safe, effective and environmentally friendly, thus gaining growing popularity among new strategies. This study was designed with three trials aimed to determine the effective supplemental levels of Scutellaria baicalensis and Lonicera japonica mixed extracts (SLE) in sow diets based on production performance and explore its related mechanisms of action based on serum metabolites, antioxidant capacity, and immune profile of sows and nursing piglets. Trials 1 and 2 were conducted to determine the effective dose and ratio of SLE by supplementation of various proportions and doses of SLE to sows diets from the late pregnancy to weaning, with litter performance at farrowing and weaning and disease conditions being evaluated. Trial 3 was conducted to further explore the mechanisms of action of SLE as evaluated by serum immunity and antioxidants indices in late gestation and lactation sows. The results of trials 1 and 2 showed that dietary supplementation of 1.0 g/kg SLE (50% S. baicalensis extract, 30% L. japonica extract, and 20% wheat bran fiber as carrier) enhanced the number of piglets born alive, litter birth weight, litter weight gain, and average daily feed intake of sows during lactation, while decreased diarrhea of suckling piglets. In Trial 3, compared with the control group, dietary SLE supplementation increased (P < 0.05) sow serum glucose (GLU), triglyceride (TG), total cholesterol (TC), prolactin (PRL) and interleukin-10 (IL-10) concentrations, and total superoxide dismutase (T-SOD) activities at the farrowing, and increased (P < 0.05) sow serum prolactin, leptin, and insulin concentrations at d 14 of lactation. Fat concentrations in sow colostrum and in milk on day 14 of lactation, both IgA and IgG concentrations in colostrum, and both IL-10 and IgA concentrations in piglet serum at d 14 of lactation were all increased (P < 0.05) following dietary SLE supplementation. Altogether, dietary supplementation with the appropriate levels of SLE promoted health and growth of suckling piglets, which was associated with the improvement of maternal metabolism and transmission of antibodies.

Effects of Dietary Lysine Levels on Growth Performance, Nutrient Digestibility, Serum Metabolites, and Meat Quality of Baqing Pigs.

This study was carried out to determine the Lys requirements of Baqing pigs and the effects of different dietary lysine levels on growth performance, apparent nutrient digestibility, serum metabolites, and carcass and meat traits. A total of 120 castrated Baqing pigs were selected by body weight and randomly assigned to five dietary treatments with six replicate pens (4 pigs per pen, castrated) per treatment in a randomized complete block design. Five diets in mash form were formulated to contain SID Lys at 0.56%, 0.68%, 0.80%, 0.92%, and 1.04% of diet in phase 1 (20−40 kg), at 0.45%, 0.54%, 0.63%, 0.72%, and 0.81% of diet in phase 2 (40−60 kg), and at 0.39%, 0.47%, 0.55%, 0.63%, and 0.71% of diet in phase 3 (60−90 kg), respectively. The results showed that the bodyweight of pigs was not affected by dietary SID Lys content during each period. However, the addition of dietary SID Lys linearly reduced F/G in the first period and quadratically increased ADG during the second period (p < 0.05). The digestible energy (DE) was increased linearly and quadratically in the first phases with the dietary increased SID Lys levels, while DE was reduced in the third and second phases (p < 0.05). Increasing SID Lys contents linearly increased the serum TG concentration and quadratically decreased the serum GLU concentration, while linearly reducing the serum HDLC concentration of first period pigs (p < 0.05). Serum concentrations of TP, TG, TC, and LDLC were increased linearly with the increasing dietary SID Lys levels in the second period (p < 0.05). The serum concentrations of Lys increased quadratically, and histidine increased linearly with the increased dietary SID Lys levels (p < 0.05). Compared with the treatment three group, dietary SID Lys addition content at treatment four increased the shear force of the longissimus dorsi muscle (p < 0.05), but it did not affect the other carcass and meat traits. The optimal SID Lys requirement of 20−40 kg, 40−60 kg, and 60−90 kg of Baqing pigs fed corn−soybean meal-based diets is estimated to be 0.92%, 0.66%, and 0.55% of the diets by the quadratic curve models, respectively.

The Impact of Enhancing Diet Quality or Dietary Supplementation of Flavor and Multi-Enzymes on Primiparous Lactating Sows.

This study was aimed to explore how a high-quality diet or a flavor plus multi-enzyme diet affects the feed intake, nutrient digestibility and antioxidation capacity of lactating sows and the growth of their progeny. Thirty primiparous sows were randomly assigned to three treatments from d 2 of lactation until weaning (d 21): control (CON), with a basal diet; high quality (HQ), with 200 kcal/kg higher net energy than CON; or the CON diet supplemented with 500 mg/kg flavor and 100 mg/kg multi-enzymes (F + E). Sows fed with the HQ or F + E diets improved piglets' live weight (p < 0.05) and average daily weight gain (p < 0.10), litter weight gain (p < 0.10) and piglet growth to milk yield ratio (p < 0.10). Compared with CON, the HQ and F + E groups increased the digestibility of ether extract, ash, neutral detergent fiber, crude fiber and phosphorus (p < 0.10), and the HQ group also increased dry matter, gross energy, crude protein, acid detergent fiber and energy intake (p < 0.05). Compared with CON, the F + E group decreased serum urea nitrogen and aspartate aminotransferase (p < 0.05) and enhanced superoxide dismutase, catalase and glutathione peroxidase, but it decreased malondialdehyde in milk supernatant (p < 0.05).

Substrate-specific recognition of IKKs mediated by USP16 facilitates autoimmune inflammation.

The classic NF-κB pathway plays crucial roles in various immune responses and inflammatory diseases. Its key kinase, IKKß, participates in a variety of pathological and physiological processes by selectively recognizing its downstream substrates, including p105, p65, and IκBα, but the specific mechanisms of these substrates are unclear. Hyperactivation of one of the substrates, p105, is closely related to the onset of inflammatory bowel disease (IBD) in Nfkb1-deficient mice. In this study, we found that IKKß ubiquitination on lysine-238 was substantially increased during inflammation. Using mass spectrometry, we identified USP16 as an essential regulator of the IKKß ubiquitination level that selectively affected p105 phosphorylation without directly affecting p65 or IκBα phosphorylation. Furthermore, USP16 was highly expressed in colon macrophages in patients with IBD, and myeloid-conditional USP16-knockout mice exhibited reduced IBD severity. Our study provides a new theoretical basis for IBD pathogenesis and targeted precision intervention therapy.

Methionine Protects Mammary Cells against Oxidative Stress through Producing S-Adenosylmethionine to Maintain mTORC1 Signaling Activity.

The mechanistic target of rapamycin complex 1 (mTORC1) signaling plays pivotal roles in cell growth and diseases. However, it remains mechanistically unclear about how to maintain mTORC1 activity during mammary glands development. Here we showed that mammary glands suffered from aggravated oxidative stress as pregnancy advanced and was accompanied by an increase in H2O2 levels, while the consumption for methionine and S-adenosylmethionine (SAM) rather than S-adenosylhomocysteine (SAH) were promoted in vivo. Likewise, H2O2 promoted SAM synthesis and reduced SAM utilization for methylation depending on H2O2 levels and treatment time in vitro. H2O2 inhibited phosphorylation of S6 kinase Thr 389 (p-S6K1 (T389)), 4E-BP1 Thr 37/46 and ULK1 Ser 757, the downstream of mTORC1, in mammary epithelial cells. However, methionine and SAM were shown to activate mTORC1 under H2O2-exposed condition. Moreover, this effect was not disabled by SGI-1027 which inhibits SAM transmethylation. In conclusion, methionine appeared to protect mammary cells against oxidative stress through producing SAM to maintain mTORC1 signaling activity.

Differential responses of weaned piglets to supplemental porcine or chicken plasma in diets without inclusion of antibiotics and zinc oxide.

This study was conducted to investigate the effects of spray-dried porcine plasma protein (SDPP) or spray-dried chicken plasma protein (SDCP) supplementation in diets without the inclusion of antibiotics and zinc oxide (ZnO) on growth performance, fecal score, and fecal microbiota in early-weaned piglets. A total of 192 healthy weaning piglets (Duroc × Landrace × Yorkshire, 21 d old) were blocked by BW (6.53 ± 0.60 kg) and randomly assigned to 4 dietary treatments: negative control (NC, basal diet), positive control (PC), basal diet + ZnO at 2 g/kg and antibiotics at 0.8 g/kg), SDPP (containing 5% SDPP), and SDCP (containing 5% SDCP). The experiment lasted 14 d. The SDPP group had higher (P < 0.05) final BW, average daily gain and average daily feed intake than the NC and SDCP groups. The percentage of piglets with fecal scores at 2 or ≥2 was higher (P < 0.05) in the NC and SDCP groups than in the PC group. A decreased (P < 0.05) bacterial alpha diversity and Bacteroidetes abundance, but increased (P < 0.05) Firmicutes abundance were observed in the PC and SDPP groups when compared to the NC group. The relative abundance of Lactobacillus was higher (P < 0.05) in the SDPP than in the SDCP group, and that of Streptococcus was higher (P < 0.01) in the PC and SDPP groups than in the NC group. The PC group also had higher (P < 0.01) Faecalibacterium abundance than the NC and SDCP groups. Additionally, the SDCP group had higher (P < 0.05) serum urea nitrogen than those fed other diets, and lower (P < 0.10) short-chain fatty acids to branched-chain fatty acids ratio than the PC and SDPP groups. Overall, SDPP was a promising animal protein for piglets in increasing feed intake, modifying gut microbiota profile, reducing gut protein fermentation and alleviating diarrhea frequency, thus promoting growth performance, under the conditions with limited in-feed utilization of antibiotics and ZnO.

USP16-mediated deubiquitination of calcineurin A controls peripheral T cell maintenance.

Calcineurin acts as a calcium-activated phosphatase that dephosphorylates various substrates, including members of the nuclear factor of activated T cells (NFAT) family, to trigger their nuclear translocation and transcriptional activity. However, the detailed mechanism regulating the recruitment of NFATs to calcineurin remains poorly understood. Here, we report that calcineurin A (CNA), encoded by PPP3CB or PPP3CC, is constitutively ubiquitinated on lysine 327, and this polyubiquitin chain is rapidly removed by ubiquitin carboxyl-terminal hydrolase 16 (USP16) in response to intracellular calcium stimulation. The K29-linked ubiquitination of CNA impairs NFAT recruitment and transcription of NFAT-targeted genes. USP16 deficiency prevents calcium-triggered deubiquitination of CNA in a manner consistent with defective maintenance and proliferation of peripheral T cells. T cell-specific USP16 knockout mice exhibit reduced severity of experimental autoimmune encephalitis and inflammatory bowel disease. Our data reveal the physiological function of CNA ubiquitination and its deubiquitinase USP16 in peripheral T cells. Notably, our results highlight a critical mechanism for the regulation of calcineurin activity and a novel immunosuppressive drug target for the treatment of autoimmune diseases.

High-risk human papilloma virus infection and cervical neoplasm in female inflammatory bowel disease patients: a cross-sectional study.

BACKGROUND AND AIM: This cross-sectional study investigated the prevalence and risk factors of high-risk human papilloma virus (HPV) infection, especially types 16 and 18, and cervical neoplasia in female Inflammatory bowel disease (IBD) patients. METHODS: From July 2014 to January 2017, sexually active, female, Chinese IBD patients (21-60 years) and age-matched controls underwent cervical ThinPrep cytology testing (TCT) and high-risk HPV-DNA detection, and completed questionnaires about awareness of cervical cancer and HPV. Cervical dysplasia was categorized as cervical intraepithelial neoplasia (CIN) 1, 2 and 3. RESULTS: Of 124 IBD patients (30 ulcerative colitis and 94 Crohn's disease), 17 (13.7%) had high-risk HPV among whom 9 (7.3%) had HPV 16/18 infection and 4 (3.2%) had cervical CIN (3 CIN 3, 1 CIN 1) by pathology. Among 372 controls, 33 (8.9%) had high-risk HPV and only 1 (0.3%) had HPV 16 infection. Cervical TCT detected atypical squamous cells of unknown significance in one control; no control had CIN. The HPV 16/18 infection rate and CIN prevalence were significantly higher in IBD patients than controls (both P < 0.001). The HPV-infection rate was higher in patients administered methotrexate [P = 0.005, odds ratio (95% confidence interval) 4.76 (1.471-15.402)] or more than two immunosuppressants [P = 0.013, odds ratio (95% confidence interval) 3.64 (1.255-10.562)]. Thiopurine, steroid, infliximab and disease behavior/location were not associated with HPV infection. Only 29.3% of patients had undergone cervical-cancer screening. Awareness of HPV infection and HPV-related cervical cancer was poor (28.2%). CONCLUSIONS: Female IBD patients are at increased risk of high-risk HPV infection and cervical neoplasia, which may be associated with immunosuppressants. Education and routine follow-up with HPV-DNA testing and TCT are recommended, especially in female Chinese IBD patients.