The Regulation of Selenoproteins in Diabetes: A New Way to Treat Diabetes.

Selenium is an essential micronutrient required for the synthesis and function of selenoproteins, most of which are enzymes involved in maintaining oxidative balance in the body. Diabetes is a group of metabolic disorders characterized by high blood glucose levels over a prolonged period of time. There are three main types of diabetes: type 1, type 2, and gestational diabetes. This review summarizes recent advances in the field of diabetes research with an emphasis on the roles of selenoproteins on metabolic disturbance in diabetes. We also discuss the interaction between selenoproteins and glucose and lipid metabolism to provide new insights into the prevention and treatment of diabetes.

Excitatory amino acid transporter supports inflammatory macrophage responses.

Excitatory amino acid transporters (EAATs) are responsible for excitatory amino acid transportation and are associated with auto-immune diseases in the central nervous system and peripheral tissues. However, the subcellular location and function of EAAT2 in macrophages are still obscure. In this study, we demonstrated that LPS stimulation increases expression of EAAT2 (coded by Slc1a2) via NF-κB signaling. EAAT2 is necessary for inflammatory macrophage polarization through sustaining mTORC1 activation. Mechanistically, lysosomal EAAT2 mediates lysosomal glutamate and aspartate efflux to maintain V-ATPase activation, which sustains macropinocytosis and mTORC1. We also found that mice with myeloid depletion of Slc1a2 show alleviated inflammatory responses in LPS-induced systemic inflammation and high-fat diet induced obesity. Notably, patients with type II diabetes (T2D) have a higher level of expression of lysosomal EAAT2 and activation of mTORC1 in blood macrophages. Taken together, our study links the subcellular location of amino acid transporters with the fate decision of immune cells, which provides potential therapeutic targets for the treatment of inflammatory diseases.

The status and influencing factors of fatigue in kidney transplant recipients based on the theory of unpleasant symptoms: A cross-sectional study in China.

AIMS: This study describes the incidence of fatigue in kidney transplant recipients and analyses the relationship between physiological factors, psychological factors, situational factors and fatigue in kidney transplant recipients. BACKGROUND: Fatigue, as a common symptom after kidney transplantation, is affected by many factors, but the influence of some factors on the fatigue of kidney transplant recipients is still controversial. DESIGN: This cross-sectional study was designed based on the theory of unpleasant symptoms. METHODS: Our survey involved 307 participants attending the kidney transplant outpatient clinic of a tertiary Class A hospital (Changsha, Hunan, China). Data were collected between February and April 2021 using a structured questionnaire and electronic medical records. Data were analysed using IBM SPSS 25.0 (SPSS Inc.) RESULTS: It was found that the incidence of fatigue in kidney transplant recipients was 53.1%. According to the binary logistic regression analysis, sleep quality, hypokalemia, anxiety, depression and education level were independent risk factors for fatigue in kidney transplant recipients. CONCLUSION: The incidence of fatigue in kidney transplant recipients was high and was influenced by physical, psychological and situational factors. Clinical nurses should assess fatigue levels in a timely and multidimensional manner in clinical practice and provide effective and scientific guidance about fatigue self-coping and symptom management for kidney transplant recipients.

Amino acids in piglet diarrhea: Effects, mechanisms and insights.

Piglet diarrhea is among one of the most serious health problems faced by the pig industry, resulting in significant economic losses. Diarrheal disease in piglets has a multifactorial etiology that is affected by physiology, environment, and management strategy. Diarrhea is the most apparent symptom of intestinal dysfunction. As a key class of essential nutrients in the piglet diet, amino acids confer a variety of beneficial effects on piglets in addition to being used as a substrate for protein synthesis, including maintaining appropriate intestinal integrity, permeability and epithelial renewal, and alleviating morphological damage and inflammatory and oxidative stress. Thus, provision of appropriate levels of amino acids could alleviate piglet diarrhea. Most amino acid effects are mediated by metabolites, gut microbes, and related signaling pathways. In this review, we summarize the current understanding of dietary amino acid effects on gut health and diarrhea incidence in piglets, and reveal the mechanisms involved. We also provide ideas for using amino acid blends and emphasize the importance of amino acid balance in the diet to prevent diarrhea in piglets.

Serine synthesis sustains macrophage IL-1ß production via NAD+-dependent protein acetylation.

Serine metabolism is involved in the fate decisions of immune cells; however, whether and how de novo serine synthesis shapes innate immune cell function remain unknown. Here, we first demonstrated that inflammatory macrophages have high expression of phosphoglycerate dehydrogenase (PHGDH, the rate-limiting enzyme of de novo serine synthesis) via nuclear factor κB signaling. Notably, the pharmacological inhibition or genetic modulation of PHGDH limits macrophage interleukin (IL)-1ß production through NAD+ accumulation and subsequent NAD+-dependent SIRT1 and SIRT3 expression and activity. Mechanistically, PHGDH not only sustains IL-1ß expression through H3K9/27 acetylation-mediated transcriptional activation of Toll-like receptor 4 but also supports IL-1ß maturation via NLRP3-K21/22/24/ASC-K21/22/24 acetylation-mediated activation of the NLRP3 inflammasome. Moreover, mice with myeloid-specific depletion of Phgdh show alleviated inflammatory responses in lipopolysaccharide-induced systemic inflammation. This study reveals a network by which a metabolic enzyme, involved in de novo serine synthesis, mediates post-translational modifications and epigenetic regulation to orchestrate IL-1ß production, providing a potential inflammatory disease target.

Age-Dependent Developmental Changes of Selenium Content and Selenoprotein Expression and Content in Longissimus Dorsi Muscle and Liver of Duroc Pigs.

The trace element selenium (Se) plays a key role in development and various physiological processes, mainly through its transformation into selenoproteins. To investigate the developmental patterns of Se content and expression of selenoproteins, the liver and longissimus dorsi (LD) muscle of Duroc pigs were collected at 1, 21, 80, and 185 days of age (7 pigs each age) for the determination of Se content, mRNA expression of selenoproteins, and concentrations of glutathione peroxidase (GPX), thioredoxin reductase (TrxR or TXNRD), and selenoprotein P (SELP). The results showed that age significantly affected the expression of GPX1, GPX2, GPX3, TXNRD1, TXNRD2, TXNRD3, iodothyronine deiodinases 2 (DIO2), DIO3, SELF, SELH, SELM, SELP, SELS, SELW, and selenophosphate synthetase2 (SPS2) in the liver, as well as GPX3, GPX4, TXNRD1, TXNRD2, DIO2, DIO3, SELF, SELN, SELP, SELR, SELS, and SELW in the LD muscle of Duroc pigs. The concentrations of GPX, TrxR, and SELP showed an increasing trend with age, and they were positively correlated with Se content at 1, 21, and 185 days of age and negatively correlated at 80 days of age, both in the liver and LD muscle. The Se content decreased at the age of 80 days, especially in the LD muscle. In summary, our study revealed developmental changes in Se content and expression of selenoproteins in the liver and LD muscle of Duroc pigs at different growth stages, which provided a theoretical basis for further study of Se nutrition and functions of selenoproteins.

Colonic phosphocholine is correlated with Candida tropicalis and promotes diarrhea and pathogen clearance.

Diarrhea is characterized by alterations in the gut microbiota, metabolites, and host response to these changes. Studies have focused on the role of commensal bacteria in diarrhea; however, the effect of fungi on its pathogenesis remains unexplored. Here, using post-weaned piglets with or without diarrhea, we found an unexpected decrease in the abundance of Candida tropicalis in diarrheal piglets. We also observed increased accumulation of reactive oxygen species (ROS) and the formation of neutrophil extracellular traps (NETs) in the colonic tissues of diarrheal piglets. Using dectin-1-knockout mice, we found that the over-accumulation of ROS killed C. tropicalis by promoting NET formation, which was dependent on dectin-1. The decreased abundance of C. tropicalis resulted in reduced phosphocholine consumption. Then, colonic phosphocholine accumulation drives water efflux by increasing cAMP levels by activating adenylyl cyclase, which promotes the clearance of pathogenic bacteria. Collectively, we demonstrated that phosphocholine is correlated with colonic C. tropicalis and promotes diarrhea and pathogen clearance. Our results suggest that mycobiota colonizing the colon might be involved in maintaining intestinal metabolic homeostasis through the consumption of certain metabolites.

Gut microbiota bridges dietary nutrients and host immunity.

Dietary nutrients and the gut microbiota are increasingly recognized to cross-regulate and entrain each other, and thus affect host health and immune-mediated diseases. Here, we systematically review the current understanding linking dietary nutrients to gut microbiota-host immune interactions, emphasizing how this axis might influence host immunity in health and diseases. Of relevance, we highlight that the implications of gut microbiota-targeted dietary intervention could be harnessed in orchestrating a spectrum of immune-associated diseases.

Combined supplementation with Lactobacillus sp. and Bifidobacterium thermacidophilum isolated from Tibetan pigs improves growth performance, immunity, and microbiota composition in weaned piglets.

Probiotics, such as Lactobacillus and Bifidobacterium, promote growth in piglets by modulating gut microbiota composition and improving the host immune system. A strain of Lactobacillus sp. and Bifidobacterium thermacidophilum were previously isolated from fresh feces of Tibetan pigs. The effects of these isolated strains on growth performance, intestinal morphology, immunity, microbiota composition, and their metabolites were evaluated in weaned piglets. Thirty crossbred piglets were selected and fed either a basal diet (CON), a basal diet supplemented with aureomycin (ANT), or a basal diet supplemented with Lactobacillus sp. and B. thermacidophilum (LB) for 28 d. The piglets in the ANT and LB groups had significantly higher body weight gain than those in the CON group (P < 0.05). Piglets in the ANT and LB groups had regularly arranged villi and microvilli in the small intestine. Furthermore, they had improved immune function, as indicated by decreased serum concentrations of inflammatory cytokines (P < 0.05), improved components of immune cells in the blood, mesenteric lymph nodes, and spleen. Additionally, metagenomic sequencing indicated a significant shift in cecal bacterial composition and alterations in microbiota functional profiles following Lactobacillus sp. and B. thermacidophilum supplementation. Metabolomic results revealed that the metabolites were also altered, and Kyoto Encyclopedia of Genes and Genomes analysis revealed that several significantly altered metabolites were enriched in glycerophospholipid and cholesterol metabolism (P < 0.05). Furthermore, correlation analysis showed that several bacterial members were closely related to the alterations in metabolites, including Bacteroides sp., which were negatively correlated with triglyceride (16:0/18:0/20:4[5Z,8Z,11Z,14Z]), the metabolite that owned the highest variable importance of projection scores. Collectively, our findings suggest that combined supplementation with Lactobacillus sp. and B. thermacidophilum significantly improved the growth performance, immunity, and microbiota composition in weaned piglets, making them prospective alternatives to antibiotics in swine production.

Probiotics such as Lactobacillus and Bifidobacterium have growth- and immunity-promoting effects in piglets. Thirty weaned piglets were selected and fed either a basal diet, a basal diet supplemented with aureomycin, or a basal diet supplemented with Lactobacillus sp. and Bifidobacterium thermacidophilum isolated from Tibetan pigs for 28 d. The results showed that combined supplementation with B. thermacidophilum and Lactobacillus sp. significantly improved growth performance, intestinal morphology, and immunity in weaned piglets, which is similar to piglets treated with antibiotics. They also improved cecal bacterial composition as indicated by the metagenomic sequencing results. Metabolomic results revealed that the altered metabolites were primarily enriched in glycerophospholipid and cholesterol metabolism. Correlation analysis showed that many bacterial members were closely related to the alterations of metabolites, suggesting B. thermacidophilum and Lactobacillus sp. exert effects via bacterial metabolism. Thus, Lactobacillus sp. and B. thermacidophilum could potentially be used as a prospective alternative of antibiotic growth promoters in piglets.

Low-protein diets supplemented with glycine improves pig growth performance and meat quality: An untargeted metabolomic analysis.

For the purpose to improve meat quality, pigs were fed a normal diet (ND), a low protein diet (LPD) and a LPD supplemented with glycine (LPDG). Chemical and metabolomic analyses showed that LPD increased IMF deposition and the activities of GPa and PK, but decreased glycogen content, the activities of CS and CcO, and the abundance of acetyl-CoA, tyrosine and its metabolites in muscle. LPDG promoted muscle fiber transition from type II to type I, increased the synthesis of multiple nonessential amino acids, and pantothenic acid in muscle, which should contributed to the improved meat quality and growth rate. This study provides some new insight into the mechanism of diet induced alteration of animal growth performance and meat quality. In addition, the study shows that dietary supplementation of glycine to LPD could be used to improved meat quality without impairment of animal growth.

Bacillus subtilis DSM29784 attenuates Clostridium perfringens-induced intestinal damage of broilers by modulating intestinal microbiota and the metabolome.

Necrotic enteritis (NE), especially subclinical NE (SNE), without clinical symptoms, in chicks has become one of the most threatening problems to the poultry industry. Therefore, increasing attention has been focused on the research and application of effective probiotic strains as an alternative to antibiotics to prevent SNE in broilers. In the present study, we evaluated the effects of Bacillus subtilis DSM29784 (BS) on the prevention of subclinical necrotic enteritis (SNE) in broilers. A total of 480 1-day-old broiler chickens were randomly assigned to four dietary treatments, each with six replicates pens of twenty birds for 63 d. The negative (Ctr group) and positive (SNE group) groups were only fed a basal diet, while the two treatment groups received basal diets supplemented with BS (1 × 109 colony-forming units BS/kg) (BS group) and 10mg/kg enramycin (ER group), respectively. On days 15, birds except those in the Ctr group were challenged with 20-fold dose coccidiosis vaccine, and then with 1 ml of C. perfringens (2 × 108) at days 18 to 21 for SNE induction. BS, similar to ER, effectively attenuated CP-induced poor growth performance. Moreover, BS pretreatment increased villi height, claudin-1 expression, maltase activity, and immunoglobulin abundance, while decreasing lesional scores, as well as mucosal IFN-γ and TNF-α concentrations. In addition, BS pretreatment increased the relative abundance of beneficial bacteria and decreased that of pathogenic species; many lipid metabolites were enriched in the cecum of treated chickens. These results suggest that BS potentially provides active ingredients that may serve as an antibiotic substitute, effectively preventing SNE-induced growth decline by enhancing intestinal health in broilers.

Serine signaling governs metabolic homeostasis and health.

Serine has functions that are involved in metabolic homeostasis and health in pathological or stressful situations. Notably, the de novo serine synthesis pathway (SSP) plays a vital role in targeted regulation of immune responses, cell proliferation, and lipid/protein metabolism. The presentation of serine residues derived from SSP may be a signal of stress and provide novel insights into the relationship between metabolic homeostasis and diseases. Here, we summarize the current trends in understanding the regulatory mechanisms of serine metabolism, discuss how serine signaling governs metabolic and antistress processes, including oxidative stress, immunity, energy and lipid metabolism, intestinal microbiota, and the neurological system. We present a possible framework by which serine metabolism maintains metabolic homeostasis and treats human diseases.

Serine Administration Improves Selenium Status, Oxidative Stress, and Mitochondrial Function in Longissimus Dorsi Muscle of Piglets with Intrauterine Growth Retardation.

Intrauterine growth retardation (IUGR) causes oxidative stress in the skeletal muscle. Serine and selenoproteins are involved in anti-oxidative processes; however, whether IUGR affects selenium status and whether serine has beneficial effects remain elusive. Here, we investigated the effects of serine administration on selenium nutritional status and oxidative stress in the longissimus dorsi muscle of piglets with IUGR. Six newborn Min piglets having normal birth weight were administered saline, and 12 IUGR piglets were either administered saline or 0.8% serine. The results showed a lower selenium content in skeletal muscle in IUGR piglets, which was restored after serine administration. IUGR piglets showed a disturbed expression of genes encoding selenoproteins, with decreased expression of GPX2, GPX4, TXNRD1, and TXNRD3 and increased expression of DIO1, DIO2, SELF, SELM, SELP, and SELW. Notably, serine administration restored the expression levels of these genes. In accordance with the changes in gene expression, the activity of GPX, TXNRD, and DIO and the content of GSH and SELP were also altered, whereas serine administration restored their contents and activities. Moreover, we observed severe oxidative stress in the skeletal muscle of IUGR piglets, as indicated by decreased GSH content and increased MDA and PC content, whereas serine administration alleviated these changes. In conclusion, our results indicate that IUGR piglets showed a disturbed expression of genes encoding selenoproteins, accompanied by severe oxidative stress. Serine administration can improve selenium status, oxidative stress, and mitochondrial function in the longissimus dorsi muscle of piglets with IUGR. These results suggest that serine could potentially be used in the treatment of IUGR in piglets.

Effects of Different Levels of Organic Trace Minerals on Oxidative Status and Intestinal Function in Weanling Piglets.

An experiment was conducted to compare the effects of replacing inorganic trace minerals (ITM) with different levels of complex organic trace minerals (OTM) on the growth performance, oxidative status, and intestinal function of piglets. Weanling piglets were assigned to five groups: a control group fed a basal diet supplemented with inorganic trace minerals and the other four groups fed basal diets supplemented with different levels of OTMs. The results showed that diets supplemented with 50 ppm Fe, 30 ppm Zn, 15 ppm Mn, and 0.2 ppm Se from OTM (L-OTM), or with 75 ppm Fe, 45 ppm Zn, 22.5 ppm Mn, and 0.3 ppm Se from OTM (M-OTM) significantly decreased the diarrhea ratio in the piglets compared with those supplemented with 100 ppm Fe, 90 ppm Zn, 40 ppm Mn, and 0.4 ppm Se from ITM. Compared with those in the ITM group, the piglets in the M-OTM group had significantly higher serum CuZnSOD, MnSOD, and GSH-Px levels. Moreover, piglets in the L-OTM and M-OTM groups had higher Sod and Gpx gene expression than those in the ITM group. Additionally, piglets in the L-OTM and M-OTM groups had significantly higher villus height than those in the ITM group, and the M-OTM group piglets had lower serum diamine oxidase content and higher ileal ZO-1 and occludin protein expression levels than those in the ITM group. These results indicate that replacing dietary ITMs with OTMs could decrease diarrhea occurrence and improve the oxidative status and intestinal barrier function in weanling piglets.

Effects of two concentrations of dietary tribasic zinc sulfate on growth performance, gut morphology, and zinc transporter expression levels in pigs.

Tribasic zinc sulfate (TBZ) is insoluble in water and chemically less active than zinc sulfate, making it more suitable to be used in pig diet. To investigate the effects of TBZ on the growth performance, gut morphology, and zinc transporter expression levels, we performed a single-factor experiment and 168 pigs were allocated to three groups with seven pens per treatment. Pigs were either fed a basal diet without zinc supplementation (control group), or a basal diet supplemented with TBZ at 100 mg/kg diet (LTBZ group) or 1000 mg/kg diet (HTBZ group). We found that daily weight gain and feed intake were higher in the LTBZ group than in the HTBZ and control groups. The pigs in the LTBZ group had a higher villus height and villus height/crypt depth ratio when compared with other pigs. Moreover, the pigs in the LTBZ group exhibited higher mRNA expression levels of solute carrier family 39 and lower expression levels of solute carrier family 30 than those fed the HTBZ-supplemented diet. Together, these results indicate that TBZ may potentially be used as a dietary zinc source for young growing pigs and that dietary supplementation with LTBZ benefits growth performance and gut morphology.

Monitoring hypertensive disorders in pregnancy to prevent preeclampsia in pregnant women of advanced maternal age: Trial mimicking with retrospective data.

This study investigated the implication of monitoring hypertensive disorders in pregnancy (HDP) to prevent preeclampsia (PE) in pregnant women of advanced maternal age. Between January 2016 and April 2021, 262 consecutive pregnant women aged ≥40 years were recruited. Extensive monitoring of hypertensive disorders in pregnancy, including blood hypercoagulability screening and subsequent interventions, was performed in 129 pregnant women in our university hospital. The remaining 133 patients from other centres, who did not receive antenatal maternal pregnancy screening and preventive intervention during the same period, constituted the non-intervention group enabling comparison to mimic a trial. The incidences of hypertensive disorders, mild and severe PE, eclampsia, and chronic hypertension complicated by PE in the intervention group were significantly lower than in the non-intervention group (10.08 versus 20.30%, 8.52 versus 18.80%, 7.75 versus 21.05%, 0 versus 3.01%, and 3.86 versus 15.04%, respectively; P < 0.05). Premature birth, low birth weight, and foetal loss were significantly rarer in the intervention group than in the non-intervention group (6.98 versus 24.81%, 7.75 versus 21.80%, and 0.78 versus 14.29% respectively; P < 0.001). The comparison of MP with routine blood coagulation biochemical examination found that the MP detection system of Beijing Yes Medical Devices Co., Ltd., had similar sensitivity as thromboelastogram. Still, it was significantly better than the routine biochemical indicators (P < 0.01). Based on MP parameters, early anticoagulant treatment with low-molecular-weight heparin or low-dose aspirin in pregnant women with hypercoagulability can effectively prevent the occurrence of PE and significantly improve the prognosis of both mothers and infants.

Role of brain-gut-muscle axis in human health and energy homeostasis.

The interrelationship between brain, gut and skeletal muscle plays a key role in energy homeostasis of the body, and is becoming a hot topic of research. Intestinal microbial metabolites, such as short-chain fatty acids (SCFAs), bile acids (BAs) and tryptophan metabolites, communicate with the central nervous system (CNS) by binding to their receptors. In fact, there is a cross-talk between the CNS and the gut. The CNS, under the stimulation of pressure, will also affect the stability of the intestinal system, including the local intestinal transport, secretion and permeability of the intestinal system. After the gastrointestinal tract collects information about food absorption, it sends signals to the central system through vagus nerve and other channels to stimulate the secretion of brain-gut peptide and produce feeding behavior, which is also an important part of maintaining energy homeostasis. Skeletal muscle has receptors for SCFAs and BAs. Therefore, intestinal microbiota can participate in skeletal muscle energy metabolism and muscle fiber conversion through their metabolites. Skeletal muscles can also communicate with the gut system during exercise. Under the stimulation of exercise, myokines secreted by skeletal muscle causes the secretion of intestinal hormones, and these hormones can act on the central system and affect food intake. The idea of the brain-gut-muscle axis is gradually being confirmed, and at present it is important for regulating energy homeostasis, which also seems to be relevant to human health. This article focuses on the interaction of intestinal microbiota, central nervous, skeletal muscle energy metabolism, and feeding behavior regulation, which will provide new insight into the diagnostic and treatment strategies for obesity, diabetes, and other metabolic diseases.

Intestinal accumulation of microbiota-produced succinate caused by loss of microRNAs leads to diarrhea in weanling piglets.

Diarrheal disease is a common health problem with complex causality. Although diarrhea is accompanied by disturbances in microbial diversity, how gut microbes are involved in the occurrence of diarrhea remains largely unknown. Here, using a pig model of post-weaning stress-induced diarrhea, we aim to elucidate and enrich the mechanistic basis of diarrhea. We found significant alterations in fecal microbiome, their metabolites, and microRNAs levels in piglets with diarrhea. Specifically, loss of ssc-miRNA-425-5p and ssc-miRNA-423-3p, which inhibit the gene expression of fumarate reductase (frd) in Prevotella genus, caused succinate accumulation in piglets, which resulted in diarrhea. Single-cell RNA sequencing indicated impaired epithelial function and increased immune response in the colon of piglet with diarrhea. Notably, the accumulated succinate increased colonic fluid secretion by regulating transepithelial Cl-secretion in the epithelial cells. Meanwhile, succinate promoted colonic inflammatory responses by activating MyD88-dependent TLR4 signaling in the macrophages. Overall, our findings expand the mechanistic basis of diarrhea and suggest that colonic accumulation of microbiota-produced succinate caused by loss of miRNAs leads to diarrhea in weanling piglets.