SENP1 mediates zinc-induced ZnT6 deSUMOylation at Lys-409 involved in the regulation of zinc metabolism in Golgi apparatus.

Zinc (Zn) transporters contribute to the maintenance of intracellular Zn homeostasis in vertebrate, whose activity and function are modulated by post-translational modification. However, the function of small ubiquitin-like modifier (SUMOylation) in Zn metabolism remains elusive. Here, compared with low Zn group, a high-Zn diet significantly increases hepatic Zn content and upregulates the expression of metal-response element-binding transcription factor-1 (MTF-1), Zn transporter 6 (ZnT6) and deSUMOylation enzymes (SENP1, SENP2, and SENP6), but inhibits the expression of SUMO proteins and the E1, E2, and E3 enzymes. Mechanistically, Zn triggers the activation of the MTF-1/SENP1 pathway, resulting in the reduction of ZnT6 SUMOylation at Lys 409 by small ubiquitin-like modifier 1 (SUMO1), and promoting the deSUMOylation process mediated by SENP1. SUMOylation modification of ZnT6 has no influence on its localization but reduces its protein stability. Importantly, deSUMOylation of ZnT6 is crucial for controlling Zn export from the cytosols into the Golgi apparatus. In conclusion, for the first time, we elucidate a novel mechanism by which SUMO1-catalyzed SUMOylation and SENP1-mediated deSUMOylation of ZnT6 orchestrate the regulation of Zn metabolism within the Golgi apparatus.

CPK10 protein kinase regulates Arabidopsis tolerance to boron deficiency through phosphorylation and activation of BOR1 transporter.

Boron (B) is crucial for plant growth and development. B deficiency can impair numerous physiological and metabolic processes, particularly in root development and pollen germination, seriously impeding crop growth and yield. However, the molecular mechanism underlying boron signal perception and signal transduction is rather limited. In this study, we discovered that CPK10, a calcium-dependent protein kinase in the CPK family, has the strongest interaction with the boron transporter BOR1. Mutations in CPK10 led to growth and root development defects under B-deficiency conditions, while constitutively active CPK10 enhanced plant tolerance to B deficiency. Furthermore, we found that CPK10 interacted with and phosphorylated BOR1 at the Ser689 residue. Through various biochemical analyses and complementation of B transport in yeast and plants, we revealed that Ser689 of BOR1 is important for its transport activity. In summary, these findings highlight the significance of the CPK10-BOR1 signaling pathway in maintaining B homeostasis in plants and provide targets for the genetic improvement of crop tolerance to B-deficiency stress.

Optimum Doses and Forms of Selenium Maintaining Reproductive Health via Regulating Homeostasis of Gut Microbiota and Testicular Redox, Inflammation, Cell Proliferation, and Apoptosis in Roosters.

BACKGROUND: There is a U-shaped relationship between dietary selenium (Se) ingestion and optimal sperm quality. OBJECTIVES: This study aimed to investigate the optimal dietary dose and forms of Se for sperm quality of breeder roosters and the relevant mechanisms. METHODS: In experiment 1, 18-wk-old Jingbai laying breeder roosters were fed a Se-deficient base diet (BD, 0.06 mg Se/kg), or the BD + 0.1, 0.2, 0.3, 0.4, 0.5, or 1.0 mg Se/kg for 9 wk. In experiment 2, the roosters were fed the BD or the BD + sodium selenite (SeNa), seleno-yeast (SeY), or Se-nanoparticles (SeNPs) at 0.2 mg Se/kg for 9 wk. RESULTS: In experiment 1, added dietary 0.2 and 0.3 mg Se/kg led to higher sperm motility and lower sperm mortality than the other groups at weeks 5, 7, and/or 9. Furthermore, added dietary 0.2-0.4 mg Se/kg produced better testicular histology and/or lower testicular 8-hydroxy-deoxyguanosine than the other groups. Moreover, integrated testicular transcriptomic and cecal microbiomic analysis revealed that inflammation, cell proliferation, and apoptosis-related genes and bacteria were dysregulated by Se deficiency or excess. In experiment 2, compared with SeNa, SeNPs slightly increased sperm motility throughout the experiment, whereas SeNPs slightly reduced sperm mortality compared with SeY at week 9. Both SeY and SeNPs decreased malondialdehyde in the serum than those of SeNa, and SeNPs led to higher glutathione peroxidase (GPX) and thioredoxin reductase activities and GPX1 and B-cell lymphoma 2 protein concentrations in the testis compared with SeY and SeNa. CONCLUSIONS: The optimal dietary Se dose for reproductive health of breeder roosters is 0.25-0.35 mg Se/kg, and SeNPs displayed better effects on reproductive health than SeNa and SeY in laying breeder roosters. The optimal doses and forms of Se maintain reproductive health of roosters associated with regulation intestinal microbiota homeostasis and/or testicular redox balance, inflammation, cell proliferation, and apoptosis.

Alternative splicing of TaHSFA6e modulates heat shock protein-mediated translational regulation in response to heat stress in wheat.

Heat stress greatly threatens crop production. Plants have evolved multiple adaptive mechanisms, including alternative splicing, that allow them to withstand this stress. However, how alternative splicing contributes to heat stress responses in wheat (Triticum aestivum) is unclear. We reveal that the heat shock transcription factor gene TaHSFA6e is alternatively spliced in response to heat stress. TaHSFA6e generates two major functional transcripts: TaHSFA6e-II and TaHSFA6e-III. TaHSFA6e-III enhances the transcriptional activity of three downstream heat shock protein 70 (TaHSP70) genes to a greater extent than does TaHSFA6e-II. Further investigation reveals that the enhanced transcriptional activity of TaHSFA6e-III is due to a 14-amino acid peptide at its C-terminus, which arises from alternative splicing and is predicted to form an amphipathic helix. Results show that knockout of TaHSFA6e or TaHSP70s increases heat sensitivity in wheat. Moreover, TaHSP70s are localized in stress granule following exposure to heat stress and are involved in regulating stress granule disassembly and translation re-initiation upon stress relief. Polysome profiling analysis confirms that the translational efficiency of stress granule stored mRNAs is lower at the recovery stage in Tahsp70s mutants than in the wild types. Our finding provides insight into the molecular mechanisms by which alternative splicing improves the thermotolerance in wheat.

Heat Stress Impairs Male Reproductive System with Potential Disruption of Retinol Metabolism and Microbial Balance in the Testis of Mice.

BACKGROUND: Heat stress (HS) has a harmful impact on the male reproductive system, primarily by reducing the sperm quality. The testicular microenvironment plays an important role in sperm quality. OBJECTIVES: This study aimed to explore the underlying mechanism by which HS impairs the male reproductive system through the testicular microenvironment. METHODS: Ten-week-old male mice (n = 8 mice/group) were maintained at a normal temperature (25°C, control) or subjected to HS (38°C for 2 h each day, HS) for 2 wk. The epididymides and testes were collected at week 2 to determine sperm quality, histopathology, retinol concentration, the expression of retinol metabolism-related genes, and the testicular microbiome. The testicular microbiome profiles were analyzed using biostatistics and bioinformatics; other data were analyzed using a 2-sided Student's t test. RESULTS: Compared with the control, HS reduced (P < 0.05) sperm count (42.4%) and motility (97.7%) and disrupted the integrity of the blood-testis barrier. Testicular microbial profiling analysis revealed that HS increased the abundance of the genera Asticcacaulis, Enhydrobacter, and Stenotrophomonas (P < 0.05) and decreased the abundance of the genera Enterococcus and Pleomorphomonas (P < 0.05). Notably, the abundance of Asticcacaulis spp. showed a significant negative correlation with sperm count (P < 0.001) and sperm motility (P < 0.001). Moreover, Asticcacaulis spp. correlated significantly with most blood differential metabolites, particularly retinol (P < 0.05). Compared with the control, HS increased serum retinol concentrations (25.3%) but decreased the testis retinol concentration by 23.7%. Meanwhile, HS downregulated (P < 0.05) the expression of 2 genes (STRA6 and RDH10) and a protein (RDH10) involved in retinol metabolism by 27.3%-36.6% in the testis compared with the control. CONCLUSIONS: HS reduced sperm quality, mainly because of an imbalance in the testicular microenvironment potentially caused by an increase in Asticcacaulis spp. and disturbed retinol metabolism. These findings may offer new strategies for improving male reproductive capacity under HS.

Selenium Deficiency Dysregulates One-Carbon Metabolism in Nutritional Muscular Dystrophy of Chicks.

BACKGROUND: Nutritional muscular dystrophy (NMD) in animals is induced by dietary selenium (Se) deficiency. OBJECTIVES: This study was conducted to explore the underlying mechanism of Se deficiency-induced NMD in broilers. METHODS: One-day-old male Cobb broilers (n = 6 cages/diet, 6 birds/cage) were fed a Se-deficient diet (Se-Def, 47 µg Se/kg) or the Se-Def supplemented with 0.3 mg Se/kg (control) for 6 wk. Thigh muscles of broilers were collected at week 6 for measuring Se concentration, histopathology, and transcriptome and metabolome assays. The transcriptome and metabolome data were analyzed with bioinformatics tools and other data were analyzed with Student's t tests. RESULTS: Compared with the control, Se-Def induced NMD in broilers, including reduced (P < 0.05) final body weight (30.7%) and thigh muscle size, reduced number and cross-sectional area of fibers, and loose organization of muscle fibers. Compared with the control, Se-Def decreased (P < 0.05) the Se concentration in the thigh muscle by 52.4%. It also downregulated (P < 0.05) GPX1, SELENOW, TXNRD1-3, DIO1, SELENOF, H, I, K, M, and U by 23.4-80.3% in the thigh muscle compared with the control. Multi-omics analyses indicated that the levels of 320 transcripts and 33 metabolites were significantly altered (P < 0.05) in response to dietary Se deficiency. Integrated transcriptomics and metabolomics analysis revealed that one-carbon metabolism, including the folate and methionine cycle, was primarily dysregulated by Se deficiency in the thigh muscles of broilers. CONCLUSIONS: Dietary Se deficiency induced NMD in broiler chicks, potentially with the dysregulation of one-carbon metabolism. These findings may provide novel treatment strategies for muscle disease.

T-2 toxin-induced intestinal damage with dysregulation of metabolism, redox homeostasis, inflammation, and apoptosis in chicks.

T-2 toxin is a worldwide problem for feed and food safety, leading to livestock and human health risks. The objective of this study was to explore the mechanism of T-2 toxin-induced small intestine injury in broilers by integrating the advanced microbiomic, metabolomic and transcriptomic technologies. Four groups of 1-day-old male broilers (n = 4 cages/group, 6 birds/cage) were fed a control diet and control diet supplemented with T-2 toxin at 1.0, 3.0, and 6.0 mg/kg, respectively, for 2 weeks. Compared with the control, dietary T-2 toxin reduced feed intake, body weight gain, feed conversion ratio, and the apparent metabolic rates and induced histopathological lesions in the small intestine to varying degrees by different doses. Furthermore, the T-2 toxin decreased the activities of glutathione peroxidase, thioredoxin reductase and total antioxidant capacity but increased the concentrations of protein carbonyl and malondialdehyde in the duodenum in a dose-dependent manner. Moreover, the integrated microbiomic, metabolomic and transcriptomic analysis results revealed that the microbes, metabolites, and transcripts were primarily involved in the regulation of nucleotide and glycerophospholipid metabolism, redox homeostasis, inflammation, and apoptosis were related to the T-2 toxin-induced intestinal damage. In summary, the present study systematically elucidated the intestinal toxic mechanisms of T-2 toxin, which provides novel ideas to develop a detoxification strategy for T-2 toxin in animals.

The effect of posterior cruciate ligament tibial avulsion fracture on functional outcomes in knees with concomitant ipsilateral lower limb fractures: a matched-cohort analysis.

BACKGROUND: At present, the optimal treatment for posterior cruciate ligament tibial avulsion fracture (PCLTAF) combined with concomitant ipsilateral lower limb fractures remains unclear. The present study aimed to assess the preliminary outcomes of treatment for PCLTAF with concomitant ipsilateral lower limb fractures by open reduction and internal fixation (ORIF). MATERIALS AND METHODS: The medical records of patients who sustained PCLTAF with concomitant ipsilateral lower limb fractures between March 2015 and February 2019 and underwent treatment at a single institution were retrospectively reviewed. Imaging examinations performed at the time of injury were applied to identify concomitant ipsilateral lower limb fractures. We used 1:2 matching between patients with PCLTAF combined with concomitant ipsilateral lower limb fractures (combined group; n = 11) and those with isolated PCLTAF (isolated group; n = 22). Outcome data were collected, including the range of motion (ROM) and visual analogue scale (VAS), Tegner, Lysholm, and International Knee Documentation Committee (IKDC) scores. At the final follow-up, the clinical outcomes were compared between the combined and isolated groups and between patients who underwent early-stage surgery and those who underwent delayed treatment for PCLTAF. RESULTS: Thirty-three patients (26 males, 7 females) were included in this study, with eleven patients having PCLTAF and concomitant ipsilateral lower limb fractures and a follow-up of 3.1 to 7.4 years (average, 4.8 years). Compared to patients in the isolated group, patients in the combined group demonstrated significantly worse Lysholm scores (85.7 ± 5.8 vs. 91.5 ± 3.9, p = 0.040), Tegner scores (4.4 ± 0.9 vs. 5.4 ± 0.8, p = 0.006), and IKDC scores (83.6 ± 9.3 vs. 90.5 ± 3.0, p = 0.008). Inferior outcomes were found in patients with delayed treatment. CONCLUSIONS: Inferior results were found in patients with concomitant ipsilateral lower limb fractures, while better outcomes were obtained in patients with PCLTAF through early-stage ORIF using the posteromedial approach. The present findings may help determine the prognoses of patients with PCLTAF combined with concomitant ipsilateral lower limb fractures treated through early-stage ORIF.

Paternally imprinted LATE-FLOWERING2 transcription factor contributes to paternal-excess interploidy hybridization barriers in wheat.

Interploidy hybridization between hexaploid and tetraploid genotypes occurred repeatedly during genomic introgression events throughout wheat evolution, and is commonly employed in wheat breeding programs. Hexaploid wheat usually serves as maternal parent because the reciprocal cross generates progeny with severe defects and poor seed germination, but the underlying mechanism is poorly understood. Here, we performed detailed analysis of phenotypic variation in endosperm between two interploidy reciprocal crosses arising from tetraploid (Triticum durum, AABB) and hexaploid wheat (Triticum aestivum, AABBDD). In the paternal- versus the maternal-excess cross, the timing of endosperm cellularization was delayed and starch granule accumulation in the endosperm was repressed, causing reduced germination percentage. The expression profiles of genes involved in nutrient metabolism differed strongly between these endosperm types. Furthermore, expression patterns of parental alleles were dramatically disturbed in interploidy versus intraploidy crosses, leading to increased number of imprinted genes. The endosperm-specific TaLFL2 showed a paternally imprinted expression pattern in interploidy crosses partially due to allele-specific DNA methylation. Paternal TaLFL2 binds to and represses a nutrient accumulation regulator TaNAC019, leading to reduced storage protein and starch accumulation during endosperm development in paternal-excess cross, as confirmed by interploidy crosses between tetraploid wild-type and clustered regularly interspaced palindromic repeats (CRISPR) - CRISPR-associated protein 9 generated hexaploid mutants. These findings reveal a contribution of genomic imprinting to paternal-excess interploidy hybridization barriers during wheat evolution history and explains why experienced breeders preferentially exploit maternal-excess interploidy crosses in wheat breeding programs.

Selenium-Enriched Cardamine violifolia Increases Selenium and Decreases Cholesterol Concentrations in Liver and Pectoral Muscle of Broilers.

BACKGROUND: Supernutrition of selenium (Se) in an effort to produce Se-enriched meat may inadvertently cause lipid accumulation. Se-enriched Cardamine violifolia (SeCv) contains >80% of Se in organic forms. OBJECTIVES: This study was to determine whether feeding chickens a high dose of SeCv could produce Se-biofortified muscle without altering their lipid metabolism. METHODS: Day-old male broilers were allocated to 4 groups (6 cages/group and 6 chicks/cage) and were fed either a corn-soy base diet (BD, 0.13-0.15 mg Se/kg), the BD plus 0.5 mg Se/kg as sodium selenite (SeNa) or as SeCv, or the BD plus a low-Se Cardamine violifolia (Cv, 0.20-0.21mg Se/kg). At week 6, concentrations of Se and lipid and expression of selenoprotein and lipid metabolism-related genes were determined in the pectoral muscle and liver. RESULTS: The 4 diets showed no effects on growth performance of broilers. Compared with the other 3 diets, SeCv elevated (P < 0.05) Se concentrations in the pectoral muscle and liver by 14.4-127% and decreased (P < 0.05) total cholesterol concentrations by 12.5-46.7% and/or triglyceride concentrations by 28.8-31.1% in the pectoral muscle and/or liver, respectively. Meanwhile, SeCv enhanced (P < 0.05) muscular α-linolenic acid (80.0%) and hepatic arachidonic acid (58.3%) concentrations compared with SeNa and BD, respectively. SeCv downregulated (P < 0.05) the cholesterol and triglyceride synthesis-related proteins (sterol regulatory element binding transcription factor 2 and diacylglycerol O-acyltransferase 2) and upregulated (P < 0.05) hydrolysis and ß-oxidation of fatty acid-related proteins (lipoprotein lipase, fatty acid binding protein 1, and carnitine palmitoyltransferase 1A), as well as selenoprotein P1 and thioredoxin reductase activity in the pectoral muscle and/or liver compared with SeNa. CONCLUSIONS: Compared with SeNa, SeCv effectively raised Se and reduced lipids in the liver and muscle of broilers. The effect was mediated through the regulation of the cholesterol and triglyceride biosynthesis and utilization-related genes.

Changes in Alternative Splicing in Response to Domestication and Polyploidization in Wheat.

Alternative splicing (AS) occurs extensively in eukaryotes as an important mechanism for regulating transcriptome complexity and proteome diversity, but variation in the AS landscape in response to domestication and polyploidization in crops is unclear. Hexaploid wheat (AABBDD, Triticum aestivum) has undergone two separate allopolyploidization events, providing an ideal model for studying AS changes during domestication and polyploidization events. In this study, we performed high-throughput transcriptome sequencing of roots and leaves from wheat species with varied ploidies, including wild diploids (AbAb, Triticum boeoticum) and tetraploids (AABB, Triticum dicoccoides), domesticated diploids (AmAm, Triticum monococcum) and tetraploids (AABB, Triticum dicoccum), hexaploid wheat (AABBDD, T aestivum), as well as newly synthesized hexaploids together with their parents. Approximately 22.1% of genes exhibited AS, with the major AS type being intron retention. The number of AS events decreased after domestication in both diploids and tetraploids. Moreover, the frequency of AS occurrence tended to decrease after polyploidization, consistent with the functional sharing model that proposes AS and duplicated genes are complementary in regulating transcriptome plasticity in polyploid crops. In addition, the subgenomes exhibited biased AS responses to polyploidization, and ∼87.1% of homeologs showed AS partitioning in hexaploid wheat. Interestingly, substitution of the D-subgenome modified 42.8% of AS patterns of the A- and B-subgenomes, indicating subgenome interplay reprograms AS profiles at a genome-wide level, although the causal-consequence relationship requires further study. Conclusively, our study shows that AS variation occurs extensively after polyploidization and domestication in wheat species.

Correlation study between flash dual source CT perfusion imaging and regional lymph node metastasis of non-small cell lung cancer.

BACKGROUND: To explore the correlation of flash dual source computed tomography perfusion imaging (CTPI) and regional lymph node metastasis of non-small cell lung cancer (NSCLC), and to evaluate the value of CT perfusion parameters in predicting regional lymph node metastasis of NSCLC. METHODS: 120 consecutive patients with NSCLC confirmed by postoperative histopathology were underwent flash dual source CT perfusion imaging in pre-operation. The CT perfusion parameters of NSCLC, such as blood flow (BF), blood volume (BV), mean transit time (MTT) and permeability (PMB) were obtained by the image post-processing. Then microvessel density (MVD), luminal vascular number (LVN), luminal vascular area (LVA) and luminal vascular perimeter (LVP) of NSCLC were counted by immunohistochemistry. These cases were divided into group A (patients with lymph node metastasis, 58 cases) and group B (patients without lymph node metastasis, 62 cases) according to their pathological results. The CT perfusion parameters and the microvessel parameters were contrastively analysed between the two groups. Receiver operating characteristic (ROC) curve was used to assess the diagnostic efficiency of CT perfusion parameters in predicting regional lymph node metastasis of NSCLC in pre-operation. RESULTS: Group A presented significantly lower LVA, BF and higher MTT, PMB than Group B (P < 0.05), while BV, LVN, LVP and MVD were no significant difference (P > 0.05). Correlation analysis showed that BF was correlated with LVA and LVP (P < 0.05), while BV, MTT and PMB were not correlated with LVN, LVA and LVP (P > 0.05). All the perfusion parameters were not correlated with MVD. According to the ROC curve analysis, when BF < 85.16 ml/100 ml/min as a cutoff point to predict regional lymph node metastasis of NSCLC, the sensitivity, specificity, accuracy, positive predictive value and negative predictive value were 60.8, 81.7, 71.5, 75.6 and 69.5% respectively. CONCLUSION: Flash dual source CT perfusion imaging can non-invasively indicate the luminal vascular structure of tumor and BF can be used as one of the important indexes in predicting regional lymph node metastasis of NSCLC in pre-operation.

Selenium Deficiency Aggravates Aflatoxin B1-Induced Immunotoxicity in Chick Spleen by Regulating 6 Selenoprotein Genes and Redox/Inflammation/Apoptotic Signaling.

BACKGROUND: Selenium (Se) plays a protective role in aflatoxin B1 (AFB1)-induced splenic immunotoxicity in chicks. OBJECTIVE: This study was designed to reveal the underlying mechanism of Se-mediated protection against AFB1-induced splenic injury in broilers. METHODS: Four groups of 1-d-old Cobb male broilers (n = 5 cages/diet, 6 chicks/cage) were arranged in a 3-wk 2 × 2 factorial design trial whereby they were fed an Se-deficient, corn- and soy-based diet [base diet (BD), 36 µg Se/kg], BD plus 1.0 mg AFB1/kg, BD plus 0.3 mg Se/kg, or BD plus 1.0 mg AFB1/kg and 0.3 mg Se/kg (as 2-hydroxy-4-methylselenobutanoic acid). Serum and spleen were collected at week 3 to assay for cytokines, histology, redox status, selected inflammation- and apoptosis-related genes and proteins, and the selenogenome. RESULTS: Dietary AFB1 induced growth retardation and spleen injury, decreasing (P < 0.05) body weight gain, feed intake, feed conversion efficiency, and serum interleukin-1ß by 17.8-98.1% and increasing (P < 0.05) the spleen index and serum interleukin-6 by 37.6-113%. It also reduced the splenic lymphocyte number, the white pulp region, and histiocyte proliferation in Se-adequate groups. However, Se deficiency aggravated (P < 0.05) these AFB1-induced alterations by 16.2-103%. Moreover, Se deficiency decreased (P < 0.05) splenic glutathione peroxidase (GPX) activity and glutathione-S transferase and glutathione concentrations by 35.6-89.4% in AFB1-exposed groups. Furthermore, Se deficiency upregulated (P < 0.05) the apoptotic (Caspase 3 and Caspase 9) and antimicrobial (ß defensin 1 and 2) genes, but downregulated (P < 0.05) antiapoptotic (B-cell lymphoma 2) and inflammatory (E3 ubiquitin-protein ligase CBL-B) genes at the mRNA and/or protein level in AFB1 supplementation groups. Additionally, Se deficiency downregulated (P < 0.05) GPX3, thioredoxin reductase 1 (TXNRD 1), GPX4, and selenoprotein (SELENO) S, and upregulated (P < 0.05) SELENOT and SELENOU in spleen in AFB1 administered groups. CONCLUSIONS: Dietary Se deficiency exacerbated AFB1-induced spleen injury in chicks, partially through the regulation of oxidative stress, inflammatory and apoptotic signaling, and 6 selenoproteins.

Dietary Silymarin Supplementation Alleviates Zearalenone-Induced Hepatotoxicity and Reproductive Toxicity in Rats.

Background: Zearalenone (ZEN) can cause serious defects in development and reproduction in humans and animals. Silymarin shows antioxidant and estrogenic effects. Objective: This study was conducted to determine if silymarin can antagonize ZEN-induced hepatic and reproductive toxicities. Methods: Thirty-five 21-d-old female Sprague-Dawley rats (n = 7/diet) were fed a control diet (Ctrl) or Ctrl plus 20 mg ZEN/kg or Ctrl plus 20 mg ZEN/kg with 100, 200, or 500 mg silymarin/kg for 6 wk. Serum, livers, ovaries, and uterus were collected at week 6 for biochemistry, hormone, and redox status and selected gene and protein assays. Results: The consumption of ZEN decreased (P < 0.05) the final body weight by 17.9%, induced liver injury, increased (P < 0.05) aspartate aminotransferase and alkaline phosphatase activities, and decreased (P < 0.05) total protein and albumin concentrations in serum by 16.7-40.6%. ZEN also caused reproductive toxicity, including decreased (P < 0.05) 17ß-estradiol and increased (P < 0.05) follicle-stimulating hormone concentrations in serum by 12.7-46.3% and induced histopathologic alterations in the liver, ovaries, and uterus. Interestingly, these alterations induced by ZEN were alleviated (P < 0.05) by silymarin supplementation at 100, 200, and 500 mg/kg. Moreover, silymarin supplementation at the 3 doses mitigated (P < 0.05) ZEN-induced impairment in hepatic glutathione peroxidase activity, total antioxidant capacity, and malondialdehyde concentration by 17.6-100%. Meanwhile, silymarin supplementation at all doses upregulated (P < 0.05) phospho-ribosomal protein S6 kinase 1 (p-RPS6KB1) and 3ß-hydroxysteroid dehydrogenase (HSD3B) by 43.0-121% but downregulated (P < 0.05) AMP-activated protein kinase (AMPK) and 3α-hydroxysteroid dehydrogenase (HSD3A) in the liver relative to the ZEN group by 11.2-40.6%. In addition, silymarin supplementation at all doses elevated (P < 0.05) HSD3B by 1.8- to 2.5-fold and decreased (P < 0.05) estrogen receptor 1 (ESR1), ATP binding cassette (ABC) c1, and Abcc5 in ovaries and the uterus by 10.7-63.2%. Conclusion: Dietary silymarin supplementation at 100, 200, and 500 mg/kg protected rats from ZEN-induced hepatotoxicity and reproductive toxicity, potentially through improvement in the antioxidant capacity and regulation in the genes related to protein synthesis, ZEN metabolism, hormone synthesis, and ABC transporters in the tissues.

A Novel Organic Selenium Compound Exerts Unique Regulation of Selenium Speciation, Selenogenome, and Selenoproteins in Broiler Chicks.

Background: A new organic selenium compound, 2-hydroxy-4-methylselenobutanoic acid (SeO), displayed a greater bioavailability than sodium selenite (SeNa) or seleno-yeast (SeY) in several species.Objective: This study sought to determine the regulation of the speciation of selenium, expression of selenogenome and selenocysteine biosynthesis and degradation-related genes, and production of selenoproteins by the 3 forms of selenium in the tissues of broiler chicks.Methods: Day-old male chicks (n = 6 cages/diet, 6 chicks/cage) were fed a selenium-deficient, corn and soy-based diet [base diet (BD), 0.05 mg Se/kg] or the BD + SeNa, SeY, or SeO at 0.2 mg Se/kg for 6 wk. Plasma, livers, and pectoral and thigh muscles were collected at weeks 3 and 6 to assay for total selenium, selenomethionine, selenocysteine, redox status, and selected genes, proteins, and enzymes.Results: Although both SeY and SeO produced greater concentrations (P < 0.05) of total selenium (20-172%) and of selenomethionine (≤15-fold) in the liver, pectoral muscle, and thigh than those of SeNa, SeO further raised (P < 0.05) these concentrations by 13-37% and 43-87%, respectively, compared with SeY. Compared with the BD, only SeO enhanced (P < 0.05) the mRNA of selenoprotein (Seleno) s and methionine sulfoxide reductase B1 (Msrb1) in the liver and thigh (62-98%) and thioredoxin reductase (TXRND) activity in the pectoral and thigh muscles (20-37%) at week 3. Furthermore, SeO increased (P < 0.05) the expression of glutathione peroxidase (Gpx) 3, GPX4, SELENOP, and SELENOU relative to the SeNa group by 26-207%, and the expression of Selenop, O-phosphoseryl-transfer RNA (tRNA):selenocysteinyl-tRNA synthase, GPX4, and SELENOP relative to the SeY group by 23-55% in various tissues.Conclusions: Compared with SeNa or SeY, SeO demonstrated a unique ability to enrich selenomethionine and total selenium depositions, to induce the early expression of Selenos and Mrsb1 mRNA and TXRND activity, and to enhance the protein production of GPX4, SELENOP, and SELENOU in the tissues of chicks.

Prevention of Aflatoxin B1 Hepatoxicity by Dietary Selenium Is Associated with Inhibition of Cytochrome P450 Isozymes and Up-Regulation of 6 Selenoprotein Genes in Chick Liver.

BACKGROUND: The involvement of cytochrome P450 (CYP450) isozymes and the selenogenome in selenium-mediated protection against aflatoxin B1 (AFB1)-induced adverse effects in broilers remains unclear. OBJECTIVE: This study was designed first to determine whether selenium could reduce AFB1-induced hepatotoxic effects and then to determine whether these effects were due to changes in the CYP450 isozymes and selenogenome expression in the liver of chicks. METHODS: Male avian broilers (aged 120 d) were allocated to 4 groups with 5 replicates of 6 birds to be included in a 2-by-2 factorial trial in which the main factors included supplementation of AFB1 (<5 compared with 100 µg/kg) and selenium (0.2 compared with 0.5 mg/kg) in a corn/soybean-based diet for 4 wk. Serum biochemistry, hepatic histology, and mRNA and/or activities of hepatic antioxidant enzymes, CYP450 isozymes, and 26 selenoproteins were analyzed at week 2 and/or 4. RESULTS: Administration of AFB1 induced liver injury, decreasing (P < 0.05) total protein and albumin concentrations by 33.3-43.8% and increasing (P < 0.05) alanine aminotransferase and aspartate aminotransferase activities by 26.0-33.8% in serum, and induced hepatic necrosis and bile duct hyperplasia at week 2. AFB1 also decreased (P < 0.05) hepatic activities of glutathione peroxidase (GPX), thioredoxin reductase (TXNRD), and catalase, and the glutathione concentration by 13.1-59.9% and increased (P < 0.05) malondialdehyde, 8-hydroxydeoxyguanosine and exo-AFB1-8,9-epoxide (AFBO) DNA concentrations by 17.9-1200%. In addition, the mRNA and activity of enzymes responsible for the bioactivation of AFB1 into AFBO, which included CYP450 A1, 1A2, 2A6, and 3A4, were significantly induced (P < 0.05) by 29.2-271% in liver microsomes after 2-wk exposure to AFB1. These alterations induced by AFB1 were prevented by selenium supplementation. Dietary selenium supplementation increased (P < 0.05) mRNA and/or activities of 6 selenoprotein genes (Gpx3, Txnrd1, Txnrd2, Txnrd3, iodothyronine deiodinase 2, and selenoprotein N) in the liver of AFB1-treated groups at week 2. CONCLUSIONS: Dietary selenium protected chicks from AFB1-induced liver injury, potentially through the synergistic actions of inhibition of the pivotal CYP450 isozyme-mediated activation of AFB1 to toxic AFBO, and increased antioxidant capacities by upregulation of selenoprotein genes coding for antioxidant proteins.

Effective protective agents against the organ toxicity of T-2 toxin and corresponding detoxification mechanisms: A narrative review.

T-2 toxin is one of the most widespread and toxic fungal toxins in food and feed. It can cause gastrointestinal toxicity, hepatotoxicity, immunotoxicity, reproductive toxicity, neurotoxicity, and nephrotoxicity in humans and animals. T-2 toxin is physicochemically stable and does not readily degrade during food and feed processing. Therefore, suppressing T-2 toxin-induced organ toxicity through antidotes is an urgent issue. Protective agents against the organ toxicity of T-2 toxin have been recorded widely in the literature, but these protective agents and their molecular mechanisms of detoxification have not been comprehensively summarized. In this review, we provide an overview of the various protective agents to T-2 toxin and the molecular mechanisms underlying the detoxification effects. Targeting appropriate targets to antagonize T-2 toxin toxicity is also an important option. This review will provide essential guidance and strategies for the better application and development of T-2 toxin antidotes specific for organ toxicity in the future.

AP-1 and SP1 trans-activate the expression of hepatic CYP1A1 and CYP2A6 in the bioactivation of AFB1 in chicken.

Dietary exposure to aflatoxin B1 (AFB1) is harmful to the health and performance of domestic animals. The hepatic cytochrome P450s (CYPs), CYP1A1 and CYP2A6, are the primary enzymes responsible for the bioactivation of AFB1 to the highly toxic exo-AFB1-8,9-epoxide (AFBO) in chicks. However, the transcriptional regulation mechanism of these CYP genes in the liver of chicks in AFB1 metabolism remains unknown. Dual-luciferase reporter assay, bioinformatics and site-directed mutation results indicated that specificity protein 1 (SP1) and activator protein-1 (AP-1) motifs were located in the core region -1,063/-948, -606/-541 of the CYP1A1 promoter as well as -636/-595, -503/-462, -147/-1 of the CYP2A6 promoter. Furthermore, overexpression and decoy oligodeoxynucleotide technologies demonstrated that SP1 and AP-1 were pivotal transcriptional activators regulating the promoter activity of CYP1A1 and CYP2A6. Moreover, bioactivation of AFB1 to AFBO could be increased by upregulation of CYP1A1 and CYP2A6 expression, which was trans-activated owing to the upregulalion of AP-1, rather than SP1, stimulated by AFB1-induced reactive oxygen species. Additionally, nano-selenium could reduce ROS, downregulate AP-1 expression and then decrease the expression of CYP1A1 and CYP2A6, thus alleviating the toxicity of AFB1. In conclusion, AP-1 and SP1 played important roles in the transactivation of CYP1A1 and CYP2A6 expression and further bioactivated AFB1 to AFBO in chicken liver, which could provide novel targets for the remediation of aflatoxicosis in chicks.

Evaluating the Impact of an Organic Trace Mineral mix on the Redox Homeostasis, Immunity, and Performance of Sows and their Offspring.

The objective of the study was to evaluate the effects of trace mineral supplementation in sows during gestation and lactation on the performance and health status of sows and their offspring. Sows (n = 30; Landrace × Yorkshire; avg parity = 3.9) were randomly allocated into two dietary treatments. Sows received a basal diet supplemented with 12 mg/kg Cu, 30 mg/kg Fe, 90 mg/kg Zn, 70 mg/kg Mn, 0.30 mg/kg Se, and 1.5 mg/kg I from an inorganic trace mineral source (ITM) or a blend of hydroxychloride and organic trace mineral source (HOTM) from day 1 of gestation until the end of the lactation period at day 21. Compared to the ITM, the HOTM supplementation increased (P < 0.05) both litter birth weight and individual piglet birth weight. Although not statistically significant, HOTM tended to increase (P = 0.069) the level of lactose in colostrum. HOTM increased (P < 0.05) the concentration of Mn and Se in the colostrum, milk, and serum of sows and/or piglets. Notably, the Zn concentration in the serum of sows was higher in sows supplemented with ITM compared to HOTM. Moreover, HOTM increased (P < 0.05) the activities of GPX and SOD in gestating sows and piglets, as well as increased (P < 0.05) cytokines (IL-1ß, TNF-α, and IL-10) in the serum of sows. The immunoglobulins (IgA, IgG, and IgM) also increased in sows and/or piglets at certain experimental time points. In conclusion, HOTM supplementation positively affected piglet development and improved the health status of sows and piglets potentially by regulating redox homeostasis and immunity.

Loss of SELENOW aggravates muscle loss with regulation of protein synthesis and the ubiquitin-proteasome system.

Sarcopenia is characterized by accelerated muscle mass and function loss, which burdens and challenges public health worldwide. Several studies indicated that selenium deficiency is associated with sarcopenia; however, the specific mechanism remains unclear. Here, we demonstrated that selenoprotein W (SELENOW) containing selenium in the form of selenocysteine functioned in sarcopenia. SELENOW expression is up-regulated in dexamethasone (DEX)-induced muscle atrophy and age-related sarcopenia mouse models. Knockout (KO) of SELENOW profoundly aggravated the process of muscle mass loss in the two mouse models. Mechanistically, SELENOW KO suppressed the RAC1-mTOR cascade by the interaction between SELENOW and RAC1 and induced the imbalance of protein synthesis and degradation. Consistently, overexpression of SELENOW in vivo and in vitro alleviated the muscle and myotube atrophy induced by DEX. SELENOW played a role in age-related sarcopenia and regulated the genes associated with aging. Together, our study uncovered the function of SELENOW in age-related sarcopenia and provides promising evidence for the prevention and treatment of sarcopenia.