SeMet alleviates LPS-induced eggshell gland necroptosis mediated inflammation by regulating the Keap1/Nrf2/HO-1 pathway.

Exposure to lipopolysaccharide (LPS) can lead to inflammation in a variety of tissues and organs. Selenium (Se) plays a crucial role in mitigating inflammatory damage. Compared with inorganic selenium, organic selenium, such as selenomethionine (SeMet), has the advantages of a higher absorption rate and lower toxicity in animals. This study examined the protective effects of SeMet on eggshell gland tissue damage caused by LPS. Hy-Line Brown laying hens were chosen as the experimental animals and were randomly assigned to four groups: control group (C), lipopolysaccharide group (LPS), SeMet group (Se), and SeMet + lipopolysaccharide group (Se + LPS). H&E staining and transmission electron microscope were performed to observe the pathological changes of eggshell glands, oxidative stress related indicators were measured using relevant kits, qRT‒PCR and western blotting were used to evaluate the mRNA and protein levels of the Nrf2 pathway, necroptosis, and inflammation related indicators. The results showed that LPS treatment increased the content of malondialdehyde (MDA), decreased the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX), and decreased the content of glutathione (GSH). LPS increased the levels of Keap1, RIPK1, RIPK3, MLKL, TNF-α, COX-2, and NF-κB, while decreasing the levels of HO-1, NQO1, Nrf2, and Caspase-8. However, SeMet treatment effectively reversed the changes of the above indicators, indicating that SeMet alleviates eggshell gland cell necroptosis-mediated inflammation induced by LPS via regulating the Keap1/Nrf2/HO-1 pathway. This study elucidated the mechanism by which SeMet alleviates LPS-induced eggshell gland tissue damage in Hy-Line Brown laying hens and provided a new direction for expanding the application of SeMet in the feeding and production of laying hens.

Low-Se Diet Increased Mitochondrial ROS to Suppress Myoblasts Proliferation and Promote Apoptosis in Broilers via miR-365-3p/SelT Signaling Axis.

microRNA (miRNA) controls the post-transcriptional translation of mRNA to affect the expression of many genes participating in functional interaction pathways. Selenoproteins are characterized by their antioxidant activity, wherein selenoprotein T (SelT) is an essential membrane-bound selenoprotein serving as a guardian of intracellular homeostasis. During muscle development and regeneration, myoblasts enter the cell cycle and rapidly proliferate. However, the role of SelT in muscle development and selenium (Se) deficiency-induced muscle damage remains poorly investigated. This study established Se deficient broiler models, chicken embryos models, and cultured chicken primary myoblasts in vitro. We showed that Se deficiency induced skeletal muscle damage in broilers, promoted miR-365-3p expression, and downregulated the level of SelT, significantly. The absence of SelT led to the accumulation of mitochondrial superoxide and downregulated mitochondrial dynamics gene expression, which, in turn, induced the disruption of mitochondria potential and blocked the oxidative phosphorylation (OXPHOS) process. Limited ATP production rate caused by mitochondrial ROS overproduction went along with cell cycle arrest, cell proliferation slowness, and myocyte apoptosis increase. Using Mito-TEMPO for mitochondrial ROS elimination could effectively mitigate the above adverse reactions and significantly restore the proliferation potential of myoblasts. Moreover, we identified miR-365-3p, a miRNA that targeted SelT mRNA to inhibit myoblast proliferation by disrupting intracellular redox balance. The omics analysis results showed that Se deficiency led to the significant enrichment of "cell cycle", "oxidative stress response", and "oxidative phosphorylation" pathway genes. Finally, we proved that the effect of the miR-365-3p/SelT signaling axis on muscle development did exist in the chicken embryo stage. In summary, our findings revealed that miR-365-3p was involved in broiler skeletal muscle damage in Se deficiency by targeting SelT, and SelT, serving as an intracellular homeostasis guardian, resisted mitochondrial oxidative stress, and protected ATP generation, promoting myoblast proliferation and inhibiting apoptosis. This study provides an attractive target for the cultivated meat industry and regenerative medicine.

Extracellular Vesicles Derived from Selenium-Deficient MAC-T Cells Aggravated Inflammation and Apoptosis by Triggering the Endoplasmic Reticulum (ER) Stress/PI3K-AKT-mTOR Pathway in Bovine Mammary Epithelial Cells.

Selenium (Se) deficiency disrupts intracellular REDOX homeostasis and severely deteriorates immune and anti-inflammatory function in high-yielding periparturient dairy cattle. To investigate the damage of extracellular vesicles derived from Se-deficient MAC-T cells (SeD-EV) on normal mammary epithelial cells, an in vitro model of Se deficiency was established. Se-deficient MAC-T cells produced many ROS, promoting apoptosis and the release of inflammatory factors. Extracellular vesicles were successfully isolated by ultrahigh-speed centrifugation and identified by transmission electron microscopy, particle size analysis, and surface markers (CD63, CD81, HSP70, and TSG101). RNA sequencing was performed on exosomal RNA. A total of 9393 lncRNAs and 63,155 mRNAs transcripts were identified in the SeC and SeD groups, respectively, of which 126 lncRNAs and 955 mRNAs were differentially expressed. Furthermore, SeD-EV promoted apoptosis of normal MAC-T cells by TUNEL analysis. SeD-EV significantly inhibited Bcl-2, while Bax and Cleaved Caspase3 were greatly increased. Antioxidant capacity (CAT, T-AOC, SOD, and GSH-Px) was inhibited in SeD-EV-treated MAC-T cells. Additionally, p-PERK, p-eIF2α, ATF4, CHOP, and XBP1 were all elevated in MAC-T cells supplemented with SeD-EV. In addition, p-PI3K, p-Akt, and p-mTOR were decreased strikingly by SeD-EV. In conclusion, SeD-EV caused oxidative stress, thus triggering apoptosis and inflammation through endoplasmic reticulum stress and the PI3K-Akt-mTOR signaling pathway, which contributed to explaining the mechanism of Se deficiency causing mastitis.

Bisphenol A exposure exacerbates tracheal inflammatory injury in selenium-deficient chickens by regulating the miR-155/TRAF3/ROS pathway.

Bisphenol A (BPA) is an endocrine disruptor. Excessive BPA intake can damage the structure and function of the respiratory tract. Dietary selenium (Se) deficiency may also cause immune tissue damage. To investigate the potential mechanism of BPA on tracheal damage in selenium-deficient chickens and the role of microRNAs (miRNAs) in this process, we established in vitro and in vivo Se deficiency and BPA exposure models and screened out miR-155 for follow-up experiments. We further predicted and confirmed the targeting relationship between miR-155 and TRAF3 using TargetScan and dual luciferase assays and found that miR-155 was highly expressed and caused inflammatory damage. Further studies showed that BPA exposure increased airway oxidative stress, activated the NF-κB pathway, and caused inflammation and immune damage in selenium-deficient chickens, but down-regulating miR-155 and NAC treatment could reverse this phenomenon. This suggested that these pathways are regulated by the miR-155/TRAF3/ROS axis. In conclusion, BPA exposure aggravates airway inflammation in selenium-deficient chickens by regulating miR-155/TRAF3/ROS. This study revealed the mechanism of BPA exposure combined with Se deficiency in tracheal inflammatory injury in chickens and enriched the theoretical basis of BPA injury in poultry.

New insights into brain injury in chickens induced by bisphenol A and selenium deficiency-Mitochondrial reactive oxygen species and mitophagy-apoptosis crosstalk homeostasis.

Bisphenol A (BPA), a component of plastic products, can penetrate the blood-brain barrier and pose a threat to the nervous system. Selenium (Se) deficiency can also cause nervous system damage. Resulting from the rapid industrial development, BPA pollution and Se deficiency often coexist. However, it is unclear whether brain damage in chickens caused by BPA exposure and Se deficiency is related to the crosstalk disorder between mitophagy and apoptosis. In this study, 60 chickens (1 day old) were fed with a diet that contained 20 mg/kg BPA but was insufficient in Se (only 0.039 mg/kg) for 42 days to establish a chicken brain injury model. In vitro, the primary chicken embryo brain neurons were treated for 24 h with Se-deficient medium containing 75 µM BPA. The results showed that BPA exposure and Se deficiency inhibited the expression of the mitochondrial respiratory chain complex in brain neurons, and a large number of mitochondrial reactive oxygen species were released. Furthermore, the expression levels of mitochondrial fusion proteins (OPA1, Mfn1, and Mfn2) decreased, while the expression levels of mitochondrial fission proteins (Drp1, Mff, and Fis1) increased, thus exacerbating mitochondrial division. In addition, the results of immunofluorescence and flow cytometry analysis, as well as the elevated expressions of mitophagy related genes (PINK1, Parkin, ATG5, and LC3II/I) and pro-apoptotic markers (Bax, Cytc, Caspase3, and Caspase9) indicated that BPA exposure and Se deficiency disrupted the crosstalk homeostasis between mitophagy and apoptosis. However, this crosstalk homeostasis was restored after Mito-Tempo and Rapamycin treatment. In contrast, 3-methyladenine treatment exacerbated this crosstalk disorder. In conclusion, BPA exposure and Se deficiency can induce mitochondrial reactive oxygen species bursts and disorders of mitochondrial dynamics by destroying the mitochondrial respiratory chain complex. The result is indicative of an imbalance in mitochondrial autophagy and apoptosis crosstalk homeostasis, which damages the chicken brain.

Supplemental methionine selenium effects on egg yolk physicochemical, functional, and protein structure during storage.

To clarify the effect of the addition of methionine selenium on the physicochemical, functional, and protein structural properties of egg yolk during storage. We analyzed the changes in the main indicators of egg yolks stored at 4°C and 25°C for 28 days. The results showed that the increase in water content and pH, and the decrease in absolute zeta potential and apparent viscosity of the selenium-rich egg yolks (Se-group) during storage were smaller than those of the control group egg yolks (C-group). In addition, the antioxidant capacity and emulsifying ability of the Se-group during storage were better than those of the C-group. Simultaneously, the hardness and chewiness of the Se-group gel during storage were lower than those of the C-group. The protein structure results showed that selenium rich treatment did not affect the secondary structure of egg yolk protein during storage but could improve the fluorescence intensity of the egg yolk protein. Therefore, the addition of methionine selenium can reduce the degree of deterioration in the physicochemical properties of egg yolk during storage and extend its shelf life.

ROS mediated pyroptosis-M1 polarization crosstalk participates in inflammation of chicken liver induced by bisphenol A and selenium deficiency.

The earth's natural environmental factors and man-made industrial pollution often lead to the co-occurrence of environmental pathogenic factors and malnutrition. Bisphenol A (BPA) is a serious environmental endocrine disruptor, and its exposure can cause liver tissue damage. Selenium (Se) deficiency is a worldwide problem that afflicts thousands of people, and Se deficiency can cause M1/M2 imbalance. In addition, the crosstalk between hepatocyte and immune cell is closely related to the occurrence of hepatitis. Therefore, this study found for the first time that the combined exposure of BPA and Se deficiency caused liver pyroptosis and M1 polarization through ROS, and the crosstalk between pyroptosis and M1 polarization aggravated liver inflammation in chicken. In this study, the BPA or/and Se deficiency chicken liver, single and co-culture model of LMH and HD11 cells were established. The results displayed that BPA or Se deficiency induced liver inflammation accompanied by pyroptosis and M1 polarization through oxidative stress, and increased expressions of chemokines (CCL4, CCL17, CCL19, and MIF) and inflammatory factors (IL-1ß and TNF-α). The vitro experiments further verified the above changes and showed that LMH pyroptosis promoted M1 polarization of HD11 cells, and vice versa. NAC counteracted pyroptosis and M1 polarization caused by BPA and low-Se, reducing the release of inflammatory factors. In brief, BPA and Se deficiency treatment can exacerbate liver inflammation by increasing oxidative stress to induce pyroptosis and M1 polarization.

ROS/ER stress contributes to trimethyltin chloride-mediated hepatotoxicity; Tea polyphenols alleviate apoptosis and immunosuppression.

Trimethyltin chloride (TMT) is an organotin-based contaminant present in the water environment that poses a great threat to aquatic organisms and humans. The liver is the detoxification organ of the body and TMT exposure accumulates in the liver. Tea polyphenol (TP) is a natural antioxidant extracted from tea leaves and has been widely used as a food and feed additive. To investigate the mechanism of toxicity caused by TMT exposure on grass carp hepatocytes (L8824 cells) and the mitigating effect of TP, we established a hepatocyte model of TMT toxicity and/or TP treatment. L8824 cells were treated with 0.5 µM of TMT and/or 4 µg/mL of TP for 24 h and assayed for relevant indices. The results showed that TMT exposure caused oxidative stress, resulting in increased intracellular ROS content, resulting in intracellular ROS accumulation and increased MDA content, and inhibiting the activities of T-AOC, SOD, CAT, and GSH. Meanwhile, TMT exposure activated the endoplasmic reticulum apoptotic signaling pathway, resulting in abnormal expression of GRP78, ATF-6, IRE1, PERK, Caspase-3 and Caspase-12. In addition, TMT exposure also led to up-regulation of cytokines IL-1ß, IL-6, TNF-α, and decreased expression of IL-2, IFN-γ, and antimicrobial peptides Hepcidin, ß-defensin, and LEAP2. However, the addition of TP could mitigate the above changes. In conclusion, TP can alleviate TMT exposure-mediated hepatotoxicity by inhibiting ROS/ER stress in L8824 cells. In addition, this trial enriches the cytotoxicity study of TMT and provides a new theoretical basis for the use of TP as a mitigating agent for TMT.

Melatonin attenuates bisphenol A-induced colon injury by dual targeting mitochondrial dynamics and Nrf2 antioxidant system via activation of SIRT1/PGC-1α signaling pathway.

Industrial advancement has led to an increase in the production and usage of bisphenol A (BPA), thereby resulting in serious environmental pollution problems. BPA ingestion causes multiorgan toxicity. However, the exact mechanism underlying BPA-induced colon damage remains elusive. Moreover, no safe treatment is available to alleviate BPA-induced colon injury. Therefore, the in vivo and in vitro approaches were employed to detect the protective effects of melatonin (MT) on BPA-induced colon injury and to determine the underpinning molecular mechanisms. MT treatment of mice and the colonic epithelial cells NCM460 alleviated BPA-induced colon damage by inhibiting the mitochondrial dynamic imbalance, enhancing mitochondrial respiratory chain (MRC) complexes expression, reducing reactive oxygen species (ROS) production, and suppressing apoptosis and necroptosis. MT upregulated the proteins level of silent information regulator 1 (SIRT1) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), which further increased the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and the downstream antioxidant target genes heme oxygenase-1 (HO-1) and NAD(P)H quinone redox enzyme-1 (NQO1). Treatment with the SIRT1 inhibitor EX527 effectively reversed the MT-induced upregulation of the aforementioned protein levels. Thus, the MT-activated Sirt1/PGC-1α signaling pathway restored the mitochondrial dynamic balance and activated the Nrf2 antioxidant axis to attenuate BPA-induced colon injury. These results demonstrate that MT supplementation may potentially mitigate BPA toxicity.

Selenium deficiency aggravates bisphenol A-induced autophagy in chicken kidney through regulation of nitric oxide and adenosine monophosphate activated protein kinase/mammalian target of rapamycin signaling pathway.

Bisphenol A (BPA), a phenolic compound, is harmful to humans and animals as its residue in the water threatens multiple organs, especially the kidney. Low selenium (Se) diets are consumed in many regions of the world, and poor Se status has exacerbating effect on toxicity of several environmental chemicals. Here, we described the discovery path of Se deficiency aggravation on autophagy in BPA treated chicken kidney through regulating nitric oxide (NO) and adenosine monophosphate activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) signaling pathways. The actual dietary Se intake for chickens was 0.30 mg/kg in control group and 0.03 mg/kg in Low-Se group, and BPA exposure concentration for chickens was 0.05 g/kg. Chicken embryo kidney (CEK) cells were used in vitro and the BPA exposure concentration for CEK cells was 150 nM. We found that BPA significantly increased levels of NO and inducible nitric oxide synthase, activated AMPK/mTOR signaling pathways, thereby triggering p62/LC3/Beclin1 signaling, resulting in formations of autophagosome and autolysosome, and finally stimulating autophagy in the chicken kidney. Additionally, Se deficiency promoted the occurrence of autophagy in BPA-treated kidneys. Altogether, our findings showed that Se deficiency exacerbates BPA-induced renal autophagy in chickens via regulation of NO and AMPK/mTOR signaling pathways. These findings will improve our understandings of the mechanisms of nephrotoxicity of BPA and detoxification by Se in chickens. In addition, further work is required to determine if Se status of exposed populations needs to be considered in future epidemiological assessments.

Cadmium exposure causes mitochondrial fission and fusion disorder in the pig hypothalamus via the PI3K/AKT pathway.

Cadmium (Cd) is the main environmental pollutant causing endocrine and nervous system dysfunction in animals. High doses of Cd cause cytotoxicity, including programmed necrosis and apoptosis, which has aroused widespread concern. Mitochondrial dynamics plays a key role in programmed necrosis and apoptosis of endocrine organs. Nevertheless, there is a lack of information on the relationship between Cd-induced programmed necrosis/apoptosis of the hypothalamus and the mitochondrial fusion-fission balance. Therefore, a hypothalamic injury model of Cd exposure was established by adding 20 mg/kg CdCl2 to the basic pig diet for 40 days. Analysis of the Cd toxicity mechanism was conducted by inductively coupled plasma mass spectrometry, hematoxylin and eosin staining, the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay, and quantitative reverse transcription-polymerase chain reaction, as well as western blot analyses. The results suggested that exposure to Cd inhibited the expression of PI3K and AKT, interfered with the balance of mitochondrial fusion and division, downregulated the expression of Mfn2, Mfn1, and OPA1, and upregulated the expression of Drp1 and Mff, which led to cell apoptosis and programmed necrosis in the pig hypothalamus. This study finds that cadmium exposure leads to mitochondrial fission and fusion dysfunction in porcine hypothalamus via the PI3K/AKT pathway.

Bisphenol A aggravates renal apoptosis and necroptosis in selenium-deficient chickens via oxidative stress and PI3K/AKT pathway.

Bisphenol A (BPA) in the environment can have deleterious effects on humans and animals. BPA can exert nephrotoxicity by inducing oxidative stress. Selenium (Se) deficiency can specifically impair kidney tissues and additionally show a synergistic effect on the toxicity of several environmental chemicals. However, the toxic effects of BPA on the chicken kidney and whether Se deficiency produces synergistic effects on the toxicity of BPA remain poorly understood. Herein, we established BPA exposure models and Se deficiency model in vivo and in vitro, and described the discovery path of BPA aggravation on apoptosis and necroptosis in Se-deficient chicken kidneys via regulation of oxidative stress and phosphatidylinositol 3-kinase/threonine kinase (PI3K/AKT) signaling pathway. We found that BPA exposure increased reactive oxygen species and malondialdehyde levels, reduced activities of catalase, GPx, and superoxide dismutase, downregulated PI3K and AKT expressions, activated Bcl/Bax-Caspase 9-Caspase 3, and receptor-interacting protein kinase 1/mixed lineage kinase domain-like protein signaling pathways, resulting in apoptosis and necroptosis in the chicken kidney. In addition, Se deficiency significantly promoted the expression of renal apoptosis and necroptosis in BPA-exposed chicken kidneys. Altogether, our results showed that BPA aggravates apoptosis and necroptosis in Se-deficient chicken kidneys via regulation of oxidative stress and PI3K/AKT signaling pathway. Our findings elucidate the mechanism of BPA nephrotoxicity and Se deficiency exacerbation toxicity in chickens and will provide great significance for the protection of the ecological environment and animal health.

Apigenin ameliorates di(2-ethylhexyl) phthalate-induced ferroptosis: The activation of glutathione peroxidase 4 and suppression of iron intake.

Di(2-ethylhexyl) phthalate (DEHP) is a widely artificial persistent organic pollutant, the contamination of which infiltrates daily human life from many aspects, imperceptibly causing damage to multiple organs in the body, including the liver. Apigenin (APG) is widely distributed in vegetables and fruits and can relieve or prevent the injuries caused by exogenous chemicals through various pharmacological effects, such as antioxidant effects. To investigate the mechanism of DEHP-induced liver injury and the antagonistic effects of APG, we treated AML12 cells with 1 mM DEHP and/or APG. Ultrastructural morphology analysis indicated that DEHP induced typical ferroptosis-like damage. In addition, we found that DEHP exposure induced ferroptosis by enhancing reactive oxygen species (ROS) levels, disrupting iron homeostasis and lipid peroxidation, and regulating the expression of ferroptosis-related genes. Notably, supplementation with APG significantly inhibited these abnormal changes, and molecular docking further showed evidence of the activating effects of APG ligand on glutathione peroxidase 4 (GPX4). These results demonstrated that the protective effects of APG on DEHP-induced ferroptosis were achieved by activating GPX4 and suppressing intracellular iron accumulation. This information not only adds to DEHP toxicological data but also provides a basis for the practical application of APG.

BPA exposure aggravates necroptosis of myocardial tissue in selenium deficient broilers through NO-dependent endoplasmic reticulum stress.

The environmental problem of BPA pollution has seriously endangered the health of humans and animals. As an essential trace element, the health problems caused by insufficient intake of selenium have always been widespread. Under toxic and other harmful stimuli, severe endoplasmic reticulum (ER) stress is one of multitude factors leading to death such as apoptosis and necrotic apoptosis. For investigating the damage of BPA and selenium deficiency combined effect to the myocardial tissue of broilers and the role of ER stress, 1-day-old broilers were fed with toxic feed and selenium deficiency feed for 35 days. Histopathological results showed that the combined exposure of BPA and low selenium resulted in more severe necrosis of cardiomyocytes in broilers than the single exposure, but there was no significant change in apoptosis compared with single exposure. Molecular biology studies showed that NO-dependent ER stress induced by BPA increased the expression of necroptosis related genes in myocardium of selenium deficient broilers, but had no effect on apoptosis pathway. In conclusion, our records state that the NO-dependent ER stress caused by combined exposure of BPA and low selenium can cause serious damage to the myocardial tissue of broilers by promoting the activation of the necroptosis pathway.

The antagonistic effect of selenium on lead-induced apoptosis and necroptosis via P38/JNK/ERK pathway in chicken kidney.

Lead (Pb), as a toxic heavy metal pollutant, has been paid much attention. Pb is often discharged into the environment through the soot, wastewater and waste residue in industrial production, which poses a great threat to animal health. Selenium (Se) is a trace element known to antagonize the toxicity caused by heavy metals. However, the interaction between Se and Pb in chicken kidney and its specific biological mechanism are still unclear. So, we constructed chicken models of Pb exposure and Pb, Se co-exposure. Therefore, we used western blot and qRT-PCR to detect the expression of related genes. The results showed that Pb activated the MAPK signaling pathway by up-regulating the expression of MARK pathway genes to induce the expression of pro-apoptotic genes and necroptosis-related genes. Se can regulate the MARK signaling pathway and attenuated the expression of MAPK pathway genes altered by Pb to reduce apoptosis and necroptosis of chicken kidney cells. Our study gives new ideas for the specific mechanism of Pb nephrotoxicity and provides a reference for comparative medicine and clinical medication.

Selenium Deficiency Aggravates Heat Stress Pneumonia in Chickens by Disrupting the M1/M2 Balance.

Selenium (Se) is an essential trace element found in the body. Se deficiency and M1/M2 imbalance are closely related to inflammation. Heat stress can decrease immune function and cause inflammation. In order to investigate whether Se deficiency can aggravate pneumonia caused by heat stress and the role of M1/M2 imbalance in the occurrence of pneumonia, 100 AA broilers were divided into two groups and fed the conventional diet (0.2 mg/kg Se) and the Se-deficient diet (0.03 mg/kg Se). After 40 days of feeding, the normal feeding group was randomly divided into a control group and a heat stress group. At the same time, the Se-deficient diet feeding group was randomly divided into a low Se group and a low Se heat stress group, with 25 chickens in each group. The model was established by exposure at 40℃. Six hours later, broilers were euthanized, and their lung tissues were collected. Hematoxylin and eosin staining, immunofluorescence, quantitative real-time PCR, and western blotting were used to detect lung histopathological changes and the expression of M1/M2 markers, nuclear receptor-κB (NF-κB) pathway genes, and heat shock proteins. Meanwhile, the activity and content of oxidative stress-related indices were also detected. We found that the expression of interleukin-1ß, interleukin-6, interleukin-12, and tumor necrosis factor-α was upregulated and the expression of interleukin-2, interleukin-10, and interferon-γ was downregulated. Immunofluorescence showed that the expression of CD16 was increased, the expression of CD163 was weakened, and the M1/M2 imbalance was present. In addition, the NF-κB pathway was activated by the increased expressions of heat shock proteins and oxidative stress. There was an increase in malondialdehyde, nitric oxide, and inducible nitric oxide synthase content, while the activity of total antioxidant capacity, glutathione peroxidase, catalase, and superoxide dismutase decreased, and the expression of NF-κB and cyclooxygenase-2 increased. These results suggest that low Se induces M1/M2 imbalance through oxidative stress activation of the NF-κB pathway and aggravates lung tissue inflammation caused by heat stress. This study offers a theoretical basis for exploring the pathogenesis of various kinds of inflammation induced by Se deficiency from the perspective of M1/M2 and provides a reference for the prevention of such diseases.

miR-130-CYLD Axis Is Involved in the Necroptosis and Inflammation Induced by Selenium Deficiency in Pig Cerebellum.

Selenium (Se) is an essential trace element in creatures which deficiency can cause necroptosis and inflammation of multiple tissues. MicroRNAs (miRNAs) have been identified to participate multiple biological processes by regulating the expression of target genes. In the present study, the Se-deficient pig cerebellar model was established and conducted by light microscopy, qRT-PCR, and Western blot. Morphological observation exhibited necrosis-like lesions and inflammatory infiltration in the cerebellum of the Se-deficient group. Quantitative analysis result showed that Se deficiency significantly suppressed miR-130 expression, which in turn disinhibited the expression of CYLD. Meanwhile, in comparison to the control group, the expression levels of TNF-α pathway genes (TNF-α, TNFR1, and NF-κB p65) and necroptosis-related genes (RIPK1, RIPK3, and MLKL) in Se deficiency group were obviously increased (P < 0.05). Moreover, Se deficiency induced the occurrence of inflammation by upregulating the expression of inflammatory cytokines (IL-1ß, IL-2, IL-8, IL-18, IFN-γ, COX-2, PTGEs, and NLRP3). In conclusion, we proved Se deficiency could induce the deregulation of miR-130-CYLD axis to cause RIPK3-dependent necroptosis and inflammation in pig cerebellum.

Selenomethionine alleviates LPS-induced JNK/NLRP3 inflammasome-dependent necroptosis by modulating miR-15a and oxidative stress in chicken lungs.

Selenium (Se) was involved in many physiological processes in humans and animals. microRNAs (miRNAs) also played important roles in lung diseases. However, the regulatory mechanism of miRNA in chicken lungs and the mechanism of lipopolysaccharide (LPS)-induced pneumonia remained unclear. To further study these mechanisms, we established a supplement of selenomethionine (SeMet) and/or LPS-treated chicken model and a cell model of LPS and/or high and low expression of miR-15a in chicken hepatocellular carcinoma (LMH) cells. We detected the expression of some selenoproteins, p-c-Jun N-terminal kinase (JNK), nod-like receptor protein 3 (NLRP3), caspase1, receptor-interacting serine-threonine kinase 1 (RIPK1), receptor-interacting serine-threonine kinase 3 (RIPK3), mixed lineage kinase domain-like pseudokinase (MLKL), miR-15a, and oxidative stress kits. Additionally, we observed the morphology of lungs by H.E. staining in vitro. The results indicated that necroptosis occurred in LPS-treated chicken and LMH cells. Moreover, LPS stimulation inhibited miR-15a, and increased the expression of JNK, NLRP3, caspase1, RIPK1, RIPK3, and MLKL. We also found that LPS treatment not only increased the content of H2O2 and MDA in the lungs but also increased the activities of iNOS and CAT and the content of GSH decreased. Conclusion: SeMet could reduce the oxidative damage and activate NLRP3 inflammasome reaction by stimulating miR-15a/JNK, thus reduced the pulmonary necroptosis induced by LPS.

Roles of selenoprotein S in reactive oxygen species-dependent neutrophil extracellular trap formation induced by selenium-deficient arteritis.

Selenium (Se) deficiency and poor plasma Se levels can cause cardiovascular diseases by decreasing selenoprotein levels. Neutrophil extracellular traps (NETs) may be the vicious cycle center of inflammation in vasculitis. Here, we show that Se deficiency induced arteritis mainly by reducing selenoprotein S (SelS), and promoted the progression of arteritis by regulating the recruitment of neutrophils and NET formation. Silencing SelS induced chicken arterial endothelial cells (PAECs) to secrete cytokines, and activated neutrophils to promote NET formation. Conversely, scavenging DNA-NETs promoted cytokine secretion in PAECs. The NET formation regulated by siSelS was dependent on a reactive oxygen species (ROS) burst. We also found that the PPAR pathway was a major mediator of NET formation induced by Se-deficient arteritis. Overall, our results reveal how Se deficiency regulates NET formation in the progression of arteritis and support silencing-SelS worsens arteritis.