Highlights d Antioxidants stimulate KRAS-driven lung cancer metastasis d Antioxidants reduce free heme levels and stabilize BACH1 d BACH1 activates Hk2 and Gapdh transcription triggering glycolysis-induced metastasis d Targeting BACH1 or its glycolytic targets prevents antioxidant-induced metastasis

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Dietary selenium (Se) deficiency causes muscular dystrophy in various species, but the molecular mechanism remains unclear. Our objectives were to investigate: 1) if dietary Se deficiency induced different amounts of oxidative stress, lipid peroxidation, and cell apoptosis in 3 skeletal muscles; and 2) if the distribution and expression of 4 endoplasmic reticulum (ER) resident selenoprotein genes (Sepn1, Selk, Sels, and Selt) were related to oxidative damages in these muscles. Two groups of day-old layer chicks (n = 60/group) were fed a corn-soy basal diet (33 μg Se/kg; produced in the Se-deficient area of Heilongjiang, China) or the diet supplemented with Se (as sodium selenite) at 0.15 mg/kg for 55 d. Dietary Se deficiency resulted in accelerated (P < 0.05) cell apoptosis that was associated with decreased glutathione peroxidase activity and elevated lipid peroxidation in these muscles. All these responses were stronger in the pectoral muscle than in the thigh and wing muscles (P < 0.05). Relative distribution of the 4 ER resident selenoprotein gene mRNA amounts and their responses to dietary Se deficiency were consistent with the resultant oxidative stress and cell apoptosis in the 3 muscles. Expression of Sepn1, Sels, and Selt in these muscles was correlated with (r > 0.72; P < 0.05) that of Sepsecs encoding a key enzyme for biosynthesis of selenocysteine (selenocysteinyl-tRNA synthase). In conclusion, the pectoral muscle demonstrated unique expression patterns of the ER resident selenoprotein genes and GPx activity, along with elevated susceptibility to oxidative cell death, compared with the other skeletal muscles. These features might help explain why it is a primary target of Se deficiency diseases in chicks.

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The aim of this study was to investigate the effects of cold stress on the expression levels of heat shock proteins (Hsps90, 70, 60, 40, and 27) and inflammatory factors (iNOS, COX-2, NF-κB, TNF-α, and PTGEs) and oxidative indexes in hearts of chickens. Two hundred forty 15-day-old male chickens were randomly divided into 12 groups and kept at the temperature of 12±1°C for acute and chronic cold stress. There were one control group and five treatment groups for acute cold stress, three control groups, and three treatment groups for chronic cold stress. After cold stress, malondialdehyde level increased in chicken heart; the activity of superoxide dismutase and glutathione peroxidase in the heart first increased and then decreased. The inflammatory factors mRNA levels were increased in cold stress groups relative to control groups. The histopathological analysis showed that heart tissues were seriously injured in the cold stress group. Additionally, the mRNA levels of Hsps (70, 60, 40, and 27) increased significantly (P<0.05) in the cold stress groups relative to the corresponding control group. Meanwhile, the mRNA level and protein expression of Hsp90 decreased significantly (P<0.05) in the stress group, and showed a gradually decreasing tendency. These results suggested that the levels of inflammatory factors and Hsps expression levels in heart tissues can be influenced by cold stress. Hsps commonly played an important role in the protection of the heart after cold stress.

Oxidative stress and endoplasmic reticulum (ER) stress are involved in different types of stress-induced injuries. The aim of the present study was to evaluate the effect of Se deficiency on oxidative stress, ER stress and apoptosis in chicken livers. Chickens (1 day old, n = 180) were randomly divided into two groups: the L group [fed with a Se-deficient (Se 0.033 mg/kg) diet] and the control group [fed with a normal (Se 0.2 mg/kg) diet]. Factor-associated oxidative stress, catalase (CAT) activity, H2O2 production and the inhibition of hydroxyl radicals (·OH) in the chicken liver were determined on days 15, 25, 35, 45, 55 and 65, respectively. In addition, ER stress-related genes (GRP78, GRP94, ATF4, ATF6 and IRE) and apoptosis-related genes (caspase3 and Bcl-2) were examined by fluorescence quantitative PCR or western blot analysis. Apoptosis levels were also measured using ultrastructural observations and the TdT-mediated dUTP nick end labeling assay. The results showed that CAT activity and ·OH inhibition were decreased and that H2O2 production was increased in the low-Se group, which demonstrated that oxidative stress occurred in the chicken liver. The ER stress-related genes (GRP78, GRP94, ATF4, ATF6 and IRE) and the apoptosis-related gene caspase3 were increased (p < 0.05), while Bcl-2 was decreased (p < 0.05) by Se deficiency. In addition, apoptosis and ER lesions were observed by ultrastructural observations of the chicken liver in the low-Se group. The level of apoptosis and the number of apoptotic cells increased with time. These results indicated that the oxidative-ER stress pathway participates in Se deficiency-induced apoptosis in the chicken liver.

Nitric oxide (NO) is an essential messenger molecule and is associated with inflammation and oxidative stress. Although NO has important biological functions in mammals, its role in the mechanism that occurs after intestinal injuries in chickens remains unknown. The objective of the present study was to investigate the real role of NO and oxidative stress in the intestinal injuries of chickens induced by selenium (Se) deficiency. A total 150 chickens were randomly divided into the following two groups: a low-Se group (L group, fed a Se-deficient diet containing 0.020 mg/kg Se) and a control group (C group, fed a commercial diet containing 0.2 mg/kg Se). The activities and mRNA levels of glutathione peroxidase (GSH-Px), the production of glutathione (GSH) and NO, and the protein and mRNA levels of inducible nitric oxide synthase (iNOS) were examined in the intestinal tissues (duodenum, jejunum, and rectum) at 15, 25, 35, 45, and 55 days. Methane dicarboxylic aldehyde (MDA) levels were also detected by assay kits. Then, the morphologies of the tissues were observed under the microscope after hematoxylin and eosin staining (H&E staining). The results showed that Se deficiency induced higher inflammatory damage and MDA levels (P < 0.05), which were accompanied by higher levels of iNOS and NO but lower levels of GSH and GSH-Px (P < 0.05). Our results indicated that Se deficiency induced oxidative damage in the intestinal tracts of chickens and that low levels of GSH-Px and high contents of NO may exert a major role in the injury of the intestinal tract induced by Se deficiency.

Selenium (Se) deficiency induces Ca2+ leak and calcification in mammal skeletal muscles; however, the exact mechanism is still unclear. In the present study, both Se-deficient chicken muscle models and selenoprotein W (SelW) gene knockdown myoblast and embryo models were used to study the mechanism. The results showed that Se deficiency-induced typical muscular injuries accompanied with Ca2+ leak and oxidative stress (P < 0.05) injured the ultrastructure of the sarcoplasmic reticulum (SR) and mitochondria; decreased the levels of the Ca2+ channels, SERCA, SLC8A, CACNA1S, ORAI1, STIM1, TRPC1, and TRPC3 (P < 0.05); and increased the levels of Ca2+ channel PMCA (P < 0.05). Similarly, SelW knockdown also induced Ca2+ leak from the SR and cytoplasm; increased mitochondrial Ca2+ levels and oxidative stress; injured SR and mitochondrial ultrastructure; decreased levels of SLC8A, CACNA1S, ORA1, TRPC1, and TRPC3; and caused abnormal activities of Ca2+ channels in response to inhibitors in myoblasts and chicken embryos. Thus, both Se deficiency and SelW knockdown induced Ca2+ leak, oxidative stress, and Ca2+ channel reduction. In addition, Ca2+ levels and the expression of the Ca2+ channels, RyR1, SERCA, CACNA1S, TRPC1, and TRPC3 were recovered to normal levels by N-acetyl-L-cysteine (NAC) treatment compared with SelW knockdown cells. Thus, with regard to the decreased Ca2+ channels, SelW knockdown closely correlated Se deficiency with Ca2+ leak in muscles. The redox regulation role of SelW is crucial in Se deficiency-induced Ca2+ leak in muscles.