Investigation of the mutual crosstalk between ER stress and PI3K/AKT/mTOR signaling pathway in iron overload-induced liver injury in chicks.

Iron is an essential element for the normal functioning of living organisms, but excessive iron deposition can lead to organ damage. This study aims to investigate the interaction between the endoplasmic reticulum stress signaling pathway and the PI3K/AKT/mTOR signaling pathway in liver injury induced by iron overload in chicks. Rspectively, 150 one-day-old broilers were divided into three groups and supplemented with 50 (C), 500 (E1), and 1000 (E2) mg ferrous sulfate monohydrate/kg in the basal diet. Samples were taken after continuous feeding for 14 days. The results showed that iron overload could upregulate the levels of ALT and AST. Histopathological examination revealed bleeding in the central vein of the liver accompanied by inflammatory cell infiltration. Hoechst staining showed that the iron overload group showed significant bright blue fluorescence, and ultrastructural observations showed chromatin condensation as well as mitochondrial swelling and cristae disorganization in the iron overload group. RT-qPCR and Western blot results showed that iron overload upregulated the expression of Bax, Caspase-3, Caspase-9, GRP78, GRP94, P-PERK, ATF4, eIF2α, IRE1, and ATF6, while downregulating the expression of Bcl-2 and the PI3K/AKT/mTOR pathway. XBP-1 splicing experiment showed significant splicing of XBP-1 gene after iron overload. PCA and correlation analysis suggested a potential association between endoplasmic reticulum stress, the PI3K/AKT/mTOR signaling pathway, and liver injury in chicks. In summary, iron overload can induce cell apoptosis and liver injury by affecting endoplasmic reticulum stress and the PI3K/AKT/mTOR signaling pathway.

Effects of Different Doses of Excessive Iron in Diets on Oxidative Stress in Immune Organs of Sheep.

The aim of this work is to investigate the relationship between iron and oxidative stress in the immune organs of excessive iron-fed sheep. Sixteen German Mutton Merino rams were randomly divided into 4 groups, which were fed the basal diets supplemented with 50 (CON), 500 (L-iron), 1000 (M-iron), and 1500 (H-iron) mg Fe/kg as ferrous sulfate monohydrate (FeSO4·H2O), respectively. The actual iron content in the diet was determined to be 457.68 (CON), 816.42 (L-iron), 1256.78 (M-iron), and 1725.63 (H-iron) mg/kg, respectively. The consequences of oxidative damage were tested in 4 groups. The results showed that the contents of malondialdehyde (MDA), nitric oxide (NO), hydrogen peroxide (H2O2), and the activity of nitric oxide synthase (iNOS) were increased in excessive iron-fed sheep. Moreover, the present results revealed that excess iron was associated with a significant decrease in the activities of antioxidant capacity, such as glutathione peroxidase (GPx) activity and total antioxidant capacity (T-AOC) levels. The iNOS mRNA expression declined in excessive iron-fed sheep, indicating that down-regulation is likely to occur at the transcription level, which is consistent with the studies of iron blockades iNOS transcription. Surprisingly, the activity of glutathione peroxidase 1 (GPx1) continued to decline, but the expression levels of GPX1 mRNA and protein increased first and then decreased. This suggests that at the transcriptional and translation levels, the body compensatively increases the amount of GPx1 to maintain the balance of the oxidation-antioxidant system to resist peroxidation. Hematoxylin-eosin (HE) staining revealed histopathological changes in immune organs, such as lymphocyte infiltration and cell death, indicating that excessive iron-induced oxidative damage indirectly affects the body's immune function. These findings confirm the role of iron in regulating the homeostasis of the oxidation-antioxidant system.

Curcumin improves TNBS-induced colitis in rats by inhibiting IL-27 expression via the TLR4/NF-κB signaling pathway.

Curcumin is a widely used spice with anti-inflammatory and anticancer properties. It has been reported to have beneficial effects in experimental colitis. This study explored whether curcumin improves colonic inflammation in a rat colitis model through inhibition of the TLR4/NF-κB signaling pathway and IL-27 expression. After induction of colitis with 2,4,6-trinitrobenzene sulfonic acid, rats were intragastrically administered with curcumin or sulfasalazine daily for one week. Rat intestinal mucosa was collected for evaluation of the disease activity index, colonic mucosa damage index, and histological score. Myeloperoxidase activity was detected by immunohistochemistry, and mRNA and protein expression levels of TLR4, NF-κB, and IL-27 in colonic mucosa were detected by RT-PCR and Western blot. Compared with the untreated colitis group, the curcumin-treated group showed significant decreases in the disease activity index, colonic mucosa damage index, histological score, myeloperoxidase activity, and expressions of NF-κB mRNA, IL-27 mRNA, TLR4 protein, NF-κB p65 protein, and IL-27 p28 protein (p < 0.05). TLR4 mRNA expression did not differ between groups. Disease activity index decreased more rapidly in the curcumin-treated group than in the sulfasalazine-treated group (p < 0.05). There was no significant difference in TLR4, NF-κB, and IL-27 mRNA and proteins between curcumin-treated and sulfasalazine-treated groups. Curcumin shows significant therapeutic effects on 2,4,6-trinitrobenzene sulfonic acid-induced colitis that are comparable to sulfasalazine. The anti-inflammatory actions of curcumin on colitis may involve inhibition of the TLR4/NF-κB signaling pathway and of IL-27 expression.