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The development of acute liver injury can result in liver cirrhosis, liver failure, and even liver cancer, yet there is currently no effective therapy for it. The purpose of this study was to investigate the protective effect and therapeutic mechanism of Lycium barbarum polysaccharides (LBPs) on acute liver injury induced by carbon tetrachloride (CCl(4)). To create a model of acute liver injury, experimental canines received an intraperitoneal injection of 1 mL/kg of CCl(4) solution. The experimental canines in the therapy group were then fed LBPs (20 mg/kg). CCl(4)-induced liver structural damage, excessive fibrosis, and reduced mitochondrial density were all improved by LBPs, according to microstructure data. By suppressing Kelch-like epichlorohydrin (ECH)-associated protein 1 (Keap1), promoting the production of sequestosome 1 (SQSTM1)/p62, nuclear factor erythroid 2-related factor 2 (Nrf2), and phase II detoxification genes and proteins downstream of Nrf2, and restoring the activity of anti-oxidant enzymes like catalase (CAT), LBPs can restore and increase the antioxidant capacity of liver. To lessen mitochondrial damage, LBPs can also enhance mitochondrial respiration, raise tissue adenosine triphosphate (ATP) levels, and reactivate the respiratory chain complexes I‒V. According to serum metabolomics, the therapeutic impact of LBPs on acute liver damage is accomplished mostly by controlling the pathways to lipid metabolism. 9-Hydroxyoctadecadienoic acid (9-HODE), lysophosphatidylcholine (LysoPC/LPC), and phosphatidylethanolamine (PE) may be potential indicators of acute liver injury. This study confirmed that LBPs, an effective hepatoprotective drug, may cure acute liver injury by lowering oxidative stress, repairing mitochondrial damage, and regulating metabolic pathways.

The purpose of this research was to investigate whether copper (Cu) exposure could induce apoptosis via endoplasmic reticulum stress (ERS) in skeletal muscle of broilers. A total of 240 one-day-old chickens were randomly divided into four groups by free access; the diets are as follows: control diet (Cu 11 mg/kg, control group) and high level of Cu diets (Cu 110 mg/kg, group I; Cu 220 mg/kg, group II; Cu 330 mg/kg, group III). The skeletal muscle tissues were collected on day 49 for further examination. The content of Cu, histopathology, and the expression levels of the genes and proteins related to ERS and apoptosis were detected. Results showed that the Cu levels in skeletal muscle were increased in a dose-dependent manner. Meanwhile, the spaces between the muscle fibers were wider with the increase of Cu content, and the myolysis was observed in group III. Besides, the mRNA expression levels of GRP78, GRP94, eIF2α, ATF6, XBP1, CHOP, Caspase-12, and Caspase3 were markedly increased in treated groups compared with control group, and the protein expression levels of GRP78, Caspase3, Active-Caspase3 and JNK were significantly elevated with the increase of dietary Cu. In summary, these findings suggested that Cu could induce apoptosis through ERS in skeletal muscle of broilers.

Copper (Cu) is an essential trace element for growth and development in most organisms. However, environmental exposure to high doses of Cu can damage multiple organs. To investigate the underlying mechanism of Cu toxicity on mitochondrial dynamics and mitophagy in the cerebrum of pigs, 60 30-day-old pigs were randomly divided into three groups and treated with different contents of anhydrous Cu sulfate in the diets (Cu 10 mg/kg, control group; Cu 125 mg/kg, group I; Cu 250 mg/kg, group II) for 80 days. The Cu levels and histological changes in the cerebrum were measured. Moreover, the protein and mRNA expression levels related to mitophagy and mitochondrial dynamics were determined. The results showed that the contents of Cu were increased in the cerebrum with increasing dietary Cu. Vacuolar degeneration was found in group I and group II compared to the control group. Additionally, the protein and mRNA expression levels of PINK1, Parkin, and Drp1 and the protein level of LC3-II were remarkably upregulated with increasing levels of dietary Cu. Nevertheless, the protein and mRNA expression levels of MFN1 and MFN2 and the mRNA expression of P62 were obviously downregulated in a Cu dose-dependent manner. Overall, these results suggested that excess Cu could trigger mitochondrial dynamics disorder and mitophagy in the pig cerebrum, which provided a novel insight into Cu-induced toxicology.

Type 1 diabetes mellitus (T1DM) is a chronic disease represented by insulin-causing pancreatic β-cell disruption and hyperglycemia. Therefore, it is necessary to establish a variety of animal models of diabetes to study the pathogenesis and pathophysiology of it. However, there are few reports on the use of beagle dogs to establish an animal model of type 1 diabetes. This study aimed to explore a simple and feasible modeling method to establish a long-term and stable type 1 diabetes model in beagle dogs. Forty adult beagle dogs were randomly divided into control group and model group. After 24 h of fasting, streptozotocin (20 mg/kg) and alloxan (20 mg/kg) were injected through the cephalic vein. The second intravenous injection was given on the 4th day after the first injection. Insulin release testing was performed on the 7th day after the last intravenous injection. Fasting blood glucose and body weight were recorded monthly. Four months after the last injection, the serum fructosamine content and the ratio of glycated hemoglobin were detected. Then, the pancreatic tissue was harvested for histopathological examination. The results showed that the level of fasting blood glucose of the 16 dogs in the model group was consistently higher than 11.1 mmol/L for 4 consecutive months. Moreover, compared with the control group, the insulin release curve of the model group was flat with no increase. The body weight of the model group was significantly reduced, and the ratios of blood glucose, fructosamine, and glycosylated hemoglobin were significantly higher than those in the control group. Meanwhile, histopathological examination of the pancreas showed that the islet beta cells appeared to have vacuoles or even necrosis. In the model group, pancreatic β-cells were damaged and insulin release was reduced. These results suggest that the above modeling methods can induce long-term and stable type 1 diabetes models in beagle dogs.

Cu is a metallic element that widely spread over in the environment, which have raised wide concerns about the potential toxic effects and public health threat. The objective of this study aimed to investigate the impression of copper (Cu)-triggered toxicity on mitochondrial dynamic, oxidative stress, and unfolded protein response (UPRmt) in fundic gland of pigs. Weaned pigs were randomly distributed into three groups, fed with different Cu of 10 mg/kg (control group), 125 mg/kg (group I), and 250 mg/kg (group Ⅱ). The trial persisted for 80 days and the fundic gland tissues were collected for further researches. Moreover, the markers participated to mitochondrial dynamic, UPRmt，and oxidative stress in fundic gland were determined. Results revealed that vacuolar degeneration were observed in the treated groups contrast with control group, and the Cu level was boosted with the increasing intake of Cu. Besides that, the levels of CAT, TRX, H2O2, and G6PDH were reduced in group Ⅰ and group Ⅱ, the mRNA levels of NRF2, HO-1, SOD-1, CAT, SOD-2, GSR, GPX1, GPX4, and TRX in the treated groups were promoted contrast to control group. Furthermore, the protein expression of KEAP1 was dramatically decreased, and the protein expression of NRF2, TRX and HO-1 were markedly enhanced in group Ⅰ and Ⅱ at 80 days. Moreover, the mRNA and protein expression levels of MFN1, MFN2, and OPA1 down-regulated and protein level of DRP1 was increased with the adding levels of Cu. Nevertheless, the UPRmt-related mRNA levels of CLPP, HTRA-2, CHOP, HSP10, and HSP60 were enhanced dramatically in Cu treatment group compared with control group. In general, our current study demonstrated that excessive absorption of Cu in fundic gland were related with stimulating UPRmt, oxidative stress, and the NRF2 interceded antioxidant defense. These results could afford an updated evidence on molecular theory of Cu-invited toxicity.

Background: Copper (Cu), a common feed additive in diets for animals, is effective in improving growth performance and feed efficiency. However, excessive intake of Cu can cause toxic effects. Kidney is the main target organ of Cu, but the relationship between Cu-induced nephrotoxicity and its metabolic process remains unclear.Results: For deeply investigating the nephrotoxicity induced by Cu, a total of 240 broiler chicks were fed with different contents of Cu (11, 110, 220, and 330 mg/kg Cu) for 49 d in this study (60 chicks per group). The results of TUNEL staining showed that Cu could induce apoptosis in kidney with increasing of TUNEL-positive cells. Additionally, a total of 62 differential metabolites were detected by liquid chromatography-mass spectrometry (LC-MS), and mainly enriched in the metabolic pathways including riboflavin metabolism, glutathione metabolism, sphingolipid metabolism, and glycerophospholipid metabolism, which were closely related to mitochondrial metabolism. Meanwhile, the decrease of mitochondrial membrane potential, impairment of mitochondrial respiratory function, and the increase of mitochondrial membrane permeability indicated that renal mitochondria were damaged by excess Cu. Furthermore, the increase of mRNA and protein levels of Drp1, Bax, Bak-1, CytC, Caspase-3/cleaved Caspase-3 and the decrease of mRNA and protein levels of OPA1, Mfn1, Mfn2, and Bcl-2 confirmed that Cu could induce mitochondria-mediated apoptosis in kidney.Conclusions: These results highlighted that mitochondrial metabolism could be considered as an important factor in influencing Cu toxicity, which for further demonstrating that Cu could induce mitochondria-mediated apoptosis in kidney of broilers.

Copper (Cu) is one of the ubiquitous environmental pollutants which have raised wide concerns about the potential toxic effects and public health threat. For deeply investigating the nephrotoxicity induced by Cu, the effects of Cu on mitochondria-mediated apoptosis in kidney were first to analyze by combining metabolomics and molecular biology techniques. In this study, broiler chicks were fed with different contents of Cu (11, 110, 220, and 330 mg/kg Cu) for 49 d. The results of terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining and transmission electron microscope showed that Cu could induce apoptosis in kidney, characterized by the increasing of TUNEL-positive cells and mitochondrial vacuolation. Additionally, a total of 62 differential metabolites were detected by liquid chromatography-mass spectrometry (LC-MS), and mainly enriched in the metabolic pathways including riboflavin metabolism, glutathione metabolism, sphingolipid metabolism, and glycerophospholipid metabolism, which were closely to mitochondrial metabolism. Meanwhile, the decreased mitochondrial membrane potential (MMP), increased mitochondrial membrane permeability and the change of mRNA and protein expression levels associated with mitochondria-mediated apoptosis and mitochondrial dynamics confirmed that Cu could induce mitochondria-mediated apoptosis. Therefore, our results demonstrated that Cu induced mitochondria-mediated apoptosis in kidney. Moreover, this study highlighted the metabolic characteristics of Cu to kidney, which suggested that mitochondrial metabolism could be considered as an important factor influencing toxicity.

Atrazine (ATR), a bio accumulative herbicide is frequently used in agriculture to control unwanted weeds. Due to continuous application, atrazine persists in the environment and causes deleterious impacts including neurotoxicity, hepatotoxicity, and gut microbiota disorders. Therefore, this study for the first time reports the variation in the gut microbiota, induction of process of apoptosis and autophagy in mice induced by ATR. Results indicated that TUNEL-positive hepatocytes suggestive of apoptosis were increased in livers of different experimental mice. Results on metabolic analysis in liver tissues indicated an overall change in seventy-six metabolites particularly Uridine 5'-diphosphate, Propenoylcarnitine and Chinenoside V resulting in generation of energy-related metabolic disorders and imbalance of oxidation/autoxidation status. Results on gut microbiome inquisition showed that ATR changed the richness and diversity of gut microbiota of mice and number of Firmicutes. Moreover, results also revealed that ATR induced apoptosis via disruption of apoptotic (Bax, Bcl2, and Casp3) and autophagy (LC3/Map1lc3a, Beclin 1/Becn1 and P62/Sqstm1) genes. Results of our experimental study confirmed that changes in gut microbiota play a significant role in process of gut immune regulation and inflammation via different metabolites. In conclusion, the findings of our study provide a new idea for the involvement of mechanisms of detoxification in liver and inquisition of gut microbiota plays crucial role in regulation of physiological activities through liver-gut axis to mitigate toxic effects in animals.