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Cadmium (Cd) and high molybdenum (Mo) are injurious to the body. Previous research has substantiated that Cd and Mo exposure caused testicular injury of ducks, but concrete mechanism is not fully clarified. To further survey the toxicity of co-exposure to Cd and Mo in testis, 40 healthy 8-day-old Shaoxing ducks (Anas platyrhyncha) were stochasticly distributed to 4 groups and raised with basic diet embracing Cd (4 mg/kg Cd) or Mo (100 mg/kg Mo) or both. At the 16th wk, testis tissues were gathered. The characteristic ultrastructural changes related to apoptosis and ferroptosis were observed in Mo or Cd or both groups. Besides, Mo or Cd or both repressed nuclear factor erythroid 2-related factor 2 (Nrf2) pathway via decreasing Nrf2, Heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase 1 (NQO1), Glutamate-cysteine ligase catalytic subunit (GCLC) and Glutamate-cysteine ligase modifier subunit (GCLM) mRNA expression of and Nrf2 protein expression, then stimulated apoptosis by elevating Bcl-2 antagonist/killer-1 (Bak-1), Bcl-2-associated X-protein (Bax), Cytochrome complex (Cyt-C), caspase-3 mRNA expression, cleaved-caspase-3 protein expression and apoptosis rate, as well as reducing B-cell lymphoma-2 (Bcl-2) mRNA expression and ratio of Bcl-2 to Bax, and triggered ferroptosis by upregulating Acyl-CoA Synthetase Long Chain Family Member 4 (ACSL4), transferrin receptor (TFR1) and Prostaglandin-Endoperoxide Synthase 2 (PTGS2) expression levels, and downregulating ferritin heavy chain 1 (FTH1), ferritin light chain 1 (FTL1), ferroportin 1 (FPN1), solute carrier family 7 member 11 (SCL7A11) and glutathione peroxidase 4 (GPX4) expression levels. The most obvious changes of these indexes were observed in co-treated group. Altogether, the results announced that Mo or Cd or both evoked apoptosis and ferroptosis by inhibiting Nrf2 pathway in the testis of ducks, and co-exposure to Mo and Cd exacerbated these variations., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Increasing evidence indicates autophagy and apoptosis are involved in the toxicity mechanism of heavy metals. Our previous studies showed that cadmium (Cd) could induce autophagy and apoptosis in duck kidneys in vivo, nevertheless, the interaction between them has yet to be elucidated. Herein, the cells were either treated with 3CdSO 4 ·8H 2 O (0, 1.25, 2.5, 5.0 μM Cd) or/and 3-methyladenine (3-MA) (2.5 μM) for 12 h and the indictors related autophagy and apoptosis were detected to assess the correlation between autophagy and apoptosis induced by Cd in duck renal tubular epithelial cells. The results demonstrated that Cd exposure notably elevated intracellular and extracellular Cd contents, the number of autophagosomes and LC3 puncta, up-regulated LC3A, LC3B, Beclin-1, Atg5 mRNA levels, and Beclin-1 and LC3II/LC3I protein levels, down-regulated mTOR, p62 and Dynein mRNA levels and p62 protein level. Additionally, autophagy inhibitor 3-MA decreased Beclin-1, LC3II/LC3I protein levels and increased p62 protein level. Moreover, co-treatment with Cd and 3-MA could notably elevate Caspase-3, Cyt C, Bax, and Bak-1 mRNA levels, Caspase-3 and cleaved Caspase-3 protein levels, and cell apoptotic rate as well as cell damage, decreased mitochondrial membrane potential (MMP), Bcl-2 mRNA level and the ratio of Bcl-2 to Bax compared to treatment with Cd alone. Overall, these results indicate Cd exposure can induce autophagy in duck renal tubular epithelial cells, and inhibition of autophagy might aggravate Cd-induced apoptosis through mitochondria-mediated pathway., (Copyright © 2020 Elsevier Inc. All rights reserved.)

High doses of molybdenum (Mo) and cadmium (Cd) cause adverse reactions on animals, but the joint toxic effects of Mo and Cd on duck renal tubular epithelial cells are not fully illustrated. To investigate the combined effects of Mo and Cd on oxidative stress and mitochondrial apoptosis in primary duck renal tubular epithelial cells, the cells were either treated with (NH 4 ) 6 Mo 7 O 24 ·4H 2 O (480, 960 μM Mo), 3CdSO 4 ·8H 2 O (2.5, 5.0 μM Cd) or combination of Mo and Cd for 12 h, and then the joint cytotoxicity was evaluated. The results demonstrated that Mo or/and Cd exposure could induce release of intracellular lactate dehydrogenase, reactive oxygen species generation, acidification, increase levels of malondialdehyde and [Ca 2+ ]i, decrease levels of glutathione, glutathione peroxidase, catalase, superoxide dismutase, total antioxidant capacity, Na + /K + -ATPase, Ca 2+ -ATPase, and mitochondrial membrane potential; upregulate mRNA levels of Caspase-3, Bak-1, Bax, and cytochrome C, inhibit Bcl-2 mRNA level, and induce cell apoptosis in a dose-dependent manner. Furthermore, the changes of these indicators in co-treated groups were more remarkable. The results indicated that exposure to Mo or/and Cd could induce oxidative stress and apoptosis via the mitochondrial pathway in duck renal tubular epithelial cells and the two metals may have a synergistic effect., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Cadmium (Cd) and high dietary intake of molybdenum (Mo) can lead to adverse reactions on animals, but the combined impacts of Mo and Cd on testicle are not clear. To investigate the co-induced toxic effects of Mo and Cd in duck testicles on the mRNA levels of heat shock proteins (HSPs), inflammatory cytokines, and apoptosis. A total of sixty 11-day-old male Shaoxing ducks (Anas platyrhyncha) were randomly divided into 6 groups and testicles were collected on day 120. The mRNA levels of HSPs (HSP60, HSP70, HSP90), inflammatory cytokines (TNF-α, NF-κB, COX-2), and apoptosis genes (Bcl-2, Bak-1, Caspase-3) were determined by real-time quantitative polymerase chain reaction (RT-qPCR), meanwhile the changes of ultrastructural were evaluated. The results showed HSPs mRNA levels were increased in high Mo and Cd groups, however, they were decreased in high dose Mo and Cd co-treated group. In all treatment groups, the mRNA levels of Bak-1 and Caspase-3 were upregulated, and Bcl-2 mRNA level was downregulated, especially in combination groups. The TNF-α, NF-κB, and COX-2 expression in co-exposure groups were higher than those in single groups. Furthermore, the ultrastructural changes showed nuclear deformation, mitochondria hyperplasia and cristaes rupture, and vacuolation in combination groups. Changes of all above factors indicated a possible synergistic relationship between the two elements, and the high expression of HSPs and inflammatory cytokines may play a role in the resistance of testicles toxicity induced by Mo or Cd or both., (© 2019 Poultry Science Association Inc.)

Molybdenum (Mo) is an essential element for human beings and animals; however, high dietary intake of Mo can lead to adverse reactions. Cadmium (Cd) is one of the major transitional metals which has toxic effects in animals. To investigate the co-induced toxic effects of Mo and Cd on oxidative damage and kidney apoptosis in duck, 120 ducks were randomly divided into control group and 5 treatment groups which were treated with a commercial diet containing different dosages of Mo and Cd. Kidney samples were collected on the 60th and 120th days to determine the mRNA expression levels of ceruloplasmin (CP), metallothionein (MT), Bak-1, and Caspase-3 by quantitative RT-PCR. Additionally, we also determined the antioxidant activity indexes and contents of Mo, Cd, copper (Cu), iron (Fe), zinc (Zn), and selenium (Se) in serum. Meanwhile, ultrastructural changes of the kidney were observed. The results showed that glutathione reductase (GR) activity and CP level in serum were decreased in combination groups. In addition, the antioxidant indexes were decreased in co-treated groups compared with single treated groups. The mRNA expression levels of Bak-1 and Caspase-3 increased in co-treated groups. The mRNA expression level of CP in high-dose combination group was downregulated, while the mRNA expression of MT was upregulated except for low-dose Mo group. Additionally, in the later period the content of Cu in serum decreased in joint groups while the contents of Mo and Cd increased. In addition, ultrastructural changes showed mitochondrial crest fracture, swelling, deformed nuclei, and karyopyknosis in co-treated groups. Taken together, it was suggested that dietary Mo and Cd might lead to oxidative stress, kidney apoptosis and disturb homeostasis of trace elements in duck, and it showed a possible synergistic relationship between the two elements., (Copyright © 2017 Elsevier Inc. All rights reserved.)

To investigate the effects of molybdenum (Mo) and/or cadmium (Cd) on antioxidant function and the apoptosis-related genes in duck spleens. Sixty healthy 11-day-old ducks were randomly divided into six groups of 10 ducks (control, low Mo group, high Mo, Cd, low Mo + Cd, and high Mo + Cd groups). All were fed a basal diet containing low or high dietary doses of Mo and/or Cd. Relative spleen weight, antioxidant indices, apoptosis-related gene mRNA expression levels, and ultrastructural changes were evaluated after 120 days. The results showed that the relative spleen weight decreased significantly in the high Mo + Cd treatment group which compared with control group. Malondialdehyde levels increased and xanthine oxidase and catalase activities decreased in the Mo and/or Cd groups compared with levels in the control group. Bak-1 and Caspase-3 expressions were upregulated in the high Mo + Cd group, while Bcl-2 was downregulated. In addition, mitochondrial crest fracture, swelling, vacuolation, deformed nuclei, and karyopyknosis in both Mo + Cd treated groups were more severe than in the other groups. The results suggest that Mo and/or Cd can induce oxidative stress and apoptosis of spleen via effects on the mitochondrial intrinsic pathway. Moreover, the results indicate the two elements have a possible synergistic relationship.

To investigate the effects of co-exposure to molybdenum (Mo) and cadmium (Cd) on oxidative stress and cell apoptosis in caprine livers, 36 Boer goats were randomly divided into four groups with nine goats in each group. Three groups were randomly assigned with one of three oral treatments of CdCl2 (0.5 mg Cd kg(-1)·BW) and [(NH4)6Mo7O24·4H2O] (15 mg Mo kg(-1)·BW, 30 mg Mo kg(-1)·BW, 45 mg Mo kg(-1)·BW), while the control group received deionized water. Liver tissues on days 0, 25, and 50 were subjected to determine antioxidant activity indexes and the messenger RNA (mRNA) expression levels of ceruloplasmin (CP), cysteinyl aspartate-specific proteinase-3 (caspase-3), second mitochondria-derived activator of caspases (Smac), and cytochrome-C (Cyt-C) genes. The results showed that significant reductions were observed in total antioxidant capacity (T-AOC) and total superoxide dismutase (T-SOD) activities (P < 0.05), while activities or contents of malondialdehyde (MDA), nitric oxide (NO), and nitric oxide synthase (NOS) were increased (P < 0.05). The mRNA expression levels of CP, caspase-3, Smac, and Cyt-C genes were upregulated (P < 0.05). In addition, histopathological lesions showed different degrees of vacuolar degeneration and edematous and mitochondrial swelling. The results suggest that co-exposure to Mo and Cd could induce oxidative stress and cell apoptosis possibly associated with mitochondrial intrinsic pathway in goat liver and show possible synergistic effects between the two elements.

Molybdenum (Mo) is an essential element for human beings and animals; however, high dietary intake of Mo can lead to adverse reactions. Cadmium (Cd) is one of the major transitional metals which have toxic effects in animals. The toxicity of simple Cd or Mo has been researched frequently. However, the toxicity of Mo combined with Cd was rarely studied. To investigate the toxicity of Mo combined with Cd in liver of goats, 36 Boer goats were randomly divided into four groups and assigned with one of the three oral treatments of CdCl2 (0.5 mg kg(-1) Cd) and [(NH4)6Mo7O24·4H2O] (15 mg kg(-1) Mo, group I; 30 mg kg(-1) Mo, group II; 45 mg kg(-1) Mo, group III), while the control group received deionized water. Blood samples were collected on days 0, 10, 20, 30, 40, and 50 to determine antioxidant indices in serum. In addition, liver tissues were collected on days 0, 25, and 50 for detecting the messenger RNA (mRNA) expression levels of Bcl-2 and Bax. Moreover, liver tissues at 50 days were subjected to histopathological analysis with the optical microscope. The results revealed a significant increase (P < 0.05 or P < 0.01) in the levels of nitric oxide (NO), malonaldehyde (MDA), and the activity of nitrix oxide synthase (NOS) and a significant decline (P < 0.05) in the activities of total superoxide dismutase (T-SOD) and total antioxidative capacity (T-AOC). The mRNA expression level of Bcl-2 was suppressed (P < 0.05), while the expression of Bax was increased (P < 0.05) in liver. The histopathological changes were observed in the liver of goats including a small amount of erythrocyte, the unclear structure of hepatic cord and hepatic sinusoid, granular degeneration, vacuolar degeneration, and steatosis. In conclusion, combined chronic toxicity of Cd with different levels of Mo might induce goat liver cell apoptosis and cause oxidative stress in serum, and it showed a possible synergistic relationship between the two elements.

The present experiment aims at evaluating chronic toxic effects of the combination of cadmium (Cd) and molybdenum (Mo) according to residual element contents, apoptosis gene expression, and ultrastructure and histopathology changes of caprine spleen. In total, 36 Boer goats were randomly divided into four groups with the equal number in each group. The control group was orally administered with deionized water while the experimental groups I, II, and III were administered with the equal quantity of CdCl2 (1 mg kg(-1) BW) and (NH4)6·Mo7O24·4H2O including 15, 30, and 45 mg·Mo kg(-1) BW, respectively. Three individuals from each group were treated with euthanasia on days 0, 25, and 50. The data showed that the content of splenic residual Mo and Cd increased (P < 0.05) in the experimental groups on days 25 and 50, while no significant difference was observed in the content of Cu. The apoptosis-related gene expression levels including Bcl-2, Bax, Caspase-3, Smac, and ceruloplasmin (CP) were also determined. Results showed that significant reductions were observed in Bcl-2 and CP expressions (P < 0.01), while Caspase-3 gene was up-regulated (P < 0.05). However, no significant difference was observed in Smac and Bax expressions. Furthermore, on day 50, spleen tissues were presented to observe ultrastructural changes in lesions by means of transmission electron microscopy, with fragmentized nucleus, vesiculation of cytoplasm, mitochondria hyperplasia, and increasing lysosomes included. In addition, histopathology results corroborated the toxicity by showing cell hemorrhage, thickening central arteries, and enhanced capsule thickness. To sum up, our study revealed that the combination of Cd and Mo could induce remarkable damage to the spleen of goats by promoting cell apoptosis in the mitochondrial pathway and affecting the deposition of Mo and Cd.

To investigate the effects of molybdenum (Mo) combined with cadmium (Cd) on the antioxidant function and the mRNA expression levels of apoptosis-related genes in duck ovaries, 60 healthy 11-old-day female ducks were treated with hexaammonium molybdate ([(NH4)6Mo7O24·4H2O]) or/and cadmium sulfate (3CdSO4·8H2O) at different doses on a daily basis for 120 days. On the 120th day, ten female birds in each group were euthanized, and the ovaries and blood were collected to determine the antioxidant indexes and the mRNA expression levels of Bak-1, Bcl-2, and caspase-3 in ovaries. In addition, ovary tissues were subjected to histopathological analysis with optical microscope. The total antioxidant capacity (T-AOC) and superoxide dismutase (SOD) activity decreased significantly (P < 0.01) in treated groups comparing with control while the nitric oxide synthase (NOS) activity increased (P < 0.01) both in ovary tissue and serum. The Bak-1 and caspase-3 expressions were upregulated while the Bcl-2 was downgraded by Mo or/and Cd. Biomolecules were affected in all metal-treated groups, whereas combined-treated animals showed greater effects. What is more, pathological damage in Mo and Cd combination treated groups was more severe. The results from the present study indicated that Mo or/and Cd caused oxidative stress and apoptosis in duck ovaries. Combination of Mo and Cd showed additive or synergistic effect leading to apoptosis and oxidative stress, and the pathway might be the mitochondrial pathway.

Molybdenum (Mo) is an essential trace element for animals and humans. However, the high dietary intake of Mo leads to disease conditions in heavy metal pollution areas. To the best of our knowledge, the effect of high levels of Mo on the apoptosis of hepatocyte in goats has not been investigated. Therefore, the aim of the present in vivo study was to investigate the impact of Mo on mitochondrial oxidative stress and apoptosis genes in the liver using real-time quantitative polymerase chain reaction (RT-qPCR) and transmission electron microscopy, respectively. Thirty-six healthy goats were randomly divided into three groups: two groups treated with ammonium molybdate [(NH4)6·Mo7O24·H2O] at 15 and 45 mg Mo kg(-1) BW, respectively, and a control group without treatment. Liver samples were collected from individual goats at different time intervals. The levels of oxidative stress in the mitochondrial membrane and expression of liver-related apoptosis genes, including Bcl-2, Cyt c, caspase-3, and Smac, were examined. The results demonstrated that the levels of superoxide dismutase (SOD) and catalase (CAT) expression were significantly down-regulated in liver cells, whereas malondialdehyde (MDA), nitric oxide (NO), and total nitric oxide synthase (T-NOS) expression was up-regulated (P < 0.01). The expression of Smac, Cyt c, and caspase-3 was significantly up-regulated, whereas Bcl-2 expression was down-regulated in liver cells (P < 0.01). In addition, histopathological examination revealed varying degrees of vacuolization, irregularity, nuclear fission, and mitochondrial swelling and high-density electrons in the cytoplasm of hepatocytes in groups treated with 15 and 45 mg Mo kg(-1) BW. Thus, these results suggested that high molybdenum induced hepatocyte apoptosis and might involve a mitochondrial pathway.

In order to clarify the effects of the combination of Mo and Cd on goat and relationship between the two elements, combined chronic toxicity of cadmium with different levels of molybdenum in vivo on apoptosis gene and ultrastructure of spleen was evaluated with the methods of RT-qPCR and transmission electron microscopy. A total of thirty-six goats were randomly distributed in equal number into four groups. These groups were randomly assigned with one of three oral treatments of CdCl2 (0.5 mgCd kg(-1)) and [(NH4)6Mo7O24·4H2O] (15 mg Mo kg(-1), group I; 30 mg Mo kg(-1), group II; 45 mg Mo kg(-1), group III), while the control group received deionized water. Spleen tissues were taken from individual goat at different time intervals to measure the levels of apoptosis genes including Bcl-2, Bax, Cyt c, Caspase-3, Smac and ceruloplasmin (Cp). The results revealed that a significant suppression in Bcl-2 expression and increase in Cyt c, Caspase-3 and Cp expression in splenic cells. The Bax expression in group I and II was up-regulated, however, it displayed reduction in group III, whereas no statistical significance was observed on Smac expression. In addition, histopathologic injury revealed remarkable morphplogical changes on the splenocytes in the means of apoptosis including fragmentized nucleus, apoptotic body and vesiculation of cytoplasma and mitochondria. Taken together, combined chronic toxicity of cadmium with different levels of molybdenum induce goat spleen cell apoptosis associated with mitochondrial intrinsic pathway, and the two elements showed possible antergic relationship., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Excess molybdenum (Mo) is harmful to animals, but its nephrotoxicity has not been comprehensively explained. To appraise the influences of excess Mo on Ca homeostasis and apoptosis via PLC/IP3/IP3R axis, primary duck renal tubular epithelial cells were exposed to 480 μM and 960 μM Mo, and joint of 960 μM Mo and 10 μM 2‐APB or 0.125 μM U‐73122 for 12 h (U‐73122 pretreated for 1 h), respectively. The data revealed that the increment of [Ca2+]c induced by Mo mainly originated from intracellular Ca storage. Mo exposure reduced [Ca2+]ER, elevated [Ca2+]mit, [Ca2+]c, and the expression of Ca homeostasis‐related factors (Calpain, CaN, CRT, GRP94, GRP78 and CaMKII). 2‐APB could effectively reverse subcellular Ca2+ redistribution by inhibiting IP3R, which confirmed that [Ca2+]c overload induced by Mo originated from ER. Additionally, PLC inhibitor U‐73122 remarkably mitigated the change, and dramatically reduced the number of apoptotic cells, the expression of Bak‐1, Bax, cleaved‐Caspase‐3/Caspase‐3, and notably increased the expression of Bcl‐xL, Bcl‐2, and Bcl‐2/Bax ratio. Overall, the results confirmed that the Ca2+ liberation of ER via PLC/IP3/IP3R axis was the main cause of [Ca2+]c overload, and then stimulated apoptosis in duck renal tubular epithelial cells. [ABSTRACT FROM AUTHOR]

Hexavalent chromium (Cr(VI)) is a hazardous substance that poses significant risks to environmental ecosystems and animal organisms. However, the specific consequences of Cr(VI) exposure in terms of liver damage remain incompletely understood. This study aims to elucidate the mechanism by which Cr(VI) disrupts mitochondrial dynamics, leading to hepatic injury in ducks. Forty-eight healthy 8-day-old ducks were divided into four groups and subjected to diets containing varying doses of Cr(VI) (0, 9.28, 46.4, and 232 mg/kg) for 49 days. Our results demonstrated that Cr(VI) exposure resulted in disarranged liver lobular vacuolation, along with increasing the serum levels of ALT, AST, and AKP in a dose-dependent manner, which indicated liver damage. Furthermore, Cr(VI) exposure induced oxidative stress by reducing the activities of T-SOD, SOD, GSH-Px, GSH, and CAT, while increasing the contents of MDA and H2O2. Moreover, Cr(VI) exposure downregulated the activities of CS and MDH, resulting in energy disturbance, as evidenced by the reduced AMPK/p-AMPK ratio and PGC-1α protein expression. Additionally, Cr(VI) exposure disrupted mitochondrial dynamics through decreased expression of OPA1, Mfn1, and Mfn2 and increased expression of Drp-1, Fis1, and MFF proteins. This disruption ultimately triggered mitochondria-mediated apoptosis, as evidenced by elevated levels of caspase-3, Cyt C, and Bax, along with decreased expression of Bcl-2 and the Bcl-2/Bax ratio, at both the protein and mRNA levels. In summary, this study highlights that Cr(VI) exposure induces oxidative stress, inhibits the AMPK-PGC-1α pathway, disrupts mitochondrial dynamics, and triggers liver cell apoptosis in ducks. [ABSTRACT FROM AUTHOR]

Oxidative stress can adversely affect the health status of the body, more specifically by causing intestinal damage by disrupting the permeability of the intestinal barrier. This is closely related to intestinal epithelial cell apoptosis caused by the mass production of reactive oxygen species (ROS). Baicalin (Bai) is a major active ingredient in Chinese traditional herbal medicine that has antioxidant, anti-inflammatory, and anti-cancer properties. The purpose of this study was to explore the underlying mechanisms by which Bai protects against hydrogen peroxide (H2O2)-induced intestinal injury in vitro. Our results indicated that H2O2 treatment caused injury to IPEC-J2 cells, resulting in their apoptosis. However, Bai treatment attenuated H2O2-induced IPEC-J2 cell damage by up-regulating the mRNA and protein expression of ZO-1, Occludin, and Claudin1. Besides, Bai treatment prevented H2O2-induced ROS and MDA production and increased the activities of antioxidant enzymes (SOD, CAT, and GSH-PX). Moreover, Bai treatment also attenuated H2O2-induced apoptosis in IPEC-J2 cells by down-regulating the mRNA expression of Caspase-3 and Caspase-9 and up-regulating the mRNA expression of FAS and Bax, which are involved in the inhibition of mitochondrial pathways. The expression of Nrf2 increased after treatment with H2O2, and Bai can alleviate this phenomenon. Meanwhile, Bai down-regulated the ratio of phosphorylated AMPK to unphosphorylated AMPK, which is indicative of the mRNA abundance of antioxidant-related genes. In addition, knockdown of AMPK by short-hairpin RNA (shRNA) significantly reduced the protein levels of AMPK and Nrf2, increased the percentage of apoptotic cells, and abrogated Bai-mediated protection against oxidative stress. Collectively, our results indicated that Bai attenuated H2O2-induced cell injury and apoptosis in IPEC-J2 cells through improving the antioxidant capacity through the inhibition of the oxidative stress-mediated AMPK/Nrf2 signaling pathway. [ABSTRACT FROM AUTHOR]

Cadmium (Cd) is an environmental pollutant that has an enormous influence on agricultural production, but selenium (Se) can alleviate its toxicity. The present study aimed to illustrate the effects of Se on Cd‐induced heart injury. All 40 rabbits were randomly divided into four groups: control group, Se [0.5 mg kg−1·body weight (BW)] group, Cd (1 mg kg−1·BW) group, and Se + Cd group. After 30 days of feeding, morphological changes, the levels of oxidative stress and myocardial enzyme, the content of cardiac troponin T, programmed cell death (pyroptosis, autophagy and apoptosis), and PI3K/AKT/PTEN transduction capacity were observed. The results showed that Cd destroyed the physiological balance of trace elements and caused myocardial damage, increased the cardiac oxidative damage and led to programmed cell death. Coadministration of Se prominently ameliorated histological lesions and improved cardiac function of hearts in Cd‐induced rabbits. Furthermore, Se exerted detoxification and oxidation resistance, maintained trace element homeostasis, and alleviated the changes of mRNA and protein levels of pyroptosis‐, autophagy‐ and apoptosis‐controlling factors and PI3K/AKT/PTEN signal molecules caused by Cd. In conclusion, Se might protect against Cd‐induced pyroptosis, autophagy and apoptosis by interfering with PI3K/AKT/PTEN signaling in heart. [ABSTRACT FROM AUTHOR]

Fatty liver haemorrhagic syndrome (FLHS) is characterized by hepatic rupture and haemorrhage leading to sudden death in laying hens. Resveratrol (Res) is a natural polyphenol with antioxidant and anti-inflammatory effects that can ameliorate chronic liver disease. The aim of this study was to investigate the improved effect of Res on the altered expression of autophagy and apoptosis-related genes in laying hens with FLHS. A total of 144 healthy 150-day-old laying hens were randomly divided into four groups: control group (standard diet), HELP group (high-energy-low-protein (HELP) diet), HELP + Res group (HELP diet with 400 mg/kg Res) and Res group (standard diet with 400 mg/kg Res). Histopathological lesions of the liver and the mRNA levels of Beclin-1, Atg5, Atg7, p62, Bcl-2, Bax and Caspase-3 on days 40, 80, and 120 were measured. The results showed that lipid accumulation and hepatocyte damage in the HELP group were more serious than those in the HELP + Res group. The mRNA levels of Beclin-1, Atg5, Atg7, and Bcl-2 in the HELP and HELP + Res groups were strikingly declined (P < 0.01) compared to the control group, and their mRNA levels were markedly higher in HELP group than those in the HELP + Res group (P < 0.05). Additionally, the mRNA levels of p62, Bax and Caspase-3 were significantly increased in the HELP and HELP + Res groups (P < 0.01 or P < 0.05), but their mRNA levels in the HELP group were higher than those in the HELP + Res group (P < 0.05). Collectively, FLHS could induce severe lipid accumulation, abnormal mRNA levels of liver autophagy and apoptosis-related genes. Res as a dietary supplement could attenuate these abnormal changes. [ABSTRACT FROM AUTHOR]

Aflatoxin B1 (AFB1) is a stable mycotoxin that contaminates animal feed on a large scale and causes severe damage to intestinal cells, induces inflammation and stimulates autophagy. Transient receptor potential mucolipin subfamily 1 (TRPML1) is a regulatory factor of autophagy, but the underlying mechanisms of TRPML1-mediated autophagy in AFB1 intestine toxicity remain elucidated. In the present study, AFB1 (0, 5, 10 μg/mL) was shown to reduce cell viability, increase reactive oxygen species (ROS) accumulation and apoptosis rate. Additionally, AFB1 caused structural damage to mitochondria and lysosomes and increased autophagosomes numbers. Furthermore, AFB1 promoted Ca2+ release by activating the TRPML1 channel, stimulated the expression of autophagy-related proteins, and induced autophagic flux blockade. Moreover, pharmacological inhibition of autophagosome formation by 3-methyladenine attenuated AFB1-induced apoptosis by downregulating the levels of TRPML1 and ROS, whereas blockade of autophagosome-lysosomal fusion by chloroquine alleviated AFB1-induced apoptosis by upregulating TRPML1 expression and exacerbating ROS accumulation. Intriguingly, blocking AFB1-induced autophagic flux generated ROS- and TRPML1-dependent cell death, as shown by the decreased apoptosis in the presence the free radical scavenger N-Acetyl- L -cysteine and the TRPML1 inhibitor ML-SI1. Overall, these results showed that AFB1 promoted apoptosis of IPEC-J2 cells by disrupting autophagic flux through activation of the ROS/TRPML1 pathway. [Display omitted] • AFB1 induces ROS accumulation and apoptosis in porcine intestinal epithelial cells. • AFB1 causes the blockage in autophagic flux in porcine intestinal epithelial cells. • Inhibition of autophagosome formation by 3-MA attenuate AFB1-induced apoptosis. • Blocking autophagosome-lysosome fusion by CQ exacerbates AFB1-induced apoptosis. • Inhibition of TRPML1 activates autophagic flux to relieve AFB1-induced apoptosis. [ABSTRACT FROM AUTHOR]

Cadmium (Cd) is an occupational and environmental pollutant, which mainly causes nephrotoxicity by damaging renal proximal tubular cells. To evaluate the effects of Cd on pyroptosis and the relationship between pyroptosis and apoptosis in duck renal tubular epithelial cells, the cells were cultured with 3CdSO 4 ·8H 2 O (0, 2.5, 5.0, or 10.0 μM Cd), N-acetyl-L-cysteine (NAC) (100.0 μM), Z-YVAD-FMK (10.0 μM) or the combination of Cd and NAC or Z-YVAD-FMK for 12 h, and then cytotoxicity was assessed. The results evidenced that Cd significantly increased the releases of interleukin-18 (IL-18) and interleukin-1β (IL-1β), lactate dehydrogenase (LDH) and nitric oxide (NO), relative conductivity and cellular reactive oxygen species (ROS) level. Simultaneously, Cd also markedly upregulated NLRP3, Caspase-1, ASC, NEK7, IL-1β and IL-18 mRNA levels and NLRP3, Caspase-1 p20, GSDMD and ASC protein levels. Additionally, NAC notably improved the changes of above indicators induced by Cd. Combined treatment with Cd and Z-YVAD-FMK remarkably elevated Bcl-2 mRNA and protein levels, inhibited p53, Bax, Bak-1, Cyt C, Caspase-9 and Caspase-3 mRNA levels and p53, Bax, Bak-1, Caspase-9/cleaved Caspase-9 and Caspase-3/cleaved Caspase-3 protein levels, increased mitochondrial membrane potential (MMP), decreased apoptosis ratio and cell damage compared to treatment with Cd alone. Taken together, Cd exposure induces duck renal tubular epithelial cell pyroptosis through ROS/NLRP3/Caspase-1 signaling pathway, and inhibiting Caspase-1 dependent pyroptosis attenuates Cd-induced apoptosis. Image 1 • Cadmium (Cd) toxicity was evaluated in duck renal tubular epithelial cells. • Cd could induce pyroptosis via ROS/NLRP3/Caspase-1 pathway. • N-acetyl-L-cysteine (NAC) could inhibit pyroptosis induced by Cd. • Inhibiting Caspase-1-dependent pyroptosis might weaken Cd induced-apoptosis. [ABSTRACT FROM AUTHOR]

Copper (Cu) is a vital micronutrient required for numerous fundamental biological processes, but excessive Cu poses potential detrimental effects on public and ecosystem health. However, the molecular details linking endoplasmic reticulum (ER) stress and apoptosis in duck renal tubular epithelial cells have not been fully elucidated. In this study, duck renal tubular epithelial cells exposed to Cu sulfate (CuSO 4) (0, 100 and 200 μM) and a PERK inhibitor (GSK2606414, GSK, 1 μM) for 12 h were used to investigate the crosstalk between ER stress and apoptosis under Cu exposure. Cell and ER morphological and functional characteristics, intracellular calcium (Ca2+) levels, apoptotic rates, ER stress and apoptosis-related mRNA and protein levels were examined. The results showed that excessive Cu could cause ER expansion and swelling, increase the expression levels of ER stress-associated genes (PERK, eIF2α, ATF4 and CHOP) and proteins (p-PERK and CHOP), induce intracellular Ca2+ overload, upregulate the expression levels of apoptosis-associated genes (Bax, Bak1, Caspase9 and Caspase3) and the cleaved-Caspase3 protein, downregulate Bcl-xl and Bcl2 mRNA levels and trigger apoptosis. PERK inhibitor treatment could ameliorate the above changed factors caused by Cu. In conclusion, these findings indicate that excessive Cu could trigger ER stress via activation of the PERK/ATF4/CHOP signaling pathway and that ER stress might aggravate Cu-induced apoptosis in duck renal tubular epithelial cells. Image 1 • Copper (Cu) has toxic effect on duck renal tubular epithelial cells. • Cu could trigger endoplasmic reticulum (ER) stress via PERK/ATF4/CHOP pathway. • Cu could induce apoptosis in duck renal tubular epithelial cells. • ER stress might aggravate Cu-induced apoptosis via PERK/ATF4/CHOP pathway. [ABSTRACT FROM AUTHOR]

Excess molybdenum (Mo) is harmful to the body, and the kidney is the vital target organ for Mo exposure. This study focused on the impacts of excess Mo on pyroptosis and the relationship between pyroptosis and apoptosis in kidney. The duck renal tubular epithelial cells were treated with (NH 4) 6 Mo 7 O 24 ·4H 2 O (0, 480, 720 and 960 μM Mo), N-acetyl- L -cysteine (NAC) (100 μM), Z-YVAD-fluoromethylketone (YVAD) (10 μM) and the combination of Mo and NAC or YVAD for 12 h. The LDH release and IL-1β, IL-18 contents of cell supernatant were detected by LDH and ELISA kits. The MMP and ROS level were measured using MMP and ROS kits by flow cytometry. The apoptotic rate of cell was detected by AO/EB counterstaining. Pyroptosis and apoptosis-related factors mRNA and protein levels were assayed by real-time qPCR and western blot, respectively. Excessive Mo markedly increased LDH, IL-18, IL-1β releases and induced overproduction of ROS, pyroptosis-related factors mRNA and protein levels. NAC and YVAD dramatically decreased pyroptosis induced by Mo. Simultaneously, YVAD significantly changed apoptosis-related factors mRNA and protein levels, and reduced cell apoptotic rate. Excessive Mo exposure can induce pyroptosis by the ROS/NLRP3/Caspase-1 pathway in duck renal tubular epithelial cells, and restraining pyroptosis of Caspase-1 dependence might weaken excess Mo-induced apoptosis. The study provides theoretical basis for excess Mo exposure nephrotoxic researches on waterfowl and the interplay between pyroptosis and apoptosis highlights a new sight into the mechanism of Mo-induced nephrotoxicity. ga1 • Toxicity of excess molybdenum (Mo) was assessed in duck renal tubular epithelial cells. • Excess Mo could induce pyroptosis via ROS/NLRP3/Caspase-1 pathway. • N-acetyl- L -cysteine (NAC) could inhibit pyroptosis induced by excess Mo. • Inhibiting Caspase-1-dependent pyroptosis might weaken excess Mo induced-apoptosis. [ABSTRACT FROM AUTHOR]

Atrazine (ATR), a water-soluble herbicide commonly used to control broad-leaf and monocotyledonous weeds, presents a significant risk to environmental soil and water quality. Exposure to ATR adversely affects human and animal health, frequently resulting in cardiac impairment. Curcumin (Cur), an acidic polyphenol derivative from plants acclaimed for its pronounced anti-inflammatory and antioxidant properties, has garnered interest as a potential therapeutic agent. However, whether it has the potential to ameliorate ATR-induced cardiac toxicity via modulation of endoplasmic reticulum stress (ERS) and apoptosis pathways in mice remains unclear. Our results showed that Cur supplementation attenuates ATR-induced cardiotoxicity, evidenced by decrease in creatine kinase and lactate dehydrogenase, key biochemical markers of myocardial injury, which have a more significant protecting effect in high-dose ATR induced injury. Histopathological and electron microscopy examinations further solidified these findings, demonstrating an amelioration in organellar damage, particularly in endoplasmic reticulum swelling and subsequent mitochondrial impairment. Additionally, ATR exposure augments ERS and triggers apoptotic pathways, as indicated by the upregulation of ERS-related gene expression (ATF6, CHOP, IRE1, GRP78) and pro-apoptotic markers (BAX, BAK1, Caspase3, Caspase. Intriguingly, Cur counteracts this detrimental response, significantly reducing ERS and pro-apoptotic signals at both transcriptional and translational levels. Collectively, our findings illuminate Cur's cardioprotective effect against ATR-induced injury, primarily through its anti-ERS and anti-apoptotic activities, underscoring Cur's potential as a therapeutic for ATR-induced cardiotoxicity. [ABSTRACT FROM AUTHOR]

Cadmium (Cd) and high Molybdenum (Mo) can lead to adverse reactions on animals, but the co-induced toxicity of Mo and Cd to liver in ducks was not well understood. To investigate the co-induced toxic effects of Mo combined with Cd on mitochondrial oxidative stress and apoptosis in duck livers. 240 healthy 11-day-old ducks were randomly divided into 6 groups (control, LMo group, HMo group, Cd group, LMoCd group and HMoCd group). After being treated for 30, 60, 90 and 120 days, liver mitochondrial antioxidant indexes, ceruloplasmin (CP), metallothionein (MT), Bak-1 and Caspase-3 genes mRNA expression levels, and ultrastructural changes were evaluated. The results showed that total antioxidative capacity (T-AOC), catalase (CAT), superoxide dismutase (SOD) and xanthine oxidase (XOD) activities in experimental groups were decreased, whereas malondialdehyde (MDA) content and nitric oxide synthase (NOS) activity were increased compared with control group, and these changes of co-treated groups were more obvious in the later period of the experiment. The mRNA expression levels of CP, Bak-1 and Caspase-3 were up-regulated in experimental groups compared with control group and showed significant difference between co-treated groups and single treated groups. The mRNA expression level of MT in Cd group was higher than that in co-treated groups. Additionally, ultrastructural changes showed karyopyknosis, mitochondrial swelling, vacuolation and disruption of mitochondrial cristae in co-treated groups. Taken together, it was suggested that dietary Mo and Cd might lead to mitochondrial oxidative stress and apoptosis in duck livers, and it showed a possible synergistic relationship between the two elements. [ABSTRACT FROM AUTHOR]

Excessive molybdenum (Mo) and cadmium (Cd) are deleterious to animals, but immunotoxicity co-induced by Mo and Cd remains unclear. To ascertain the confederate impacts of Mo and Cd on endoplasmic reticulum (ER) stress-mediated apoptosis by Helper T (Th) cells 1 polarization in the spleen of ducks, we randomly allocated forty 8-day-old Shaoxing ducks (Anas platyrhyncha) into 4 groups and reared them with having different doses of Mo and/or Cd basic diet. At the 16th week of the experiment, serum and spleen tissues were extracted. Data confirmed that Mo and/or Cd strikingly promoted their levels in spleen, caused histological abnormality and trace elements imbalance, and disrupted Th1/Th2 balance to divert toward Th1, then triggered ER stress by increasing three branches PERK/eIF2α/CHOP, IRE1/Caspase-12 and TRAF2/JNK signaling pathways-related genes mRNA and proteins levels, which stimulated apoptosis by elevating Bak-1, Bax, Caspase-9, Caspase-3 mRNA expression, and cleaved-Caspase-9/Caspase-9, cleaved-Caspase-3/Caspase-3 proteins expression as well as apoptosis rate, and decreasing Bcl-xL, Bcl-2 mRNA expression and Bcl-2/Bax ratio. Besides, the variation in combined group was most evident. Briefly, the study indicates that Mo and/or Cd exposure trigger ER stress-induced apoptosis via Th1 polarization in duck spleens, and its mechanism is somehow closely linked with the deposition of Cd and Mo, which may aggravate toxic damage to spleen. [Display omitted] • The joint toxicity of Mo and Cd was assessed in duck spleens. • Mo and/or Cd caused trace elements imbalance and damage to spleen. • Mo and/or Cd disrupted Th1/Th2 balance to divert toward Th1. • Mo and/or Cd may trigger ER stress-mediated apoptosis. • Mo and Cd may aggravate toxic damage to spleen. [ABSTRACT FROM AUTHOR]

Cadmium (Cd) is a well studied nephrotoxic metal element. To investigate the effects of Cd-induced cytotoxicity on oxidative stress-mediated apoptosis in primary renal tubular epithelial cells of duck. Shaoxing duck (Anas platyrhyncha) renal tubular epithelial cells were cultured in medium in absence and presence of 3CdSO 4 ·8H 2 O (1.25, 2.5, 5.0 μM Cd), in N -acetyl- l -cysteine (NAC) (100 μM), and the combination of Cd and NAC for 12 h. After 12 h exposure, morphologic observation and function, reactive oxygen species (ROS) level, antioxidant indices, the activity of ATPase, intracellular pH and [Ca2+]i, mitochondrial membrane potential (MMP), and apoptosis-related genes mRNA were determined. The results showed that Cd exposure could induce release of intracellular lactate dehydrogenase (LDH), simultaneously, enhance the ROS generation, acidification, malondialdehyde (MDA) and [Ca2+]i, decrease glutathione (GSH), Na+, K+-ATPase, Ca2+-ATPase, catalase (CAT), superoxide dismutase (SOD), total antioxidant capacity (T-AOC) and glutathione peroxidase (GSH-Px) activities as well as MMP, upregulated Bak-1, Bax and Caspase-3 mRNA expression, inhibited Bcl-2 mRNA expression, and induced cell apoptosis. The toxicity of Cd to cells showed a dose-dependent manner. Antioxidant NAC could efficiently alleviate Cd-induced the cytotoxicity. Taken together, these results suggest that Cd exposure cause cytotoxicity through oxidative stress-mediated apoptosis pathway in duck renal tubular epithelial cells. • Cd induced oxidative stress by generating excessive ROS in duck renal tubular epithelial cells. • Apoptosis occurred in duck renal tubular epithelial cells treated with Cd. • Cd induced apoptosis through oxidative stress-mediated pathway in duck renal tubular epithelial cells. • N -acetyl- l -cysteine (NAC) has protective effects on Cd-induced cytotoxicity in duck renal tubular epithelial cells. [ABSTRACT FROM AUTHOR]