Txnrd3 knockout enhancement of lung injury induced by Ni exposure via the VEGF-VEGFR-2 axis and alleviation of this effect by melatonin.

Ni exposure leads to respiratory diseases in mice. Txnrd3 has been shown to have a protective effect on the body, but there is a paucity of empirical research focusing specifically on lung tissue. Melatonin possesses potent antioxidant, anti-inflammatory, and anti-fibrotic effects. By regulating inflammation-related factors, melatonin can activate the VEGF signaling pathway, ultimately alleviating lung injuries caused by Ni exposure. One hundred and sixty 8-week-old C57BL/6N mice, that were wild-type or Txnrd3-/- mice and 25-30 g in weight, were randomly divided into eight groups, including the NC group, Ni group, melatonin-treated group, and Ni plus melatonin group. Ni (10 mg/kg) was gavaged, and melatonin (2 mg/kg) was administered for 21 days. Inflammatory cells were found in the bronchioles of Txnrd3-/- mice under Ni exposure. Ultrastructural examination revealed that the homozygous-Ni group had a high amount of collagen fibers. The antioxidant capacity studies also revealed that mice lungs underwent oxidative stress. The results of qRT-PCR and WB showed that Ni induced an inflammatory response, which was also aggravated in Txnrd3-/- mice. Melatonin can effectively reduce the above symptoms. In conclusion, Ni causes lung injury by activating the VEGF-VEGFR-2 pathway and Txnrd3 knockout aggravates injury after Ni exposure.

Role of Txnrd3 in NiCl2-induced kidney cell apoptosis in mice: Potential therapeutic effect of melatonin.

Nickel (Ni) exposure is a significant risk factor for kidney dysfunction and oxidative stress injury in humans. Thioredoxin reductase 3 (Txnrd3), an important enzyme in animals, plays a role in maintaining cellular homeostasis and regulating oxidative stress. However, its protective effect against kidney injury has been determined. Melatonin (Mel) has antioxidant and anti-apoptotic effects and therefore may be a preventive and therapeutic agent for kidney injury. Our study aimed to investigate the roles of Mel and Txnrd3 in the treatment of nickel-induced renal injury. We divided 80 wild-type mice and 80 Txnrd3 -/- mice (C57BL/6 N) into a control group treated with saline, Ni group treated with 10 mg/kg NiCl2, Mel group treated with 2 mg/kg Mel, and Ni + Mel group given NiCl2 and Mel for 21 days. Histopathological and ultrastructural observation of the kidney showed that nuclei were wrinkled and mitochondrial cristae were broken in the Ni group, and these changes were significantly attenuated by Mel treatment. Mitochondrial and nuclear damage improved significantly in the Ni + Mel and Txnrd3-/- Ni + Mel groups. Furthermore, NiCl2 exposure decreased T-AOC, SOD, and GSH activities in the kidney. The decreases in antioxidant enzyme activity were attenuated by Mel, and these improvements were abolished by Txnrd3 knockout. NiCl2-induced increases in the mRNA and protein levels of apoptosis factors (Bax, Cyt-c, caspase-3, and caspase-9) were attenuated by Mel treatment, and Txnrd3 knockout abolished the repressive effect of Mel on apoptosis genes. Overall, we concluded that Mel improves oxidative stress and apoptosis induced by NiCl2 by regulating Txnrd3 expression in the kidney. Our results provide evidence for the role of Mel in NiCl2-induced kidney injury and identify Txnrd3 as a potential therapeutic target for renal injury.

Micro-algal astaxanthin improves lambda-cyhalothrin-induced necroptosis and inflammatory responses via the ROS-mediated NF-κB signaling in lymphocytes of carp (Cyprinus carpio L.).

Lambda-cyhalothrin (LCY) is a widely used toxic pesticide that causes harmful effects on the immune organs of fish and aquatic species. Micro-algal astaxanthin (MAA), a heme pigment found in haematococcus pluvialis, has been shown to benefit antioxidants and immunity in aquaculture. To investigate how MAA protects carp lymphocytes from LCY-induced immunotoxicity, a model of fish lymphocytes treated with LCY and/or MAA was established. Lymphocytes from carp (Cyprinus carpio L.) were given LCY (80 µM) and/or MAA (50 µM) as a treatment for a period of 24 h. Firstly, LCY exposure resulted in excessive ROS and malondialdehyde production and reduces antioxidant enzymes (SOD and CAT), indicating a reduced capacity of the antioxidant system. Secondly, the results of flow cytometry and AO/EB labeling proved that lymphocytes treated with LCY have a larger ratio of necroptosis. In addition, LCY upregulated the levels of necroptosis-related regulatory factors (RIP1, RIP3 and MLKL) via the ROS-mediated NF-κB signaling pathway in lymphocytes. Thirdly, LCY treatment caused increased secretion of inflammatory genes (IL-6, INF-γ, IL-4, IL-1ß and TNF-α), leading to immune dysfunction in lymphocytes. Surprisingly, LCY-induced immunotoxicity was inhibited by MAA treatment, indicating that it effectively attenuated the LCY-induced changes described above. Overall, we concluded that MAA treatment could ameliorate LCY-induced necroptosis and immune dysfunction by inhibiting the ROS-mediated NF-κB signaling in lymphocytes. It provides insights into the protection of farmed fish from agrobiological threats in fish under LCY and the value of MAA applications in aquaculture.

N-acetyl-L-cysteine alleviated the oxidative stress-induced inflammation and necroptosis caused by excessive NiCl2 in primary spleen lymphocytes.

Introduction: Nickel (Ni) is widely used in industrial manufacturing and daily life due to its excellent physical and chemical properties. However, Ni has the potential to harm animals' immune system, and spleen is a typical immune organ. Therefore, it is crucial to understand the mechanism of NiCl2 damage to the spleen. The purpose of this study is to investigate the effects of different concentrations of NiCl2 exposure and intervening with strong antioxidants on spleen lymphocytes to better understand the damage mechanism of Ni on spleen lymphocytes. Methods: In this experiment, mice spleen lymphocytes were used as the research object. We first measured the degree of oxidative stress, inflammation, and necroptosis caused by different NiCl2 concentrations. Subsequently, we added the powerful antioxidant N-acetyl-L-cysteine (NAC) and used hydrogen peroxide (H2O2) as the positive control in subsequent experiments. Results: Our findings demonstrated that NiCl2 could cause spleen lymphocytes to produce a large number of reactive oxygen species (ROS), which reduced the mRNA level of antioxidant enzyme-related genes, the changes in GSH-PX, SOD, T-AOC, and MDA, the same to the mitochondrial membrane potential. ROS caused the body to produce an inflammatory response, which was manifested by tumor necrosis factor (TNF-α) in an immunofluorescence experiment, and the mRNA level of related inflammatory genes significantly increased. In the case of caspase 8 inhibition, TNF-α could cause the occurrence of necroptosis mediated by RIP1, RIP3, and MLKL. AO/EB revealed that spleen lymphocytes exposed to NiCl2 had significant necroptosis, and the mRNA and protein levels of RIP1, RIP3, and MLKL increased significantly. Moreover, the findings demonstrated that NAC acted as an antioxidant to reduce oxidative stress, inflammation, and necroptosis caused by NiCl2 exposure. Discussion: Our findings showed that NiCl2 could cause oxidative stress, inflammation, and necroptosis in mice spleen lymphocytes, which could be mitigated in part by NAC. The study provides a point of reference for understanding the toxicological effect of NiCl2. The study suggests that NAC may be useful in reducing the toxicological effect of NiCl2 on the immune system. The research may contribute to the development of effective measures to prevent and mitigate the toxicological effects of NiCl2 on the immune system.

The role of selenoprotein M in nickel-induced pyroptosis in mice spleen tissue via oxidative stress.

Nickel (Ni) is a heavy metal element and a pollutant that threatens the organism's health. Melatonin (Mel) is an antioxidant substance that can be secreted by the organism and has a protective effect against heavy metals. Selenoprotein M (SelM) is a selenoprotein widely distributed of the body, and its role is to protect these tissues from oxidative damage. To study the mechanism of Ni, Mel, and SelM in mouse spleen, 80 SelM+/+ wild-type and 80 SelM-/- homozygous mice were divided into 8 groups with 20 mice in each group. The Ni group was intragastric at a concentration of 10 mg/kg, while the Mel group was intragastric at 2 mg/kg. Mice were injected with 0.1 mL/10 g body weight for 21 days. Histopathological and ultrastructural observations showed the changes in Ni, such as the destruction of white and red pulp and the appearance of pyroptosomes. SelM knockout showed more severe injury, while Mel could effectively interfere with Ni-induced spleen toxicity. The results of antioxidant capacity determination showed that Ni could cause oxidative stress in the spleen, and Mel could also effectively reduce oxidative stress. Finally, Ni exposure increased the expression levels of the pyroptotic genes, including apoptosis-associated speck protein (ASC), absent in melanoma-2 (AIM2), NOD-like receptor thermal protein domain-associated protein 3 (NLRP3), Caspase-1, interleukin- (IL-) 18, and IL-1ß (p < 0.05). Loss of SelM significantly increased these (p < 0.05), while Mel decreased the alleviated impact of Ni. In conclusion, the loss of SelM aggravated Ni-induced pyroptosis of the spleen via activating oxidative stress, which was alleviated by Mel, but the effect of Mel was not obvious in the absence of SelM, which reflected the important role of SelM in Ni-induced pyroptosis.

Decreased thioredoxin reductase 3 expression promotes nickel-induced damage to cardiac tissue via activating oxidative stress-induced apoptosis and inflammation.

Thioredoxin reductase 3 (Txnrd3) plays a crucial role in antioxidant and anti-cancer activities, and sperm maturation. The damage of heavy metals, including Nickel (Ni), is the most prominent harm in social development, and hampering Txnrd3 might exacerbate Ni-induced cardiac damage. In this study, a total of 160 8-week-old C57BL/N male mice with 25-30 g weight of Txnrd3+/+ wild-type and Txnrd3-/- homozygote-type were randomly divided into eight groups. The mice in the control and Ni groups were gavaged with distilled water and a freshly prepared 10 mg/kg NiCl2 solution. Melatonin (Mel) groups were administered at a concentration of 2 mg/kg for 21 days at the mice's 0.1 ml/10 g body weight. Ni exposure up-regulated the messenger RNA (mRNA) levels of mitochondrial apoptosis (caspase-3, caspase-9, cytochrome c, p53, and BAX), autophagy (LC3, ATG 1, ATG 7, and Beclin-1), and inflammation (TNF-α, COX 2, IL-1ß, IL-2, IL-6, and IL-7)-related markers, but down-regulated the mRNA levels of BCL-2, p62 and mTOR (p < .05). Ni exposure decreased the expression of BCL-2 and p62 protein but increased the expression levels of caspase-3, caspase-9, cytochrome c, p53, BAX, ATG 7, Beclin-1, TNF-α, COX 2, IL-1ß and IL-2 protein (p < .05). Ni increased the contents of glutathione disulfide (GSSG) and malondialdehyde (MDA) and decreased the activities of catalase (CAT) and total superoxide dismutase (T-SOD) (p < .05). Decreased Txnrd3 expression significantly exacerbated changes compared to the Ni exposure (p < .05). Mel significantly attenuated these changes, but the effect decreased when Txnrd3 was inhibited (p < .05). In conclusion, decreased Txnrd3 expression promoted Ni-induced mitochondrial apoptosis and inflammation via oxidative stress and aggravated heart damage in mice. Decreased Txnrd3 expression significantly reduced the protective effect of Mel to Ni exposure.

Geniculate ganglion decompression of facial nerve by transmastoid-epitympanum approach.

CONCLUSIONS: We consider that the transmastoid-epitympanum approach to decompression of the geniculate ganglion, without a craniotomy, combining the advantages of middle cranial fossa and transmastoid extralabyrinthine approaches, is simple, minimally invasive, safe, and effective, with little postoperative hearing change. It can be employed in some cases of facial palsy due to temporal bone fracture (TBF) and middle ear cholesteatoma (MEC) in accordance with the range of facial paralysis, facial nerve electrophysiology, and imaging guidance. OBJECTIVE: To evaluate the efficacy of geniculate ganglion decompression of the facial nerve by the transmastoid-epitympanum approach. METHODS: Thirty cases of facial palsy were reviewed, including patients with TBF and MEC. All the patients were evaluated by routine preoperative tests including high-resolution computed tomography (HRCT), audiometry, and electroneuronography, and were treated by transmastoid-epitympanum decompression. The negative effects on auditory function were recorded. RESULTS: The mean percentage facial function improvement (House-Brackmann grade I-II) was 88% in TBF and 100% in MEC. The negative effects on auditory function were less than 10 dB in most cases.