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Aluminium (Al) accumulates in the spleen and causes spleen apoptosis. Mitochondrial dyshomeostasis represents primary mechanisms of spleen apoptosis induced by Al. Apoptosis-inducing factor (AIF) is located in the gap of the mitochondrial membrane and can be released into the nucleus, leading to apoptosis. Phosphatase and tensin homolog (PTEN)-induced putative kinase1 (PINK1)/E3 ubiquitin ligase PARK2 (Parkin)-mediated mitophagy maintains mitochondrial homeostasis by removing damaged mitochondria, but its function in AIF-mediated spleen apoptosis induced by Al is not clear. In our study, aluminium trichloride (AlCl 3) was diluted in water for 90 d and administered to 75 male C57BL/6N mice at 0, 44.8, 59.8, 89.7, and 179.3 mg/kg body weight. AlCl 3 triggered PINK1/Parkin pathway-mediated mitophagy, induced AIF release and AIF-mediated spleen apoptosis. AlCl 3 was administered to sixty male C57BL/6N mice of wild type and Parkin knockout for 90 d at 0 and 179.3 mg/kg body weight. The results indicated that Parkin deficiency decreased mitophagy, aggravated mitochondrial damage, AIF release and AIF-mediated spleen apoptosis induced by AlCl 3. According to our results, PINK1/Parkin-mediated mitophagy and AIF-mediated spleen apoptosis are caused by AlCl 3 , whereas mitophagy is protective in AIF-mediated apoptosis induced by AlCl 3. Mitophagy protects AIF-mediated spleen apoptosis induced by AlCl 3 through Parkin stabilization in mice. [Display omitted] [ABSTRACT FROM AUTHOR]

Aluminum (Al) is a common environmental pollutant that can induce kidney damage. However, the mechanism is not clear. In the present study, to explored the exact mechanism of AlCl 3 -induced nephrotoxicity, C57BL/6 N male mice and HK-2 cells were used as experimental subjects. Our results showed that Al induced reactive oxygen species (ROS) overproduction, c-Jun N-terminal kinase (JNK) signaling activation, RIPK3-dependent necroptosis, NLRP3 inflammasome activation, and kidney damage. In addition, inhibiting JNK signaling could downregulate the protein expressions of necroptosis and NLRP3 inflammasome, thereby alleviating kidney damage. Meanwhile, clearing ROS effectively inhibited JNK signaling activation, which in turn inhibited necroptosis and NLRP3 inflammasome activation, ultimately alleviating kidney damage. In conclusion, these findings suggest that necroptosis and NLPR3 inflammasome activation mediated by ROS/JNK pathway participate in AlCl 3 -induced kidney damage. [Display omitted] [ABSTRACT FROM AUTHOR]

Exposure to aluminum (Al) inhibits bone formation, the principal mechanism possibly due to oxidative stress. However, little data is available that establishes the precise relationship. In this study, Wistar rats were exposed to 0 (GC), 0.4 (GL), 0.8 (GM) or 1.6 (GH) mg/L aluminum trichloride (AlCl 3 ) in drinking water for 90 days, respectively. The concentrations of Al in serum and bone, serum markers of bone metabolism, bone mineral density (BMD) and body weight were measured. Histological changes within femurs were observed by H&E, ALP, and TRACP staining. Oxidative stress markers and JNK apoptotic pathway were detected in bone. The results indicate that AlCl 3 exposure decreased BMD, numbers of ALP-positive osteoblasts and serum levels of bone formation markers (B-ALP, PICP and BGP), and caused damaged to the trabecular structure. Serum levels of bone resorption markers (TRACP-5b, CTX-I) and numbers of TRACP-positive osteoclasts increased in GL, but conversely, they decreased in GM and GH. In addition, AlCl 3 caused oxidative stress, up-regulated expression of c-Jun and pro-apoptotic factors with increased p-JNK/JNK ratio and down-regulated expression of anti-apoptotic factor Bcl-2 in bone. Taken together, these results indicate that bone impairment caused by AlCl 3 is associated with activation of the oxidative stress-mediated JNK apoptotic pathway. [ABSTRACT FROM AUTHOR]

Di-n-butyl phthalate (DBP) causes adverse effects on male reproduction, especially testosterone synthesis inhibition. However, the specific mechanism of DBP-induced testosterone synthesis inhibition and its effective intervention measures of prevention and treatment are scarce presently. Lycopene (LYC) plays beneficial roles in male infertility because of its antioxidant activity. Nevertheless, it is unclear whether LYC could prevent DBP-induced male reproductive toxicity. By in vitro and in vivo investigations, this study demonstrated that DBP activated ROS/JAK2/STAT3 signaling pathway, promoted mitophagy and apoptosis, which in turn inhibited testosterone synthesis. Additionally, another major finding was that LYC supplement could reverse the above change, presenting as the restraint of ROS/JAK2/STAT3 signaling pathway, reduction of mitophagy and apoptosis, and improvement of testosterone synthesis. Our study facilitates deeper understandings of the mechanism in DBP-induced testosterone synthesis inhibition, and identifies LYC as the effective prevention and control strategies for DBP poisoning. [Display omitted] • DBP activates ROS/JAK2/STAT3 signaling pathway. • ROS/JAK2/STAT3 signaling pathway causes testosterone synthesis inhibition. • Restraint of ROS/JAK2/STAT3 signaling pathway mitigates mitophagy and apoptosis. • LYC inhibits ROS/JAK2/STAT3 signaling pathway. • LYC bates mitophagy and apoptosis, relieves testosterone synthesis inhibition. [ABSTRACT FROM AUTHOR]

Hexafluoropropylene oxide trimer acid (HFPO-TA) causes hepatotoxicity, however, its underlying mechanisms have not been conclusively determined. We investigated the effects of HFPO-TA on mice liver after 28 days of orally administered 0 or 0.5 mg/kg/d HFPO-TA. Administration of HFPO-TA induced mitochondrial ROS (mtROS) overexpression, cGAS-STING signaling activation, pyroptosis and fibrosis in mice liver. To determine the HFPO-TA-associated hepatotoxic mechanisms, mtROS, cGAS-STING signaling and pyroptosis intervention assays were performed in HFPO-TA-exposed mice liver. First, mtROS was found to be an upstream regulatory target of cGAS-STING signaling, pyroptosis and fibrosis. Second, cGAS-STING signaling was established to be an upstream regulatory mechanism of pyroptosis and fibrosis. Finally, pyroptosis was shown to regulate fibrosis. The above results confirm that HFPO-TA causes mice liver fibrosis via mtROS/cGAS-STING/NLRP3-mediated pyroptosis. [Display omitted] • HFPO-TA induced mitochondrial damage and mtROS overproduction in mice liver. • HFPO-TA induced cGAS-STING signaling activation. • NLRP3-mediated pyroptosis and fibrosis were observed in HFPO-TA-exposed mice liver. • HFPO-TA caused mice liver fibrosis via mtROS/cGAS-STING/NLRP3-mediated pyroptosis. [ABSTRACT FROM AUTHOR]

Bone morphogenetic protein-2 (BMP-2)/Smad signaling pathway plays an important role in regulating osteoblast (OB) differentiation. OB differentiation is a key process of bone formation. Aluminum (Al) exposure inhibits bone formation and causes Al-induced bone disease. However, the mechanism is not fully understood. To investigate whether BMP-2/Smad signaling pathway is associated with OB differentiation in aluminum trichloride (AlCl 3 )-treated OBs, the primary rat OBs were cultured and exposed to 0 (control group, CG), 1/40 IC 50 (low-dose group, LG), 1/20 IC 50 (mid-dose group, MG), and 1/10 IC 50 (high-dose group, HG) of AlCl 3 for 24 h, respectively. We found that the expressions of OB differentiation markers (Runx-2, Osterix and ALP) and BMP-2/Smad signaling pathway components (BMP-2, BMPR-IA, p-BMPR-IA, BMPR-II, p-Smad1/5/8 and p-Smad1/5/8/4) were all decreased in AlCl 3 -treated OBs compared with the CG. These results indicated that inhibition of OB differentiation by AlCl 3 was associated with inhibition of BMP-2/Smad pathway component expression. Our findings provide a novel insight into the mechanism of AlCl 3 -induced bone disease. [ABSTRACT FROM AUTHOR]

Aluminum (Al) is a food pollutant that has extensive deleterious effects on the liver. Our previous research proposed that E3 ubiquitin ligase PARK2 knockout (Parkin−/-) could aggravate Al-induced liver damage by inhibiting mitophagy, during which the reactive oxygen species (ROS) content increases. Inhibition of mitophagy can activate inflammasome. But the link between Parkin-mediated mitophagy and liver inflammatory injury caused by Al, and the role of ROS in it remain unclear. In this study, we applied Al, Parkin−/- and N-acetyl-L-cysteine (NAC) to act on C57BL/6N mice to investigate them. We found that Al could induce liver inflammatory injury and Parkin−/- could aggravate it. Meanwhile, inhibition of ROS alleviated oxidative stress, mitochondrial damage, mitophagy and inflammatory injury caused by Al in Parkin−/- mice liver. These results indicated that ROS antagonized the protection of Parkin-mediated mitophagy against Al-induced liver inflammatory damage in mice. [Display omitted] • Parkin−/- aggravates Al-induced liver inflammatory injury. • Inhibition of ROS suppresses Al-induced oxidative stress in Parkin−/- mice. • Inhibition of ROS alleviates Al-induced mitochondrial damage in Parkin−/- mice. • Inhibition of ROS down-regulates Al-induced mitophagy level in Parkin−/- mice. • Inhibition of ROS attenuates Al-induced inflammatory injury in Parkin−/- mice. [ABSTRACT FROM AUTHOR]

T-2 toxin can cause mitochondrial impairment and subsequent renal damage. PINK1/Parkin-mediated mitophagy can mitigate renal impairment by alleviating mitochondrial damage. Nevertheless, the impact of PINK1/Parkin-mediated mitophagy in T-2 toxin-induced renal injury remains unclear. Here, we studied the role of PINK1/Parkin-mediated mitophagy in T-2 toxin-induced nephrotoxicity. Mitochondrial damage was accompanied by NLRP3-inflammasome activation and PINK1/Parkin-mediated mitophagy in the kidney of T-2 toxin-exposed C57BL/6N mice. Knocking out Parkin inhibited the mitophagy but aggravated the structural and functional damage, NLRP3-inflammasome activation, mitochondrial damage, and apoptosis. Correlation analysis revealed that NLRP3-inflammasome activation was correlated with apoptosis. These results show that PINK1/Parkin-mediated mitophagy mitigates T-2 toxin-induced nephrotoxicity. [Display omitted] • T-2 toxin activated NLRP3 inflammasome and PINK1/Parkin-mediated mitophagy in kidney. • The induced apoptosis involved NLRP3-inflammasome activation. • PINK1/Parkin-mediated mitophagy mitigated T-2 toxin-induced nephrotoxicity. [ABSTRACT FROM AUTHOR]

Aflatoxin B 1 (AFB 1) can cause oxidative stress leading to mitochondrial damage and subsequent liver injury. Although it is well-known that damaged mitochondria are eliminated by PINK1/Parkin-mediated mitophagy, this mechanism has not yet been characterized in the context of AFB 1 -induced liver injury. In this study, male wild-type C57BL/6N mice were divided into groups 1–4, which were then orally administered 0, 0.5, 0.75, and 1 mg/kg body weight AFB 1 for 28 d, respectively. Our results demonstrated that oxidative stress, NLRP3-inflammasome activation, and mitochondrial damage were dose-dependently augmented in AFB 1 -induced liver injury. Additionally, PINK1/Parkin-mediated mitophagy peaked in the groups that had received a mid-dose of AFB 1 (0.75 mg/kg), which was attenuated slightly in high-dose groups. Afterward, we further characterized AFB 1 -induced liver injury by comparing wild-type C57BL/6N mice with Parkin knockout (Parkin-/-) mice. We found that the restricted mitophagy in Parkin-/- mice was associated with increased oxidative stress, NLRP3-inflammasome activation, mitochondrial damage, and liver injury. Taken together, these results indicate that PINK1/Parkin-mediated mitophagy plays an important role in attenuating AFB 1 -induced liver injury in mice. [Display omitted] • Hepatic NLRP3 inflammasomes are activated during AFB 1 -induced liver injury in mice. • AFB 1 activates PINK1/Parkin-mediated mitophagy in the mouse liver. • Parkin deficiency augments the AFB 1 -induced hepatic NLRP3-inflammasome activation. • PINK1/Parkin-mediated mitophagy attenuates AFB 1 -induced liver injury. [ABSTRACT FROM AUTHOR]

Aluminum (Al) is known to be hepatotoxic. Oxidative stress is the main mechanism of liver injury caused by Al, and can also lead to mitochondrial damage. Mitochondrial damage is a prerequisite for mitochondrial quality control (MQC) dysregulation. Parkin can activate MQC and maintain mitochondrial homeostasis. However, the role of Parkin-mediated MQC in Al-induced liver damage has not been elucidated. In this study, forty male wild type (WT) C57BL/6N mice were treated with 0, 44.825, 89.65 or 179.3 mg/kg body weight AlCl 3 in drinking water for 90 days, respectively. We found that Al induced mitophagy and disrupted mitochondrial dynamics and mitochondrial biogenesis. Then, twenty male WT C57BL/6N mice and twenty male Parkin knockout (Parkin−/-) C57BL/6N mice were divided into four groups and treated with 0, 89.65, 0, 89.65 mg/kg body weight AlCl 3 in drinking water for 90 days, respectively. We found that Parkin−/- inhibited mitophagy and further disrupted mitochondrial dynamics and mitochondrial biogenesis. These results indicated that Parkin-mediated MQC could be disrupted by Al and protected against Al-induced liver damage. [Display omitted] • MQC dysregulation is involved in liver damage caused by Al. • Deficiency of Parkin exacerbates liver damage caused by Al. • Deficiency of Parkin exacerbates oxidative stress in liver damage caused by Al. • Deficiency of Parkin exacerbates mitochondrial damage in liver damage caused by Al. • Deficiency of Parkin disturps MQC in liver damage caused by Al. [ABSTRACT FROM AUTHOR]

Aluminum (Al), as a common environmental pollutant, causes osteoblast (OB) dysfunction and then leads to Al-related bone diseases (ARBD). One of the mechanisms of ARBD is oxidative stress, which leads to an increase in the production of reactive oxygen species (ROS). ROS can induce mitochondrial damage, thereby inducing mitophagy and apoptosis. But whether mitophagy and apoptosis mediated by ROS, and the role of ROS in AlCl 3 -induced MC3T3-E1 cell dysfunction is still unclear. In this study, MC3T3-E1 cells used 0 mM Al (control group), 2 mM Al (Al group), 5 mM N-acetyl cysteine (NAC) (NAC group), 2 mM Al and 5 mM NAC (Al + NAC group) for 24 h. We found AlCl 3 -induced MC3T3-E1 cell dysfunction accompanied by oxidative stress, apoptosis, and mitophagy. While NAC, a ROS scavenger treatment, restored cell function and alleviated the mitophagy and apoptosis. These results suggested that mitophagy and apoptosis mediated by ROS participate in AlCl 3 -induced MC3T3-E1 cell dysfunction. [Display omitted] ● Aluminum (Al) can cause dysfunction in MC3T3-E1 cell. ● Al can cause oxidative stress in MC3T3-E1 cell. ● Al induced ROS-mediated mitophagy in MC3T3-E1 cell. ● Al induced ROS-mediated apoptosis in MC3T3-E1 cell. ● Mitophagy and apoptosis mediated by ROS participate in Al-induced MC3T3-E1 cell dysfunction. [ABSTRACT FROM AUTHOR]

T-2 toxin is an inevitable environmental and grain pollutant, which can cause kidney damage, but the mechanism is not clear. In this study, male mice were administered with T-2 toxin at 0, 0.5, 1.0, 2.0 mg/kg body weight (BW) for 28 days. We found that T-2 toxin induced renal structural damage, downregulated BW and kidney coefficient, impaired renal function accompanied by oxidative stress and apoptosis. Meanwhile, T-2 toxin increased nuclear Nrf2 protein expression and the mRNA expressions of its downstream target genes. The correlation analysis indicated that apoptosis and Nrf2 pathway were positively correlated with oxidative stress. These results suggested that the nephrotoxicity of T-2 toxin in mice caused by oxidative stress-mediated apoptosis is related to Nrf2 pathway. Image 1 [ABSTRACT FROM AUTHOR]

Aflatoxin B 1 (AFB 1) is an unavoidable food and environmental contaminant, which can lead to disorders in spermatogenesis and its mechanism remains unclear. The blood-testis barrier (BTB) is responsible for ensuring normal spermatogenesis in testes. Therefore, we hypothesized that disruption of the BTB was involved in AFB 1 -induced spermatogenesis disorders. To confirm our hypothesis, male Kunming mice were orally gavaged AFB 1 (0, 0.375, 0.75, or 1.5 mg/kg) for 30 days. Primarily, we first proved that AFB 1 disrupted the BTB integrity. Then, AFB 1 decreased BTB-related junction protein expression and elevated Sertoli cell apoptosis, which were associated with oxidative stress. Additionally, AFB 1 upregulated the p-p38 MAPK/p38 MAPK ratio. These results collectively indicated that AFB 1 disrupted the BTB via reducing the expression of BTB-related junction protein and promoting apoptosis in mice testes, which were associated with the oxidative stress-mediated p38 MAPK signaling pathway. AFB 1 has testicular toxicity, and eventually leads to spermatogenesis disorder. The BTB is a physical barrier in testes for maintaining spermatogenesis. Our study manifested that AFB 1 disrupted BTB via reducing BTB-related junction proteins expression and promoting cell apoptosis in mice testes, which were associated with oxidative stress-mediated p38 MAPK signaling pathway, and providing a novel mechanism of reproductive toxicity induced by AFB 1. Image 1 • Aflatoxin B1 disrupts blood-testis barrier (BTB) integrity in mice testes. • Aflatoxin B1 disrupts BTB by reducing BTB-related junction protein expression. • Aflatoxin B1 disrupts BTB by promoting apoptosis. • Aflatoxin B1 disrupts BTB are associated with the p38 MAPK signaling pathway. [ABSTRACT FROM AUTHOR]

The natural carotenoid lycopene (LYC) has strong antioxidant and neuroprotective capacities. This study investigated the effects and mechanisms of LYC on chronic stress-induced hippocampal lesions and learning and memory dysfunction. Rats were administered LYC and/or chronic restraint stress (CRS) for 21 days. Morris water maze results demonstrated that LYC prevented CRS-induced learning and memory dysfunction. Histopathological staining and transmission electron microscopy observation revealed that LYC ameliorated CRS-induced hippocampal microstructural and ultrastructural damage. Furthermore, LYC alleviated CRS-induced oxidative stress by reducing reactive oxygen species (ROS) production and enhancing antioxidant enzyme activities. LYC also improved CRS-induced hippocampal mitochondrial dysfunction by recovering mitochondrial membrane potential, and complex I (NADH dehydrogenase) and II (succinate dehydrogenase) activities. Moreover, LYC reduced CRS-induced apoptosis via the mitochondrial apoptotic pathway, and decreased the number of terminal deoxynucleotidyl transferase dUTP nick-end-labeled positive cells. Additionally, western blot analysis demonstrated that LYC inhibited CRS-induced activation of the c-Jun N-terminal kinase (JNK) signaling pathway. Correlation analysis indicated that ROS levels, JNK activation, and the mitochondrial apoptotic pathway were positively correlated. Further investigation of the underlying mechanisms revealed that the ROS scavenger N-acetyl-l-cysteine inhibited CRS-induced JNK activation. Furthermore, the JNK inhibitor SP600125 relieved CRS-induced hippocampal mitochondrial dysfunction, apoptosis via the mitochondrial apoptotic pathway, and learning and memory dysfunction. Together, these results suggest that LYC alleviates hippocampal oxidative stress, mitochondrial dysfunction, and apoptosis by inhibiting the ROS/JNK signaling pathway, thereby improving CRS-induced hippocampal injury and learning and memory dysfunction. This study provides a theoretical basis and new therapeutic strategies for the application of LYC to relieve chronic stress encephalopathy. Image 1 • LYC has anti-chronic stress properties. • LYC alleviated chronic stress-induced oxidative stress and apoptosis in hippocampus. • LYC inhibited chronic stress-induced apoptosis via ROS/JNK signaling pathway. [ABSTRACT FROM AUTHOR]