Cadmium promotes nonalcoholic fatty liver disease by inhibiting intercellular mitochondrial transfer.

Mitochondrial transfer regulates intercellular communication, and mitochondria regulate cell metabolism and cell survival. However, the role and mechanism of mitochondrial transfer in Cd-induced nonalcoholic fatty liver disease (NAFLD) are unclear. The present study shows that mitochondria can be transferred between hepatocytes via microtubule-dependent tunneling nanotubes. After Cd treatment, mitochondria exhibit perinuclear aggregation in hepatocytes and blocked intercellular mitochondrial transfer. The different movement directions of mitochondria depend on their interaction with different motor proteins. The results show that Cd destroys the mitochondria-kinesin interaction, thus inhibiting mitochondrial transfer. Moreover, Cd increases the interaction of P62 with Dynactin1, promotes negative mitochondrial transport, and increases intracellular lipid accumulation. Mitochondria and hepatocyte co-culture significantly reduced Cd damage to hepatocytes and lipid accumulation. Thus, Cd blocks intercellular mitochondrial transfer by disrupting the microtubule system, inhibiting mitochondrial positive transport, and promoting their negative transport, thereby promoting the development of NAFLD.

Zearalenone damages the male reproductive system of rats by destroying testicular focal adhesion.

Zearalenone (ZEA), a common mycotoxin in animal feed, is harmful to public health and causes huge economic losses. The potential target proteins of ZEA and its derivatives were screened using the PharmMapper database and the related genes (proteins) of the testis were obtained from Genecards. We obtained 144 potential targets of ZEA and its derivatives related to the testis using Venn diagrams. The PPI analysis showed that ZEA had the most targets in testis, followed by ZAN, α-ZAL, ß-ZEL, α-ZEL, and ß-ZAL. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses evaluated the metabolic and cancer pathways. We further screened four hub genes: RAC3, CCND1, EP300, and CTNNB1. Eight key biological processes were obtained by GO analysis, and four important pathways were identified by KEGG analysis. Animal and cell experimental results confirmed that ZEA could inhibit the expression of four key KEGG pathway protein components and four hub proteins that interfere with cell adhesion by inhibiting the focal adhesion structure of the testis, Leydig cells, and Sertoli cells. Collectively, our findings reveal that the destruction of the focal adhesion structure in the testis is the mechanism through which ZEA damages the male reproductive system.

Polystyrene nanoplastics aggravate reproductive system damage in obese male mice by perturbation of the testis redox homeostasis.

The potential impact of the combination of a high-fat diet (HFD) and polystyrene nanoplastics (PS-NPs) on fertility cannot be ignored, especially when the fertility rate is declining. However, it has not attracted considerable attention. In this study, an obese mouse model was established using an HFD, and the reproductive function of male mice was evaluated after intragastric administration of 100 µL of a 10 mg/mL PS-NP suspension for 4 weeks. By determining the morphology and vitality of sperm and related indicators of testosterone production, it was found that PS-NPs aggravated the destruction of sperm mitochondrial structure, decrease sperm activity, and testosterone production in HFD-fed mice. To comprehensively analyze the injury mechanism, the integrity of the blood testicular barrier (BTB) and the function of Leydig and Sertoli cells were further analyzed. It was found that PS-NPs could destroy BTB, promote the degeneration of Leydig cells, reduce the number of Sertoli cells, and decrease lactate secretion in HFD-fed mice. PS-NPs further interfered with redox homeostasis in the testicular tissues of HFD-fed mice. This study found that PS-NPs could aggravate the damage to the reproductive system of obese male mice by further perturbing its redox homeostasis and revealed the potential health risk of PS-NPs exposure under an HFD.

Cadmium induces mitochondrial dysfunction via SIRT1 suppression-mediated oxidative stress in neuronal cells.

Cadmium is a widespread environmental contaminant and its neurotoxicity has raised serious concerns. Mitochondrial dysfunction is a key event in Cd-induced nervous system disease; however, the exact molecular mechanism involved has not been fully elucidated. Increasing evidences have shown that Sirtuin 1 (SIRT1) is the key target protein impaired in Cd-induced mitochondrial dysfunction. In this study, the role of SIRT1 in Cd-induced mitochondrial dysfunction and cell death and the underlying mechanisms were evaluated in vitro using PC12 cells and primary rat cerebral cortical neurons. The results showed that Cd exposure caused cell death by inhibiting SIRT1 expression, thus inducing oxidative stress and mitochondrial dysfunction in vitro. However, inhibition of oxidative stress by the antioxidant puerarin alleviated Cd-induced mitochondrial dysfunction. Furthermore, activation of SIRT1 using the agonist Srt1720 significantly abolished Cd-induced oxidative stress and mitochondrial dysfunction and ultimately alleviated Cd-induced neuronal cell death. Collectively, our data indicate that Cd induced mitochondrial dysfunction via SIRT1 suppression-mediated oxidative stress, leading to the death of PC12 cells and primary rat cerebral cortical neurons. These findings suggest a novel mechanism for Cd-induced neurotoxicity.

Polystyrene exacerbates cadmium-induced mitochondrial damage to lung by blocking autophagy in mice.

Cadmium (Cd) is an environmental heavy metal, and its accumulation is harmful to animal and human health. The cytotoxicity of Cd includes oxidative stress, apoptosis, and mitochondrial histopathological changes. Furthermore, polystyrene (PS) is a kind of microplastic piece derived from biotic and abiotic weathering courses, and has toxicity in various aspects. However, the potential mechanism of action of Cd co-treated with PS is still poorly unclear. The objective of this study was to investigate the effects of PS on Cd-induced histopathological injury of mitochondria in the lung of mice. In this study, the results have showed that Cd could induce the activity of oxidative enzymes of the lung cells in mice, increasing the content of partial microelement and the phosphorylation of inflammatory factor NF-κB p65. Cd further destroys the integrity of mitochondria by increasing the expression of apoptotic protein and blocking the autophagy. In addition, PS solely group aggravated the lung damage in mice, especially mitochondrial toxicity, and played a synergistic effect with Cd in lung injury. However, how PS can augment mitochondrial damage and synergism with Cd in lung of mice requiring further exploration. Therefore, PS was able to exacerbate Cd-induced mitochondrial damage to the lung in mice by blocking autophagy, and was associated with the apoptosis.

Polystyrene Microplastics Induce Oxidative Stress in Mouse Hepatocytes in Relation to Their Size.

Microplastics have become a new type of environmental pollutant that can accumulate in various tissues and organs of the body and cause chronic damage. In this study, two different size polystyrene microplastics (PS-MPs, 5 µm and 0.5 µm) exposure models were established in mice to investigate the effects of PS-MPs with different particle sizes on oxidative stress in the liver. The results showed that PS-MPs exposure caused a decrease in body weight and liver-to-body weight. The hematoxylin and eosin staining and transmission electron microscopy results showed that exposure to PS-MPs led to the disorganized cellular structure of liver tissue, nuclear crinkling, and mitochondrial vacuolation. The extent of damage in the 5 µm PS-MP exposure group was more extensive when compared with the other group. The evaluation of oxidative-stress-related indicators showed that PS-MPs exposure exacerbated oxidative stress in hepatocytes, especially in the 5 µm PS-MPs group. The expression of oxidative-stress-related proteins sirtuin 3(SIRT3) and superoxide dismutase (SOD2) was significantly reduced, and the reduction was more pronounced in the 5 µm PS-MPs group. In conclusion, PS-MPs exposure led to oxidative stress in mouse hepatocytes and caused more severe damage in the 5 µm PS-MPs group when compared with the 0.5 µm PS-MPs group.

Puerarin Prevents Cadmium-Induced Neuronal Injury by Alleviating Autophagic Dysfunction in Rat Cerebral Cortical Neurons.

Autophagic dysfunction is one of the main mechanisms of cadmium (Cd)-induced neurotoxicity. Puerarin (Pue) is a natural antioxidant extracted from the medicinal and edible homologous plant Pueraria lobata. Studies have shown that Pue has neuroprotective effects in a variety of brain injuries, including Cd-induced neuronal injury. However, the role of Pue in the regulation of autophagy to alleviate Cd-induced injury in rat cerebral cortical neurons remains unclear. This study aimed to elucidate the protective mechanism of Pue in alleviating Cd-induced injury in rat cerebral cortical neurons by targeting autophagy. Our results showed that Pue alleviated Cd-induced injury in rat cerebral cortical neurons in vitro and in vivo. Pue activates autophagy and alleviates Cd-induced autophagic blockade in rat cerebral cortical neurons. Further studies have shown that Pue alleviates the Cd-induced inhibition of autophagosome-lysosome fusion, as well as the inhibition of lysosomal degradation. The specific mechanism is related to Pue alleviating the inhibition of Cd on the expression levels of the key proteins Rab7, VPS41, and SNAP29, which regulate autophagosome-lysosome fusion, as well as the lysosome-related proteins LAMP2, CTSB, and CTSD. In summary, these results indicate that Pue alleviates Cd-induced autophagic dysfunction in rat cerebral cortical neurons by alleviating autophagosome-lysosome fusion dysfunction and lysosomal degradation dysfunction, thereby alleviating Cd-induced neuronal injury.

Fusarium Mycotoxins Zearalenone and Deoxynivalenol Reduce Hepatocyte Innate Immune Response after the Listeria monocytogenes Infection by Inhibiting the TLR2/NFκB Signaling Pathway.

Zearalenone (ZEA) and deoxynivalenol (DON) are two common mycotoxins produced by the genus Fusarium and have potential immunotoxic effects that may lead to a weak immune response against bacterial infections. Listeria monocytogenes (L. monocytogenes), a food-borne pathogenic microorganism ubiquitous in the environment, actively multiplies in the liver, where hepatocytes are capable of resistance through mediated innate immune responses. At present, it is not clear if ZEA and DON affect hepatocyte immune responses to L. monocytogenes infection or the mechanisms involved. Therefore, in this study, in vivo and in vitro models were used to investigate the effects of ZEA and DON on the innate immune responses of hepatocytes and related molecules after L. monocytogenes infection. In vivo studies revealed that ZEA and DON inhibited the toll-like receptors 2 (TLR2)/nuclear factor kappa-B (NFκB) pathway in the liver tissue of L. monocytogenes-infected mice, downregulating the expression levels of Nitric oxide (NO), in the liver and repressing the immune response. In addition, ZEA and DON inhibited Lipoteichoic acid (LTA)-induced expression of TLR2 and myeloid differentiation factor 88 (MyD88) in Buffalo Rat Liver (BRL 3A) cells in vitro, downregulating the TLR2/NFκB signaling pathway and resulting in the decreased expression levels of NO, causing immunosuppressive effects. In summary, ZEA and DON can negatively regulate NO levels through TLR2/NFκB, inhibiting the innate immune responses of the liver, and aggravate L. monocytogenes infections in mouse livers.

Taurine Alleviates Cadmium-Induced Hepatotoxicity by Regulating Autophagy Flux.

Our previous studies have confirmed that cadmium (Cd) exposure causes hepatotoxicity; it also induces autophagy and blocks the autophagy flux. Therefore, we hypothesized that Cd hepatotoxicity could be alleviated through nutritional intervention. Taurine (Tau) has various biological functions such as acting as an antioxidant, acting as an anti-inflammatory, and stabilizing cell membranes. In order to explore the protective effect and internal mechanism of Tau on Cd-induced hepatotoxicity, normal rat liver cell line BRL3A cells were treated with Cd alone or in combination with Tau to detect cell injury and autophagy-related indexes in this study. We found that Tau can alleviate Cd-induced cell-proliferation decline and morphological changes in the cell. In addition, Tau activates autophagy and alleviates the blockage of Cd-induced autophagy flux. In this process, lysosome acidification and degradation were enhanced, and autophagosomes were further fused with lysosomes. Then, we found that Tau alleviated autophagic flux block by promoting the transfer of membrane fusion proteins STX17 and SNAP29 to autophagosomes and the translocation of VAMP8 to lysosomes, which in turn attenuated the hepatocyte injury induced by Cd exposure. This will further reveal the hepatotoxicity mechanism of Cd and provide the theoretical basis for the prevention and treatment of Cd poisoning.

Ca2+ transfer via the ER-mitochondria tethering complex in neuronal cells contribute to cadmium-induced autophagy.

Mitochondrial-associated endoplasmic reticulum (ER) membranes (MAMs) play a key role in several physiological functions, including calcium ion (Ca2+) transfer and autophagy; however, the molecular mechanism controlling this interaction in cadmium (Cd)-induced neurotoxicity is unknown. This study shows that Cd induces alterations in MAMs and mitochondrial Ca2+ levels in PC12 cells and primary neurons. Ablation or silencing of mitofusin 2 (Mfn2) in PC12 cells or primary neurons blocks the colocalization of ER and mitochondria while reducing the efficiency of mitochondrial Ca2+ uptake. Moreover, Mfn2 defects reduce interactions or colocalization between GRP75 and VDAC1. Interestingly, the enhancement of autophagic protein levels, colocalization of LC3 and Lamp2, and GFP-LC3 puncta induced by Cd decreased in Mfn2-/- or Grp75-/- PC12 cells and Mfn2- or Grp75-silenced primary neurons. Notably, the specific Ca2+ uniporter inhibitor RuR blocked both mitochondrial Ca2+ uptake and autophagy induced by Cd. Finally, this study proves that the mechanism by which IP3R-Grp75-VDAC1 tethers in MAMs is associated with the regulation of autophagy by Mfn2 and involves their role in mediating mitochondrial Ca2+ uptake from ER stores. These results give new evidence into the organelle metabolic process by demonstrating that Ca2+ transport between ER-mitochondria is important in autophagosome formation in Cd-induced neurodegeneration.

Beclin 1 positively regulates osteoprotegerin-induced inhibition of osteoclastogenesis by increasing autophagy in vitro.

Osteoclastogenesis is induced by receptor activator of nuclear factor-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF), and can be suppressed by osteoprotegerin (OPG). Beclin1 has a dual role in osteoclastogenesis. However, the role of Beclin1-mediated autophagy during OPG-induced inhibition of osteoclastogenesis remains unclear. Here, we found that Beclin1 and matrix metalloproteinase 9 (MMP-9) expression were increased during osteoclastogenesis. OPG (20, 40, and 80 ng/mL) decreased Src and MMP-9 expression, but augmented Beclin1 expression and fluorescence intensity. Similarly, treatment with the autophagy activator rapamycin increased Beclin1 expression during OPG-induced inhibition of osteoclastogenesis. Further, Beclin1 knockdown restored osteoclast numbers by reducing autophagy during OPG-induced inhibition of osteoclastogenesis. These results indicate that Beclin1 has a positive role during OPG-induced inhibition of osteoclastogenesis by regulating autophagy, which might provide a potential basis for osteoclastogenesis.

Puerarin alleviates cadmium-induced mitochondrial mass decrease by inhibiting PINK1-Parkin and Nix-mediated mitophagy in rat cortical neurons.

Cadmium (Cd) has well-known central nervous system toxicity, and mitochondria are direct targets of Cd-induced neuronal toxicity. However, how Cd induces mitochondrial mass decrease in terms of its neurotoxic effects remains unknown. Puerarin, an isoflavone extracted from kudzu root, can cross the blood-brain barrier and exert protective effects in nervous system disease. The purpose of the study was to determine the mechanism of Cd-induced mitochondrial mass decrease and the protective role of puerarin in rat cortical neurons. The results indicated that Cd induced mitochondrial mass decrease by activating mitophagy mediated by the PTEN-induced putative kinase protein 1 (PINK1)-E3 ubiquitin ligase (Parkin) and Nip3-like protein X (Nix) pathways in rat cortical neurons. Puerarin improved the Cd-induced decrease in mitochondrial membrane potential (MMP) in vitro, and blocked PINK1-Parkin and Nix-mediated mitophagy, inhibiting Cd-induced mitochondrial mass decrease in rat cortical neurons in vitro and in vivo. In summary, our data clearly indicated that puerarin protects rat cortical neurons against Cd-induced neurotoxicity by ameliorating mitochondrial damage, inhibiting mitophagy-mediated mitochondrial mass decrease. Puerarin appears to have great potential as a neuroprotective agent.

ZEA and DON inhibited inflammation after L. monocytogenes infection and induced ribosomal hyperfunction.

The complex microbial community in food environment is a major problem of human or animal health and safety. Mycotoxins and food-borne bacteria can both induce inflammation in the body and cause a series of changes in biological functions. In this study, mice were gavaged with low doses of ZEA, DON, or ZEA + DON, and then infected with L. monocytogenes. A cytokine microarray, including 40 inflammation-related serum cytokines, and proteomics were used to verify the effects of ZEA, DON, and ZEA + DON on the host inflammation and biological function after L. monocytogenes infection. The results showed that mononucleosis after bacterial infection was inhibited by ZEA, DON, and ZEA + DON, while the balance of macrophage differentiation was shifted toward M2-type. ZEA, DON, and ZEA + DON decreased the levels of serum proinflammatory cytokines IL-1ß and IL-12 after infection. In addition, the signal of the NF-κB pathway was inhibited. Proteomic results showed that ZEA, DON, and ZEA + DON led to biological dysfunction in ribosomal and metabolic cells, primarily leading to abnormal ribosomal hyperfunction. This study showed that ZEA, DON, and ZEA + DON can aggravate disease progression by inhibiting the inflammatory response following foodborne bacterial infection. These metabolites may also disrupt normal biological functions, which may lead to ribosomal hyperfunction, making bacterial clearance more difficult.

PINK1/Parkin-mediated mitophagy modulates cadmium-induced apoptosis in rat cerebral cortical neurons.

Cadmium is a persistent environmental pollutant whose neurotoxicity is of serious concern. Mitochondrial dysfunction and its mediated mitophagy and apoptosis are considered key events in Cd-induced neurological pathologies, but the exact molecular mechanism has not been fully elucidated. The aim of this study was to investigate the relationship between Cd-induced mitophagy and apoptosis and their role in Cd-induced neuronal death. Using the mitophagy inhibitor cyclosporine A (CsA), we found that the extent of mitophagy mediated by the PTEN-induced putative kinase protein 1 (PINK1)/E3 ubiquitin ligase (Parkin) pathway decreased, whereas the level of apoptosis and cell death increased in rat cerebral cortical neurons in vitro. Consistent with this, the knockdown of PINK1 also exacerbated Cd-induced apoptosis and neuronal death. Furthermore, the results of the in vivo experiments showed that Cd simultaneously activated both mitophagy and apoptosis and that the suppression of mitophagy by CsA aggravated Cd-induced apoptosis. In summary, our results indicate that PINK1/Parkin-mediated mitophagy exerts an important neuroprotective effect by inhibiting Cd-mediated apoptosis in rat cerebral cortical neurons both in vitro and in vivo. This work may allow the development of new therapeutic strategies for Cd-induced central nervous system disorders.

Puerarin alleviates cadmium-induced rat neurocyte injury by alleviating Nrf2-mediated oxidative stress and inhibiting mitochondrial unfolded protein response.

Cadmium (Cd) is a highly neurotoxic environmental pollutant. Puerarin (Pur) is a natural antioxidant isolated from Kudzu root that exhibits a powerful neuroprotective effect. Herein, we illustrated the mechanism underlying the protective effect of Pur on Cd-induced rat neurocyte injury in an in vivo rat model as well as in vitro using PC12 cells and primary rat cerebral cortical neurons. First, the results showed that Pur alleviated Cd-induced cerebral cortical pathological damage and decreased the viability of neurocytes. Furthermore, Cd activated the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway, which plays a negative role in Cd-induced rat neurocyte injury. In addition, Pur alleviated Cd-induced oxidative stress by enhancing antioxidant defense, reducing reactive oxygen species (ROS) accumulation and lipid peroxidation, and inhibiting activation of the Nrf2 signaling pathway in rat neurocytes. Moreover, Pur inhibited the Cd-induced mitochondrial unfolded protein response (UPRmt) in rat neurocytes. Overall, Pur alleviated Cd-induced rat neurocyte injury by alleviating Nrf2-mediated oxidative stress and inhibiting UPRmt.

Puerarin alleviates cadmium-induced oxidative damage to bone by reducing autophagy in rats.

Autophagy is a regulatory mechanism involved in cadmium (Cd)-induced bone toxicity and is suppressed by various stimuli, including oxidative stress. Puerarin is an isoflavonoid compound isolated from Pueraria, a plant used in traditional Chinese medicine. The underlying mechanisms of action of puerarin remain unclear. The objective of this study was to explore the mitigating effects of puerarin on cadmium-induced oxidative damage in the bones of rats. Cadmium exposure increased oxidative damage in rat bones; this was markedly decreased by puerarin treatment, as demonstrated by changes in the activity of antioxidative enzymes. Cadmium-induced blockage of the expression of key bone regulatory proteins, autophagy-related markers, and signaling molecules was also alleviated by puerarin treatment. Additionally, cadmium reduced expression of the autophagic protein Rab7 and of late endosomal/lysosomal adaptor and MAPK and mTOR activator 1 (LAMTOR1); the decrease in these proteins was not restored by puerarin treatment. We speculate that puerarin relieves the inhibition of fusion of autophagosomes with lysosomes that is induced by cadmium; however, this specific effect of puerarin and downstream effects on bone regulatory mechanisms require further investigation. In conclusion, puerarin alleviates cadmium-induced oxidative damage in the bones of rats by attenuating autophagy, which is likely associated with the antioxidant activity of puerarin.

Gap junction intercellular communication mediates cadmium-induced apoptosis in hepatocytes via the Fas/FasL pathway.

As a common environmental pollutant, cadmium (Cd) causes damage to many organs of the body. Gap junction intercellular communication (GJIC) represents one of the most important routes of rapid signaling between cells. However, the mechanisms underlying GJIC's role in hepatotoxicity induced by Cd remain unknown. We established a Cd poisoning model in vitro by co-culturing Cd-exposed and unexposed hepatocytes and found that 18ß-glycyrrhetinic acid (GA), a GJIC inhibitor, can effectively reduce the apoptosis rate of healthy cells co-cultured with apoptotic cells treated with Cd. We also found that anti-FasL antibody had the same effect. However, in mono-cultured cells, GA treatment in combination with Cd was found to aggravate the damage induced by Cd exposure, increase the level of oxidative stress and protein expression of HO-1, decrease the mitochondrial membrane potential, incur more serious morphological damage to mitochondria than Cd treatment alone. Moreover, compared with Cd-only exposure, GA and Cd co-treatment further increased the expression levels of the apoptosis-related proteins Fas, FasL, FADD and the ratio of Bax/Bcl-2, inhibited the protein expression of ASK1 and Daxx. We also found that the protein expression of Daxx in siFADD + Cd hepatocytes was significantly higher than in Cd-treated cells. Thus, our study suggests that gap junction inhibition may play a dual role in Cd-induced cell damage by inhibiting the transmission of death signals from damaged cells to healthy cells but also aggravating the transmission of death signals between damaged cells, and that the Fas/FasL-mediated death receptor pathway may play an important role in this process.

Rat Hepatocytes Mitigate Cadmium Toxicity by Forming Annular Gap Junctions and Degrading Them via Endosome-Lysosome Pathway.

Gap junction protein connexin 43 (Cx43) plays a critical role in gap junction communication in rat hepatocytes. However, those located between hepatocytes are easily internalized following exposure to poisons. Herein, we investigated the potential of buffalo rat liver 3A (BRL 3A) cells to generate annular gap junctions (AGJs) proficient at alleviating cadmium (Cd) cytotoxic injury through degradation via an endosome-lysosome pathway. Our results showed that Cd-induced damage of liver microtubules promoted Cx43 internalization and increased Cx43 phosphorylation at Ser373 site. Furthermore, we established that Cd induced AGJs generation in BRL 3A cells, and AGJs were subsequently degraded through the endosome-lysosome pathway. Overall, our results suggested that Cx43 internalization and the generation of AGJs were cellular protective mechanisms to alleviate Cd toxicity in rat hepatocytes.

Microplastics Exacerbate Cadmium-Induced Kidney Injury by Enhancing Oxidative Stress, Autophagy, Apoptosis, and Fibrosis.

Cadmium (Cd) is a potential pathogenic factor in the urinary system that is associated with various kidney diseases. Microplastics (MPs), comprising of plastic particles less than 5 mm in diameter, are a major carrier of contaminants. We applied 10 mg/L particle 5 µm MPs and 50 mg/L CdCl2 in water for three months in vivo assay to assess the damaging effects of MPs and Cd exposure on the kidney. In vivo tests showed that MPs exacerbated Cd-induced kidney injury. In addition, the involvement of oxidative stress, autophagy, apoptosis, and fibrosis in the damaging effects of MPs and Cd on mouse kidneys were investigated. The results showed that MPs aggravated Cd-induced kidney injury by enhancing oxidative stress, autophagy, apoptosis, and fibrosis. These findings provide new insights into the toxic effects of MPs on the mouse kidney.

Overexpression of c-Fos reverses osteoprotegerin-mediated suppression of osteoclastogenesis by increasing the Beclin1-induced autophagy.

Osteoclastogenesis requires the involvement of transcription factors and degrading enzymes, and is regulated by upstream and downstream signalling. However, c-Fos how regulates osteoclastogenesis through autophagy remain unclear. This study aimed to explore the role of c-Fos during osteoprotegerin (OPG)-mediated suppression of osteoclastogenesis. We found that the number of osteoclasts and the expression of c-Fos, MMP-9, CAⅡ, Src and p62 were decreased after treated with OPG, including attenuation the PI3K/Akt and the TAK1/S6 signalling pathways, but the expression of Beclin1 and LC3Ⅱ were increased. Knockdown of Beclin1 could reverse the expression of c-Fos and MMP-9 by activating the PI3K/Akt signalling pathway, but inhibiting the autophagy and the TAK1/S6 signalling pathway. In addition, inhibition of autophagy using the PI3K inhibitor LY294002 did not rescues OPG-mediated suppression of osteoclastogenesis, but caused reduction of the expression of c-Fos and CAⅡ by attenuating the autophagy, as well as the PI3K/Akt and the TAK1/S6 signalling pathways. Furthermore, continuous activation of c-Fos could reverse OPG-mediated suppression of osteoclastogenesis by activating the autophagy and the PI3K/Akt and the TAK1/S6 signalling pathways. Thus, overexpression of c-Fos could reverse OPG-mediated suppression of osteoclastogenesis via activation of Beclin1-induced autophagy, indicating c-Fos might serve as a new candidate for bone-related basic studies.