Publications by authors named "Zongping Liu"

113 Publications

Role of mitochondrial dysfunction and PINK1/Parkin-mediated mitophagy in Cd-induced hepatic lipid accumulation in chicken embryos.

Life Sci 2021 Nov 1;284:119906. Epub 2021 Sep 1.

Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, Jiangsu 225009, PR China; College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, Yangzhou, Jiangsu 225009, PR China. Electronic address:

The present study was performed to investigate the effects of Cd exposure on lipid metabolism and mitochondrial dysfunction and to explore the role of mitophagy in Cd-induced dysregulation of lipid metabolism in chicken embryo liver tissues and hepatocytes. To this end, seven-day-old chicken embryos were exposed to different concentrations of Cd for 7 days, and primary chicken embryo hepatocytes were treated with Cd at four different concentrations for 6 h. Furthermore, the mitophagy inhibitor cyclosporine A (CsA) was used to investigate the role of mitophagy in Cd-induced disruption of lipid metabolism. Lipid accumulation, the expression levels of genes involved in lipid metabolism, mitochondrial dysfunction, and mitophagy were measured. The results demonstrated that Cd exposure increases hepatic triglyceride (TG) accumulation and the expression levels of lipogenic genes while decreasing those of lipolytic genes. Furthermore, Cd exposure was observed to alter mitochondrial morphology in terms of reduced size, excessive mitochondrial damage, and the formation of mitophagosomes. The co-localization of lysosome-associated membrane glycoprotein 2 and LC3 puncta was significantly increased in primary chicken embryo hepatocytes after Cd exposure. Moreover, Cd exposure increased LC3, PINK1, and Parkin protein expression levels. CsA effectively alleviated Cd-induced mitochondrial dysfunction, blocked mitochondrial membrane potential collapse, and suppressed PINK1/Parkin-mediated mitophagy. Furthermore, CsA treatment reversed the Cd-induced TG accumulation in liver tissues but further increased it in hepatocytes. Taken together, our findings demonstrate (for the first time) the importance of mitochondrial dysfunction and mitophagy via the PINK1/Parkin pathway in Cd-induced disruption of lipid metabolism.
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http://dx.doi.org/10.1016/j.lfs.2021.119906DOI Listing
November 2021

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

Differentiation 2021 Sep-Oct;121:35-43. Epub 2021 Aug 23.

Institutes of Agricultural Science and Technology Development, Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, Yangzhou, 225009, Jiangsu, PR China; College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, Jiangsu, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009, Jiangsu, PR China; Jiangsu Key Laboratory of Zoonosis, Yangzhou, 225009, Jiangsu, PR China. Electronic address:

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.
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http://dx.doi.org/10.1016/j.diff.2021.08.003DOI Listing
August 2021

Zinc alleviates the heat stress of primary cultured hepatocytes of broiler embryos via enhancing the antioxidant ability and attenuating the heat shock responses.

Anim Nutr 2021 Sep 24;7(3):621-630. Epub 2021 Apr 24.

Poultry Mineral Nutrition Laboratory, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China.

Zinc (Zn) has been shown to attenuate the adverse effects of heat stress on broilers, but the mechanisms involving this process remain unclear. We aimed to investigate possible protective mechanisms of Zn on primary cultured hepatocytes of broiler embryos subjected to heat stress. Three experiments were conducted. In Exp. 1, hepatocytes were treated with 0, 50, 100, 200, or 400 μmol/L added Zn as inorganic Zn sulfate (iZn) for 12, 24 or 48 h. In Exp. 2, cells were exposed to 40 °C (a normal temperature [NT]) and 44 °C (a high temperature [HT]) for 1, 2, 4, 6, or 8 h. In Exp. 3, cells were preincubated with 0 or 50 μmol/L Zn as iZn or organic Zn lysine chelate (oZn) for 8 h under NT, and then incubated with the same Zn treatments under NT or HT for 4 or 6 h. The biomarkers of antioxidative status and heat stress in cells were measured. The results in Exp. 1 indicated that 50 μmol/L Zn and 12 h incubation were the optimal conditions for increasing antioxidant ability of hepatocytes. In Exp. 2, the 4 or 6 h incubation under HT was effective in inducing heat shock responses of hepatocytes. In Exp. 3, HT elevated ( < 0.01) malondialdehyde content and expressions of heat shock protein 70 () mRNA and protein, as well as 0 mRNA. However, Zn supplementation increased ( < 0.05) copper zinc superoxide dismutase (CuZnSOD) activity and metallothionein mRNA expression, and effectively decreased ( < 0.05) the expressions of 0 mRNA and protein, as well as 0 mRNA. Furthermore, oZn was more effective ( < 0.05) than iZn in enhancing CuZnSOD activity of hepatocytes under HT. It was concluded that Zn (especially oZn) could alleviate heat stress of broiler hepatocytes via enhancing their antioxidant ability and attenuating heat shock responses.
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http://dx.doi.org/10.1016/j.aninu.2021.01.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8334375PMC
September 2021

The epigenetic regulator BRD4 is involved in cadmium-triggered inflammatory response in rat kidney.

Ecotoxicol Environ Saf 2021 Aug 13;224:112620. Epub 2021 Aug 13.

College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, PR China; Jiangsu Key Laboratory of Zoonosis, Yangzhou, PR China. Electronic address:

Cadmium (Cd) has been described as a potential inflammatory inducer, while increasing evidence shows that inappropriate inflammation is a contributing factor to kidney injury. Hence, research on Cd-triggered inflammatory response is of great significance for elucidating the mechanism of Cd-induced nephrotoxicity. Bromodomain-containing 4 (BRD4) is an important epigenetic regulator involved in the development of many inflammatory diseases, but its regulatory roles in Cd-triggered inflammatory response remain to be clarified. Here, we found that treatment with Cd in Sprague-Dawley rats (2 mg/kg bw, i.p., 5 consecutive days) and in rat kidney cell line (NRK-52E, 0-10 μM, 12 h) induced the transcription of inflammatory cytokines, which could be reduced by JQ1 (BRD4 inhibitor, 25 mg/kg bw, i.p., 3 consecutive days in vivo; 0.5 μM, 12 h in vitro) or BRD4 small interfering RNA (siRNA, in vitro), suggesting that BRD4 participates in Cd-triggered inflammatory response. Next, our study clarified the roles of BRD4 in Cd-triggered inflammatory response. The inhibition of BRD4 decreased Cd-promoted NF-κB nuclear translocation and activation in vivo and in vitro. Cd increased the acetylation level of RelA K310 and enhanced BRD4 binding to acetylated NF-κB RelA in vivo and in vitro, which were abrogated by inhibiting BRD4. In summary, our study suggests that BRD4 is involved in Cd-triggered transcription of inflammatory cytokines by mediating the activation of NF-κB signaling pathway and increasing itself binding to acetylated NF-κB RelA in rat kidney, therefore, BRD4 could be a potential therapeutic target for Cd-induced renal diseases.
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http://dx.doi.org/10.1016/j.ecoenv.2021.112620DOI Listing
August 2021

Quercetin and Allicin Can Alleviate the Hepatotoxicity of Lead (Pb) through the PI3K Signaling Pathway.

J Agric Food Chem 2021 Aug 9;69(32):9451-9460. Epub 2021 Aug 9.

College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, Jiangsu, China.

Lead (Pb) is a common toxic heavy metal pollutant in the environment that seriously endangers the health of animals. The liver is a key target organ affected by Pb toxicity. Plant extracts allicin and quercetin have a strong antioxidant capacity that can promote the excretion of heavy metals by improving the body's antioxidant defense and chelating heavy metal ions. To explore the preventive and therapeutic effects of allicin and quercetin on Pb poisoning in chickens, 96 chickens were randomly divided into eight groups: control, Pb, allicin, quercetin, allicin + quercetin, Pb + allicin, Pb + quercetin, and Pb + allicin + quercetin groups. The chickens were given feed containing the above treatments for 90 days. The results indicated that Pb can affect the growth and development of the liver, damage the circulatory system, destroy the structure of mitochondria and nuclei in liver cells, cause an imbalance in the oxidation system, inhibit PI3K protein, and activate the mitochondrial apoptotic pathway. Allicin and quercetin, alone or in combination, can improve the antioxidant capacity of the liver and alleviate liver tissue damage caused by Pb. In summary, allicin and quercetin could alleviate oxidative damage and apoptosis in the Pb-poisoned chicken liver through the PI3K signaling pathway, with stronger effects achieved by their combination.
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http://dx.doi.org/10.1021/acs.jafc.1c03794DOI Listing
August 2021

Puerarin Attenuates Cadmium-Induced Neuronal Injury via Stimulating Cadmium Excretion, Inhibiting Oxidative Stress and Apoptosis.

Biomolecules 2021 07 2;11(7). Epub 2021 Jul 2.

College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China.

Cadmium (Cd) is a potential pathogenic factor in the nervous system associated with various neurodegenerative disorders. Puerarin (Pur) is an isoflavone purified from the Chinese medical herb, kudzu root, and exhibits antioxidant and antiapoptotic properties in the brain. In this study, the detailed mechanisms underlying the neuroprotective potential of Pur against Cd-induced neuronal injury was evaluated for the first time in vivo in a rat model and in vitro using primary rat cerebral cortical neurons. The results of the in vivo experiments showed that Pur ameliorated Cd-induced neuronal injury, reduced Cd levels in the cerebral cortices, and stimulated Cd excretion in Cd-treated rats. We also observed that the administration of Pur rescued Cd-induced oxidative stress, and attenuated Cd-induced apoptosis by concomitantly suppressing both the Fas/FasL and mitochondrial pathways in the cerebral cortical neurons of rats both in vivo and in vitro. Our results demonstrate that Pur exerted its neuroprotective effects by stimulating Cd excretion, ameliorating Cd-induced oxidative stress and apoptosis in rat cerebral cortical neurons.
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http://dx.doi.org/10.3390/biom11070978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301907PMC
July 2021

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

Cell Biol Toxicol 2021 Jul 26. Epub 2021 Jul 26.

College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, People's Republic of China.

Mitochondrial-associated endoplasmic reticulum (ER) membranes (MAMs) play a key role in several physiological functions, including calcium ion (Ca) 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 Ca 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 Ca 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 Ca uniporter inhibitor RuR blocked both mitochondrial Ca 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 Ca uptake from ER stores. These results give new evidence into the organelle metabolic process by demonstrating that Ca transport between ER-mitochondria is important in autophagosome formation in Cd-induced neurodegeneration.
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http://dx.doi.org/10.1007/s10565-021-09623-yDOI Listing
July 2021

Zearalenone and deoxynivalenol reduced Th1-mediated cellular immune response after Listeria monocytogenes infection by inhibiting CD4 T cell activation and differentiation.

Environ Pollut 2021 Sep 5;284:117514. Epub 2021 Jun 5.

College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, Jiangsu, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009, Jiangsu, China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, Yangzhou, 225009, Jiangsu, China. Electronic address:

Based on the fact that mycotoxins and the food-borne bacteria coexist in the natural environment and pose a significant health hazard to humans and animals, it is important to investigate the immunosuppressive mechanism of ZEA (zearalenone), DON (deoxynivalenol), and their combination in bacterial infections. In this study, we established a mouse model of mycotoxin low-dose exposure combined with Listeria monocytogenes infection and investigated the effects of ZEA, DON and their combination on Th1-mediated anti-intracellular bacterial infection based on CD4 T cell activation and differentiation using both in vitro and in vivo analyses. The present study showed that both ZEA and DON aggravated Listeria monocytogenes infection in mice and affected the activation of CD4 T cells and Th1 differentiation, including the effects on costimulatory molecules CD28 and CD152 and on cross-linking of IL-12 and IL-12R, by inhibiting T cell receptor (TCR) signaling. When compared with ZEA, DON was found to have a greater impact on many related indicators. Surprisingly, the combined effects of ZEA and DON did not appear to enhance toxicity compared to treatment with the individual mycotoxins. Our findings more clearly revealed that exposure to low-dose ZEA and DON caused immunosuppression in the body by mechanisms including inhibition of CD4 T cells activation and reduction of Th1 cell differentiation, thus exacerbating infection of animals by Listeria monocytogenes.
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http://dx.doi.org/10.1016/j.envpol.2021.117514DOI Listing
September 2021

Ferulic acid inhibits LPS-induced apoptosis in bovine mammary epithelial cells by regulating the NF-κB and Nrf2 signalling pathways to restore mitochondrial dynamics and ROS generation.

Vet Res 2021 Jul 13;52(1):104. Epub 2021 Jul 13.

College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, China.

In bovine mammary epithelial cells (BMECs), a cascade of inflammatory reactions induced by lipopolysaccharide (LPS) has been shown to result in cell injury and apoptosis. The present study aims to reveal the protective effect of ferulic acid (FA) on LPS-induced BMEC apoptosis and explore its potential molecular mechanisms. First, we showed that FA had low cytotoxicity to BMECs and significantly decreased cell apoptosis and the proinflammatory response induced by LPS. Next, FA blocked LPS-induced oxidative stress by restoring the balance of the redox state and inhibiting mitochondrial dysfunction, the main contributor to LPS-induced apoptosis and ROS generation. Furthermore, the relief of inflammation and redox disturbance in the FA preconditioning group were accompanied by weaker NF-κB activation, enhanced Nrf2 activation and maintained cell viability compared to the LPS group. When BMECs were treated with FA alone, we observed that Nrf2 activation was induced before the inhibition of NF-κB activation and that the Keap1-Nrf2 relationship was disturbed. We concluded that FA prevented LPS-induced BMEC apoptosis by reversing the dominant relationship between NF-κB and Nrf2.
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http://dx.doi.org/10.1186/s13567-021-00973-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278735PMC
July 2021

Induction of mitochondrial apoptosis pathway mediated through caspase-8 and c-Jun N-terminal kinase by cadmium-activated Fas in rat cortical neurons.

Metallomics 2021 07;13(7)

College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, Jiangsu, China.

Cadmium (Cd) is a toxic metal and an environmental pollutant and can cause neurotoxicity by inducing apoptosis. Fas (CD95/Apo-1) is a cell-surface receptor that triggers apoptosis upon ligand binding, mediated through the mitochondrial apoptotic pathway. However, the role and regulatory mechanism of Fas in Cd-induced neuronal apoptosis remain understudied. Here, we demonstrate that activation of caspase-8 and the c-Jun N-terminal kinase (JNK) pathway are mechanisms underlying Cd-induced Fas-mediated activation of the mitochondrial apoptotic pathway in rat cerebral cortical neurons. In vitro, Cd induced apoptosis in primary cortical neurons by activating caspase-8, JNK, and the mitochondrial apoptotic pathway. Fas knockdown enhanced cell viability in the presence of Cd and inhibited apoptosis by blocking Cd-activated Fas, caspase-8, and JNK. Fas knockdown also inhibited the decrease of mitochondrial membrane potential, cleavage of caspase-9/3 and poly (ADP-ribose) polymerase 1, and impaired nuclear translocation of apoptosis-inducing factor and endonuclease G. In vivo, Fas knockdown alleviated Cd-induced neuronal injury and inhibited apoptosis, activation of caspase-8, JNK, and mitochondrial apoptotic pathways in rat cerebral cortical neurons. In summary, our results demonstrate that Cd-activated Fas relays apoptotic signals from the cell surface to the mitochondria via caspase-8 and JNK activation in rat cerebral cortical neurons, leading to aggravation of the neuronal injury.
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http://dx.doi.org/10.1093/mtomcs/mfab042DOI Listing
July 2021

Protective Effects of α-Lipoic Acid and Chlorogenic Acid on Cadmium-Induced Liver Injury in Three-Yellow Chickens.

Animals (Basel) 2021 May 29;11(6). Epub 2021 May 29.

College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China.

Cadmium (Cd) is a type of noxious heavy metal that is distributed widely. It can severely injure the hepatocytes and cause liver dysfunction by inducing oxidative stress and mitochondrial damage. We evaluated the protective effects of α-lipoic acid (α-LA) or chlorogenic acid (CGA) and their combination on counteracting cadmium toxicity in vivo in three-yellow chickens. For three months, CdCl (50 mg/L) was administrated through their drinking water, α-LA (400 mg/kg) was added to feed and CGA (45 mg/kg) was employed by gavage. The administration of Cd led to variations in growth performance, biochemical markers (of the liver, kidney and heart), hematological parameters, liver histopathology (which suggested hepatic injury) and ultrastructure of hepatocytes. Some antioxidant enzymes and oxidative stress parameters showed significant differences in the Cd-exposure group when compared with the control group. The groups treated with Cd and administrated α-LA or CGA showed significant amelioration with inhibited mitochondrial pathway-induced apoptosis. Combining both drugs was the most effective in reducing Cd toxicity in the liver. In summary, the results demonstrated that α-LA and CGA may be beneficial in alleviating oxidative stress induced by oxygen free radicals and tissue injury resulting from Cd-triggered hepatotoxicity.
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http://dx.doi.org/10.3390/ani11061606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8228482PMC
May 2021

Activated AMPK promoted the decrease of lactate production in rat Sertoli cells exposed to Zearalenone.

Ecotoxicol Environ Saf 2021 Sep 27;220:112367. Epub 2021 May 27.

College of Veterinary Medicine, Yangzhou University, 12 Wenhui East Road, Yangzhou 225009, Jiangsu, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, Jiangsu, China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, Yangzhou 225009, Jiangsu, China. Electronic address:

Zearalenone, which is ubiquitous in grains and animal feed, is a mycotoxin that can cause serious damage to animals and humans. Sertoli cells (SCs) can be used to study ZEA male reproductive toxicity in vitro. SCs provide energy for germ cells, where AMPK regulates intracellular energy. In order to explore the regulatory effect of AMPK on ZEA-induced lactate decline, we activated AMPK by AICAR and then inhibited AMPK by Compound C with ZEA-treated SCs for 24 h to detect intracellular lactate production-related indicators. Cell viability in the presence of 20 μmol/L ZEA and either 50 μmol/L AICAR or 5 μmol/L Compound C, respectively, did not damage SCs, and could effectively either activate or inhibit AMPK. Inhibition of AMPK promoted the production of pyruvate and lactate via increased expression of the glycolysis-related genes Pgam1 and the lactate production-related proteins GLUT1, LDHA, and MCT4. Activating AMPK inhibited the production of lactate and pyruvate by suppressing the expression of glycolysis-related genes HK1, Pgam1, and Gpi1 and that of lactate production-related proteins LDHA and MCT4. Zearalenone destroys the energy balance in SCs, activates P-AMPK, which inhibit the production of lactate and pyruvate in SCs. This also leads to the decrease of energy supply of SCs to spermatogenic cells, damages to reproductive system.
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http://dx.doi.org/10.1016/j.ecoenv.2021.112367DOI Listing
September 2021

Cadmium disturbs epigenetic modification and induces DNA damage in mouse preimplantation embryos.

Ecotoxicol Environ Saf 2021 Aug 11;219:112306. Epub 2021 May 11.

College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou, Jiangsu, PR China. Electronic address:

Cadmium is an environmental pollutant that has extensive deleterious effects on the reproductive system. However, the mechanisms underlying the effects of cadmium on preimplantation embryos are unclear. Here, we used a mouse model to investigate the effects of maternal cadmium (32 mg/l) exposure in drinking water for 2 days on early embryonic development, and studied the mechanisms associated with epigenetic modifications and DNA damage induced by oxidative stress. We observed that maternal cadmium exposure impaired preimplantation embryo development by inducing embryo death, fragmentation, or developmental blockade. After cadmium exposure, the most survived embryos were at the 8-cell stage, which were used for all measurements. Histone acetylation, not methylation, was disturbed by increasing histone deacetylase 1 (HDAC1) levels after cadmium exposure. Cadmium also disrupted DNA methylation of H19; however genomic DNA methylation can be normally reprogrammed in embryos. Furthermore, cadmium increased reactive oxygen species (ROS) levels and DNA damage, and partly inhibited gene expression related to DNA repair. The distribution and activity of mitochondria was increased; therefore, embryos maintain intracellular homeostasis for survival. Collectively, our findings revealed that maternal cadmium exposure impairs preimplantation embryo development by disturbing the epigenetic modification and inducing DNA damage.
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http://dx.doi.org/10.1016/j.ecoenv.2021.112306DOI Listing
August 2021

Puerarin Restores Autophagosome-Lysosome Fusion to Alleviate Cadmium-Induced Autophagy Blockade via Restoring the Expression of Rab7 in Hepatocytes.

Front Pharmacol 2021 14;12:632825. Epub 2021 Apr 14.

College of Veterinary Medicine, Yangzhou University, Yangzhou, China.

Autophagic dysfunction is one of the main mechanisms by which the environmental pollutant cadmium (Cd) induces cell injury. Puerarin (Pue, a monomeric Chinese herbal medicine extract) has been reported to alleviate Cd-induced cell injury by regulating autophagy pathways; however, its detailed mechanisms are unclear. In the present study, to investigate the detailed mechanisms by which Pue targets autophagy to alleviate Cd hepatotoxicity, alpha mouse liver 12 (AML12) cells were used to construct a model of Cd-induced hepatocyte injury . First, the protective effect of Pue on Cd-induced cell injury was confirmed by changes in cell proliferation, cell morphology, and cell ultrastructure. Next, we found that Pue activated autophagy and mitigated Cd-induced autophagy blockade. In this process, the lysosome was further activated and the lysosomal degradation capacity was strengthened. We also found that Pue restored the autophagosome-lysosome fusion and the expression of Rab7 in Cd-exposed hepatocytes. However, the fusion of autophagosomes with lysosomes and autophagic flux were inhibited after knocking down , and were further inhibited after combined treatment with Cd. In addition, after knocking down , the protective effects of Pue on restoring autophagosome-lysosome fusion and alleviating autophagy blockade in Cd-exposed cells were inhibited. In conclusion, Pue-mediated alleviation of Cd-induced hepatocyte injury was related to the activation of autophagy and the alleviation of autophagy blockade. Pue also restored the fusion of autophagosomes and lysosomes by restoring the protein expression of Rab7, thereby alleviating Cd-induced autophagy blockade in hepatocytes.
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http://dx.doi.org/10.3389/fphar.2021.632825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079953PMC
April 2021

Cadmium exposure induces rat proximal tubular cells injury via p62-dependent Nrf2 nucleus translocation mediated activation of AMPK/AKT/mTOR pathway.

Ecotoxicol Environ Saf 2021 May 11;214:112058. Epub 2021 Mar 11.

College of Veterinary Medicine, Yangzhou University, 12 East Wenhui Road, Yangzhou 225009, People's Republic of China; Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou 225009, People's Republic of China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, People's Republic of China. Electronic address:

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a nuclear transcription factor of great concern which is widely involved in physiological and pathological processes of the organism, but the role and regulatory mechanism of Nrf2 in kidney exposed to cadmium (Cd) remain largely unknown. Here we demonstrated that Cd exposure induced injury in primary rat proximal tubular (rPT) cells and NRK-52E cell line, which was accompanied by autophagic flux blockade and subsequent accumulation of p62. Cd-activated nucleus translocation of Nrf2 depended on p62, which promoted antioxidant genes transcription, but it failed to against Cd-induced cell injury and ultimately succumbed to Cd toxicity. CDDO Methyl Ester (CDDO-ME) or ML385 treatment aggravated or alleviated rPT cells injury induced by Cd respectively, indicating that Nrf2 nucleus translocation played a negative role during Cd-induced rPT cells injury. Phosphorylation of 5' AMP-activated protein kinase (AMPK) decreased together with enhanced Nrf2 nucleus translocation in rPT cells exposed to Cd. Dephosphorylation of AMPK induced by Cd were facilitated or restored by CDDO-ME or ML385 treatment, which confirmed AMPK is a downstream factor of Nrf2. Simultaneously, CDDO-ME further enhanced Phosphorylation of mTOR and AKT which increased during Cd exposure. While, Cd-induced phosphorylation of mTOR and AKT were reversed by ML385 treatment. These results illustrated that Cd mediated Nrf2 nucleus translocation depends on p62 accumulation which results from autophagic flux inhibition. The enhanced nucleus translocation of Nrf2 suppresses phosphorylation of AMPK to inactivate AKT/mTOR signaling, and results in rPT cells injury finally.
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http://dx.doi.org/10.1016/j.ecoenv.2021.112058DOI Listing
May 2021

Corrigendum to "TGF-β-activated kinase 1 (TAK1) mediates cadmium-induced autophagy in osteoblasts via the AMPK / mTORC1 / ULK1 pathway" [Toxicology 442 (2020) 152538].

Toxicology 2021 Apr 2;453:152738. Epub 2021 Mar 2.

College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu, 225009, PR China; Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu, 225009, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, PR China. Electronic address:

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http://dx.doi.org/10.1016/j.tox.2021.152738DOI Listing
April 2021

Cadmium Toxicity on Chondrocytes and the Palliative Effects of 1α, 25-Dihydroxy Vitamin D in White Leghorns Chicken's Embryo.

Front Vet Sci 2021 10;8:637369. Epub 2021 Feb 10.

College of Veterinary Medicine, Yangzhou University, Yangzhou, China.

Cadmium (Cd) can causes osteoporosis and joint swelling. However, the mechanism of Cd toxicity in chondrocytes and how to alleviate Cd poisoning to chondrocytes are still unclear. Herein, we evaluated the toxicity of Cd to chicken chondrocytes, and whether vitamin D can relieve the toxicity of Cd to chondrocytes. Primary chondrocytes were collected from knee-joint cartilage of 15-day-old chicken embryos. They were treated with (0, 1, 2, and 4) μM Cd alone, 10 M 1α,25-(OH)D alone, or 2 μM Cd combined with 10 M 1α,25-(OH)D. We found that Cd significantly inhibited and mRNA expression, which are markers for chondrocyte differentiation, downregulated the mitochondrial membrane potential, upregulated the Bax/B-cell lymphoma 2 ratio. Furthermore, Cd significantly promoted matrix metalloproteinase (MMP)-9 expression, thus accelerating the degradation of extracellular matrix. And Cd also inhibited the expression of main macromolecular protein of extracellular matrix, Collagen type IIα1 (COL2A1) and acid mucopolysaccharide. However, 1α,25-(OH)D pretreatment significantly alleviated the toxicity effects of Cd on the differentiation, apoptosis and extracellular matrix gene expression in primary chondrocytes. Conclusively, Cd exposure could inhibited chicken embryo chondrocytes differentiation, extracellular matrix gene expression, and induced chondrocyte apoptosis. However, these toxic effects of Cd are alleviated by the pretreatment of chondrocytes with 1α,25-(OH)D.
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http://dx.doi.org/10.3389/fvets.2021.637369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902530PMC
February 2021

Zearalenone and deoxynivalenol inhibited IL-4 receptor-mediated Th2 cell differentiation and aggravated bacterial infection in mice.

Toxicol Appl Pharmacol 2021 03 5;415:115441. Epub 2021 Feb 5.

College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, Jiangsu, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, Jiangsu, China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, Yangzhou 225009, Jiangsu, China. Electronic address:

The immunotoxicity of zearalenone (ZEA) and deoxynivalenol (DON), two of the most common environmental mycotoxins, has been well investigated. However, due to the complexity of the immune system, especially during bacterial infection, many types of immune cells are involved in invasion resistance and bacterial clearance. Of these, T helper 2 (Th2) cells, which are members of the helper T cell family, assist B cells to activate and differentiate into antibody-secreting cells, participate in humoral immune response, and, ultimately, eliminate pathogens. Thus, it is important to identify the stage at which these toxins affect the immune function, and to clarity the underlying mechanisms. In this study, mice infected with Listeria monocytogenes (Listeria) were used to study the effects of ZEA, DON, and ZEA + DON on Th2 differentiation, Interleukin-4 Receptor (IL-4R) expression, costimulatory molecules expression and cytokine secretion after Listeria infection. Naive CD4 T cells, isolated from mice, were used to verify the in vivo effects and the associated mechanisms. In vivo experiments showed that these toxins aggravated spleen damage after Listeria infection and reduced the differentiation of Th2 cells by affecting the synthesis of IL-4R of CD4 T cells. In addition, the level of the costimulatory molecule CD154 decreased. Consistent with this, in vitro studies showed that these toxins inhibited the differentiation of mouse naive CD4 T cell into Th2 subtype and decreased IL-4R levels. In addition, the levels of costimulatory molecules CD154, CD278 and the Th2 cells secrete cytokines IL-4, IL-6, and IL-10 decreased. Based on our in vivo and in vitro experiments, we suggest that ZEA, DON, and ZEA + DON inhibit the expression of costimulatory molecules on CD4 T cell, and inhibit the IL-4R-mediated Th2 cell differentiation. This may indicate that the body cannot normally resist or clear the pathogen after mycotoxin poisoning.
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http://dx.doi.org/10.1016/j.taap.2021.115441DOI Listing
March 2021

Cadmium toxicity: A role in bone cell function and teeth development.

Sci Total Environ 2021 May 18;769:144646. Epub 2021 Jan 18.

College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, Yangzhou, Jiangsu 225009, PR China. Electronic address:

Cadmium (Cd) is a widespread environmental contaminant that causes severe bone metabolism disease, such as osteoporosis, osteoarthritis, and osteomalacia. The present review aimed to explore the molecular mechanisms of Cd-induced bone injury starting from bone cell function and teeth development. Cd inhibits the differentiation of bone marrow mesenchymal stem cells (BMSCs) into osteoblasts, and directly causes BMSC apoptosis. In the case of osteoporosis, Cd mainly affects the activation of osteoclasts and promotes bone resorption. Cd-induces osteoblast injury and oxidative stress, which causes DNA damage, mitochondrial dysfunction, and endoplasmic reticulum stress, resulting in apoptosis. In addition, the development of osteoarthritis (OA) might be related to Cd-induced chondrocyte damage. The high expression of metallothionein (MT) might reduce Cd toxicity toward osteocytes. The toxicity of Cd toward teeth mainly focuses on enamel development and dental caries. Understanding the effect of Cd on bone cell function and teeth development could contribute to revealing the mechanisms of Cd-induced bone damage. This review explores Cd-induced bone disease from cellular and molecular levels, and provides new directions for removing this heavy metal from the environment.
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http://dx.doi.org/10.1016/j.scitotenv.2020.144646DOI Listing
May 2021

Puerarin prevents cadmium-induced disorder of testicular lactic acid metabolism in rats by activating 5' AMP-activated protein kinase (AMPK)/sirtuin 1 (SIRT1) signaling pathway.

Environ Toxicol 2021 May 6;36(5):945-957. Epub 2021 Jan 6.

College of Veterinary Medicine, Yangzhou University, Yangzhou, China.

Cadmium (Cd) interferes with the function of the male reproductive system; however, the molecular mechanism is poorly understood. This study aimed to evaluate the effect of puerarin (PU) on Cd-induced testicular lactic acid metabolism disorder. Weaning male Sprague-Dawley rats were pre-fed for 7 days, weighed, and randomly divided into four groups: Control group, CdAc group, CdAc  + PU group, PU group. The results showed that Cd accumulated in the testis, the testicles became congested and shrank, and the testis index decreased in the rats treated in the CdAc group. Cadmium exposure reduced the serum concentration of testosterone, and the concentration of lactic acid and pyruvate in the testis. Cd decreased testicular superoxide dismutase activity and total antioxidant capacity, and increased testicular malondialdehyde levels. Cd reduced the level of ATP, glycolytic gene expression, and lactate production-related proteins in the testis. Cd also decreased the expression of 5' AMP-activated protein kinase (AMPK)/sirtuin 1 (SIRT1) signaling pathway-related proteins in the testis. However, these negative effects were attenuated by PU administration. In summary, Cd reduces the production of lactic acid in the testis of rats, while PU administration restores the production of lactic acid and reduces the toxicity of Cd to the testis of rats.
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http://dx.doi.org/10.1002/tox.23096DOI Listing
May 2021

Gap Junction Intercellular Communication Negatively Regulates Cadmium-Induced Autophagy and Inhibition of Autophagic Flux in Buffalo Rat Liver 3A Cells.

Front Pharmacol 2020 26;11:596046. Epub 2020 Nov 26.

College of Veterinary Medicine, Yangzhou University, Yangzhou, China.

Cadmium is an important environmental pollutant that poses a serious threat to the health of humans and animals. A large number of studies have shown that the liver is one of the important target organs of cadmium. Stimulation of cells can lead to rapid changes in gap junction intercellular communication (GJIC) and autophagy. Previous studies have shown that cadmium can inhibit GJIC and induce autophagy. In order to understand the dynamic changes of GJIC and autophagy in the process of cadmium-induced hepatotoxic injury and the effects of GJIC on autophagy, a time-gradient model of cadmium cytotoxicity was established. The results showed that within 24 h of cadmium exposure, 5 μmol/L cadmium inhibited GJIC by down regulating the expression levels of connexin 43 (Cx43) and disturbing the localization of Cx43 in Buffalo rat liver 3A (BRL 3A) cells. In addition, cadmium induced autophagy and then inhibited autophagic flux in the later stage. During this process, inhibiting of GJIC could exacerbate the cytotoxic damage of cadmium and induce autophagy, but further blocked autophagic flux, promoting GJIC in order to obtain the opposite results.
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http://dx.doi.org/10.3389/fphar.2020.596046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774522PMC
November 2020

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

J Cell Mol Med 2021 01 4;25(2):937-945. Epub 2020 Dec 4.

Institutes of Agricultural Science and Technology Development, Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, Yangzhou, China.

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.
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http://dx.doi.org/10.1111/jcmm.16152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812271PMC
January 2021

Effect of cell cycle synchronization on cadmium-induced apoptosis and necrosis in NRK-52E cells.

Cell Cycle 2020 12 23;19(23):3386-3397. Epub 2020 Nov 23.

College of Veterinary Medicine, Yangzhou University , Yangzhou, P.R. China.

Heavy metal pollution is a problem that cannot be ignored. Due to the prevalence of cadmium in the environment and its harmful effects on humans, cadmium pollution has become a research hotspot recently. The mechanism of cadmium-induced toxicity has also drawn much attention and most studies have been conducted using whole cells, but the toxicological mechanism of cadmium remains unclear. In this study, we aimed to obtain NRK-52E cells at different growth stages by various methods and analyze the differences in cadmium toxicity. The results show that the cadmium sensitivity of cells in each phase was different and the late apoptotic rate was increased significantly after 5 µM Cd treatment. In addition, cadmium easily induces apoptosis of G0- and S-phase cells, as well as necrosis of S- and M-phase cells, but has no significant effect on G1-phase cells. Overall, we first explored the differences in the effects of cadmium on NRK-52E cells at various growth phases. Besides, the findings of this study might provide a theoretical basis for further exploration of the toxicological mechanism of cadmium. Cd: cadmium; CDK: cyclin-dependent kinases; DAPI 2-(4-amidinophenyl)-1H-indole-6-carboxamidine; TBST: Tris-buffered saline with Tween-20; PI: propidium iodide; DMEM: Dulbecco's Modified Eagle Medium; BCA: bicinchoninic acid.
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http://dx.doi.org/10.1080/15384101.2020.1848065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7751682PMC
December 2020

Protective effect of naringenin against cadmium-induced testicular toxicity in male SD rats.

J Inorg Biochem 2021 01 14;214:111310. Epub 2020 Nov 14.

College of Veterinary Medicine, Yangzhou University, No.12, East Wenhui Road, 225009 Yangzhou, PR China.

This study aimed to investigate the effect of naringenin (Nar) on cadmium (Cd)-induced testicular toxicity. Twenty-four male Sprague-Dawley (SD) rats aged 5 weeks were used. Rats were administered with 0.9% NaCl (control group), CdCl (2 mg/kg b.w. intraperitoneally), Nar (50 mg/kg b.w, orally), and CdCl + Nar (2 mg/kg b.w intraperitoneally and 50 mg/kg b.w. orally, respectively) for 4 weeks. Results showed that body weight, relative testis weights, and sperm quality decreased in the Cd-treated group, and Cd accumulated in serum and testes. Pathological examination showed that Cd can cause testicular damage. Cd decreased the serum concentrations of gonadotropin-releasing hormone (GnRH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone. It also decreased the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). Moreover, exposure to Cd resulted in decreased content of reduced glutathione (GSH) and total antioxidant capacity (T-AOC) concentrations, as well as increased malondialdehyde (MDA) and hydrogen peroxide (HO) contents. Cd also provoked testis autophagy by upregulating the expression of the autophagy-related proteins P62 and LC3 II. However, the combined administration of Nar and Cd significantly attenuated the Cd-induced negative effects by increasing the body weight, relative testis weights, and sperm quality and by decreasing testicular damage. Simultaneous supplementation of Nar and Cd markedly restored the decreased levels of GnRH, FSH, LH, testosterone, GSH, and T-AOC and the activities of SOD, CAT, and GPx caused by Cd treatment. Nar further suppressed MDA and HO production and protected the testes from Cd-induced autophagy by downregulating P62 and LC3 II expression. Therefore, Nar protected the testes from Cd-induced toxicity.
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http://dx.doi.org/10.1016/j.jinorgbio.2020.111310DOI Listing
January 2021

The effect of P2X7 on cadmium-induced osteoporosis in mice.

J Hazard Mater 2021 03 26;405:124251. Epub 2020 Oct 26.

College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009 Jiangsu, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009 Jiangsu, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, Yangzhou, 225009 Jiangsu, PR China. Electronic address:

Cadmium (Cd), an environmental pollutant, induces osteoporosis by directly destroying bone tissue, but its direct damaging effect on bone cells is not fully illustrated. Here, we treated mouse bone marrow stem cells (BMSC) and bone marrow macrophages (BMM) with Cd, and gave BALB/c mice Cd in water. Long-term Cd exposure significantly inhibited BMSC osteogenesis and osteoclast differentiation in vitro, and induced osteoporosis in vivo. Cd exposure also reduced P2X7 expression dramatically. However, P2X7 deletion significantly inhibited osteoblast and osteoclast differentiation; P2X7 overexpression obviously reduced the suppression effect of Cd on osteoblast and osteoclast differentiation. The suppression of P2X7-PI3K-AKT signaling aggravated the effect of Cd. In mice, short-term Cd exposure did not result in osteoporosis, but bone formation was inhibited, RANKL expression was increased, and osteoclasts were significantly increased in vivo. In vitro, short-term Cd exposure not only increased osteoclast numbers, but also promoted osteoclast adhesion function at late-stage osteoclast differentiation. Cd exposure also reduced P2X7 expression in vivo and in vitro. Our results demonstrate that short-term Cd exposure does not affect osteoblast and osteoclast apoptosis in vivo and in vitro, but long-term Cd exposure significantly increases bone tissue apoptosis. Overall, our results describe a novel mechanism for Cd-induced osteoporosis.
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http://dx.doi.org/10.1016/j.jhazmat.2020.124251DOI Listing
March 2021

Cadmium induces apoptosis via generating reactive oxygen species to activate mitochondrial p53 pathway in primary rat osteoblasts.

Toxicology 2020 12 6;446:152611. Epub 2020 Oct 6.

College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, PR China. Electronic address:

Cadmium (Cd), a heavy metal produced by various industries, contaminates the environment and seriously damages the skeletal system of humans and animals. Recent studies have reported that Cd can affect the viability of cells, including osteoblasts, both in vivo and in vitro. However, the mechanism of Cd-induced apoptosis remains unclear. In the present study, primary rat osteoblasts were used to investigate the Cd-induced apoptotic mechanism. We found that treatment with 2 and 5 μM Cd for 12 h decreased osteoblast viability and increased apoptosis. Furthermore, Cd increased the generation of reactive oxygen species (ROS), and, thus, DNA damage measured via p-H2AX. The level of the nuclear transcription factor p53 was significantly increased, which upregulated the expression of PUMA, Noxa, Bax, and mitochondrial cytochrome c, downregulated the expression of Bcl-2, and increased the level of cleaved caspase-3. However, pretreatment with the ROS scavenger N-acetyl-l-cysteine (NAC) or the p53 transcription specific inhibitor PFT-α suppressed Cd-induced apoptosis. Our results indicate that Cd can induce apoptosis in osteoblasts by increasing the generation of ROS and activating the mitochondrial p53 signaling pathway, and this mechanism requires the transcriptional activation of p53.
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http://dx.doi.org/10.1016/j.tox.2020.152611DOI Listing
December 2020

Cadmium exposure triggers osteoporosis in duck via P2X7/PI3K/AKT-mediated osteoblast and osteoclast differentiation.

Sci Total Environ 2021 Jan 15;750:141638. Epub 2020 Aug 15.

College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, Yangzhou, Jiangsu 225009, PR China. Electronic address:

Cadmium is a common environmental pollutant that accumulates in the bone and kidneys and causes severe health and social problems. However, the effects of Cd on the occurrence of osteoporosis and its mechanism of action in this process are unclear. To test whether Cd-induced osteoporosis is mediated via P2X7/PI3K/AKT signaling, duck bone marrow mesenchymal stem cells (BMSCs) and bone marrow macrophage cells (BMMs) were treated with Cd for 5 days, and duck embryos were treated with Cd Micro-CT analysis indicated that Cd-induced osteoporosis occurs in vivo, and histopathology and immunohistochemical analyses also revealed that Cd induced bone damage and the downregulation of osteogenic and bone resorption-related proteins. Cd exposure significantly inhibited the differentiation of BMSCs and BMMs into osteoblasts and osteoclasts in vitro, and promoted osteoblast and osteoclast apoptosis. Cd exposure significantly downregulated the P2X7/PI3K/AKT signaling pathway in vivo and in vitro, and inhibition of this signaling pathway significantly aggravated osteoblast and osteoclast differentiation. Cd exposure also upregulated the OPG/RANKL ratio in vivo and in vitro, further inhibiting osteoclast differentiation. These results demonstrate that Cd causes osteoporosis in duck by inhibiting P2X7/PI3K/AKT signaling and increasing the OPG/RANKL ratio. These results establish a previously unknown mechanism of Cd-induced osteoporosis.
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http://dx.doi.org/10.1016/j.scitotenv.2020.141638DOI Listing
January 2021

p53 positively regulates osteoprotegerin-mediated inhibition of osteoclastogenesis by downregulating TSC2-induced autophagy in vitro.

Differentiation 2020 Jul - Aug;114:58-66. Epub 2020 Jun 21.

College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, Jiangsu, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009, Jiangsu, PR China; Jiangsu Key Laboratory of Zoonosis, Yangzhou, 225009, Jiangsu, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety, The Ministry of Education of China, Yangzhou University, Yangzhou, 225009, Jiangsu, PR China. Electronic address:

Osteoclasts are terminally multinucleated cells that are regulated by nuclear factor-activated T cells c1 (NFATc1), and are responsible for bone resorption while the tartrate resistant acid phosphatase (TRAP) enzymes releases into bone resorption lacunae. Furthermore, tumor suppressor p53 is a negative regulator during osteoclastogenesis. Osteoprotegerin (OPG) inhibits osteoclastogenesis and bone resorption by activating autophagy, however, whether p53 is involved in OPG-mediated inhibition of osteoclastogenesis remains unclear. In the current study, OPG could enhance the expression of p53 and tuberin sclerosis complex 2 (TSC2). Moreover, the expression of p53 is regulated by autophagy during OPG-mediated inhibition of osteoclastogenesis. Inhibition of p53 by treated with pifithrin-α (PFTα) causing augments of osteoclastogenesis and bone resorption, also reversed OPG-mediated inhibition of osteoclastogenesis by reducing the expression of TSC2. In addition, knockdown of TSC2 using siRNA could rescue OPG-mediated inhibition of osteoclastogenesis by reducing autophagy, which is manifested by the decrease of the expression of Beclin1 and the phosphorylation of mammalian target of rapamycin (mTOR) and ribosomal protein S6 kinase beta 1 (S6K1, also known as p70S6K). Collectively, p53 plays a critical role during OPG-mediated inhibition of osteoclastogenesis via regulating the TSC2-induced autophagy in vitro.
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http://dx.doi.org/10.1016/j.diff.2020.06.002DOI Listing
July 2021

Puerarin restores the autophagic flux to alleviate cadmium‑induced endoplasmic reticulum stress in NRK‑52E cells.

Mol Med Rep 2020 09 6;22(3):2551-2563. Epub 2020 Jul 6.

Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, P.R. China.

Cadmium (Cd) is a heavy metal that can accumulate and cause damage to a variety of tissues and organs. The kidney is the primary target organ for Cd accumulation and toxic damage. Autophagy, which is a critical intracellular process, serves an important role in maintaining the homeostasis of the intracellular environment. Endoplasmic reticulum stress (ERS) is another key process that functions to promote cell survival or results in cell injury and death. Both autophagy and ERS are associated with oxidative stress; however, the mechanism by which ERS is regulated by autophagy in Cd‑induced nephrotoxicity remains unclear. The present study employed a rat NRK‑52E cell model, where alterations in cell morphology, density and viability, the accumulation of reactive oxygen species, an increase in malondialdehyde generation and a decrease in antioxidant enzyme activity and apoptosis were induced by Cd treatment. Cd induced the activation of nuclear factor erythroid 2‑related factor 2 (NRF2), an obstruction of autophagic flux and ERS, which were attenuated by puerarin administration. Furthermore, puerarin failed to alleviate ERS following knockdown of autophagy‑related protein 7 in NRK‑52E cells. Overexpression of Ras‑related protein Rab‑7, which promotes the fusion of autophagosomes and lysosomes, efficiently reduced ERS. Taken together, these results indicate that puerarin administration restored the autophagic flux to alleviate ERS, via blocking the activation of NRF2.
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http://dx.doi.org/10.3892/mmr.2020.11301DOI Listing
September 2020

TGF-β-activated kinase 1 (TAK1) mediates cadmium-induced autophagy in osteoblasts via the AMPK / mTORC1 / ULK1 pathway.

Toxicology 2020 09 18;442:152538. Epub 2020 Jul 18.

College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu, 225009, PR China; Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu, 225009, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, PR China. Electronic address:

Cadmium (Cd) is one of worldwide environmental pollutants that causes bone homeostasis, which depends on the resorption of bones by osteoclasts and formation of bones by the osteoblasts (OB). However, the Cd toxicity on OB and its mechanism are unclear. Autophagy is an evolutionarily conserved degradation process in which domestic intracellular components are selectively digested for the recycling of nutrients and energy. This process is indispensable for cell homeostasis maintenance and stress responses. Dysregulation at the level of autophagic activity consequently disturbs the balance between bone formation and bone resorption and mediates the onset and progression of multiple bone diseases, including osteoporosis. TAK1 has been recently emerged as an activator of AMPK and hence an autophagy inducer. AMPK is a key molecule that induces autophagy and regulates cellular metabolism to maintain energy homeostasis. Conversely, autophagy is inhibited by mTORC1. In this study, we found that Cd treatment caused the formation of autophagosomes, LC3-II lipidation and p62 downregulation, and the increased autophagic flux, indicating that Cd treatment induced autophagy in OBs. Cd treatment induced TAK1 activation mediated AMPK phosphorylation, which promoted autophagy via phosphorylation of ULK1 at S317. Meanwhile, Cd treatment dramatically decreased mTORC1, S6K1, 4E-BP1, S6, ULK1 and ULK1 phosphorylation, suggesting that mTORC1 activity was inhibited and inactive mTORC1 prevents ULK1 activation by phosphorylating ULK1 at SerS555 and Ser757. Our data strongly suggest that TAK1 mediates AMPK activation, which activates ULK1 by phosphorylating ULK1 and suppressing mTORC1-mediated ULK1 and ULK1 phosphorylation. Our study has revealed a signaling mechanism for TAK1 in Cd-induced autophagy in OBs.
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http://dx.doi.org/10.1016/j.tox.2020.152538DOI Listing
September 2020
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