Publications by authors named "Huanwen Tang"

44 Publications

PARP-1 via regulation of p53 and p16, is involved in the hydroquinone-induced malignant transformation of TK6 cells by decelerating the cell cycle.

Toxicol In Vitro 2021 Mar 24;74:105153. Epub 2021 Mar 24.

Department of Environmental and Occupational Health, Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan, China. Electronic address:

Poly(ADP-ribose)polymerase-1 (PARP-1) plays a crucial role in DNA damage repair and could be viewed as both a tumor promoter and tumor-suppressor gene. However, the effects of PARP-1 in hydroquinone-induced malignant transformation of TK6 cells remain to be further elucidated. The present research evaluated the potential mechanism of PARP-1 in hydroquinone-induced malignant transformation of TK6 cells. The results indicated that high PARP-1 inhibited TK6 cells malignant transformation after chronic exposure to HQ. We further confirmed that PARP-1 overexpression blocked cell proliferation, and decelerated cell cycle progression in vitro and in vivo. The immunoblotting analysis indicated that PARP-1 regulated cell cycle progression via p16/Rb and p53. Therefore, we conclude that PARP-1 is involved in HQ-induced malignant transformation associated with increasing p16/Rb and p53 which resulting in decelerating the cell cycle progression.
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http://dx.doi.org/10.1016/j.tiv.2021.105153DOI Listing
March 2021

MicroRNA-191 blocking the translocation of GLUT4 is involved in arsenite-induced hepatic insulin resistance through inhibiting the IRS1/AKT pathway.

Ecotoxicol Environ Saf 2021 Jun 18;215:112130. Epub 2021 Mar 18.

Center for Global Health, The Key Laboratory of Modern Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China; China International Cooperation Center for Environment and Human Health, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China. Electronic address:

Environmental exposure to arsenic can cause a variety of health problems. Epidemiological and experimental studies have established a diabetogenic role for arsenic, but the mechanisms responsible for arsenic-induced impairment of insulin action are unclear. MicroRNAs (miRNAs) are involved in various metabolic disorders, particularly in the development of insulin resistance. The present study investigated whether arsenite, an active form of arsenic, induces hepatic insulin resistance and the mechanisms underlying it. After male C57BL/6J mice were exposed to arsenite (0 or 20 ppm) in drinking water for 12 months, intraperitoneal glucose tolerance tests (IPGTTs) and insulin tolerance tests (ITTs) revealed an arsenite-induced glucose metabolism disorder. Hepatic glycogen levels were lower in arsenite-exposed mice. Further, for livers of mice exposed to arsenite, miR-191 levels were higher, and protein levels of insulin receptor substrate 1 (IRS1), p-IRS1, and phospho-protein kinase B (p-AKT) were lower. Further, glucose transporter 4 (GLUT4) had lower levels on the plasma membrane. For insulin-treated L-02 cells, arsenite decreased glucose consumption and glycogen levels, increased miR-191 levels, and inhibited the IRS1/AKT pathway and the translocation of GLUT4 from the cytoplasm to the plasma membrane. For insulin-treated L-02 cells, the decreases of glucose consumption, glycogen levels, GLUT4 on the plasma membrane, and p-AKT levels induced by arsenite were reversed by SC79 (agonist of AKT) and an miR-191 inhibitor; these effects caused by miR-191 inhibitor were restored by IRS1 siRNA. In insulin-treated L-02 cells, miR-191, via IRS1, was involved in the arsenite-induced decreases of glucose consumption and glycogen levels and in inhibition of the translocation of GLUT4. Thus, miR-191 blocking the translocation of GLUT4 was involved in arsenite-induced hepatic insulin resistance through inhibiting the IRS1/AKT pathway. Our study reveals a mechanism for arsenite-induced hepatic insulin resistance, which provides clues for discovering biomarkers for the development of type 2 diabetes and for prevention and treatment of arsenic poisoning.
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http://dx.doi.org/10.1016/j.ecoenv.2021.112130DOI Listing
June 2021

Triphenyl phosphate disturbs the lipidome and induces endoplasmic reticulum stress and apoptosis in JEG-3 cells.

Chemosphere 2021 Feb 15;275:129978. Epub 2021 Feb 15.

School of Public Health, Dongguan Key Laboratory of Environmental Medicine, Guangdong Medical University, Guangdong, 523-808, China. Electronic address:

Triphenyl phosphate (TPP) is a frequently used aryl organophosphate flame retardant. Epidemiological studies have shown that TPP and its metabolite diphenyl phosphate (DPP) can accumulate in the placenta, and positively correlated with abnormal birth outcomes. TPP can disturb placental hormone secretion through the peroxisome proliferator-activated receptor γ (PPARγ) pathway. However, the extent and mechanism of placental toxicity mediation by TPP remains unknown. In this study, we used JEG-3 cells to investigate the role of PPARγ-regulated lipid metabolism in TPP-mediated placental toxicity. The results of lipidomic analysis showed that TPP increased the production of triglycerides (TG), fatty acids (FAs), and phosphatidic acid (PA), but decreased the levels of phosphatidylethanol (PE), phosphatidylserine (PS), and sphingomyelin (SM). TG accumulation was accompanied by increased levels of sterol regulatory element binding transcription factor 1 (SREBP1), acetyl-coA carboxylase (ACC), and fatty acid transport protein (CD36). Although PPARγ and its target CCAAT/enhancer binding proteins (C/EBPα) was decreased, the TG content and gene expression of SREBP1, ACC, and CD36 decreased when TPP was co-exposed to the PPARγ antagonist GW9662. TPP also induced inflammatory responses, endoplasmic reticulum stress (ERS), and cell apoptosis. Expression of genes related to ERS and apoptosis were attenuated by GW9662. Together, these results show that TPP can disturb lipid metabolism and cause lipid accumulation through PPARγ, induce ERS, and cell apoptosis. Our findings reveal that the developmental toxicity of TPP through placental toxicity should not be ignored.
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http://dx.doi.org/10.1016/j.chemosphere.2021.129978DOI Listing
February 2021

miR-21-regulated M2 polarization of macrophage is involved in arsenicosis-induced hepatic fibrosis through the activation of hepatic stellate cells.

J Cell Physiol 2021 Jan 22. Epub 2021 Jan 22.

Center for Global Health, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China.

Arsenicosis induced by chronic exposure to arsenic is recognized as one of the main damaging effects on public health. Exposure to arsenic can cause hepatic fibrosis, but the molecular mechanisms by which this occurs are complex and elusive. It is not known if miRNAs are involved in arsenic-induced liver fibrosis. We found that in the livers of mice exposed to arsenite, there were elevated levels of microRNA-21 (miR-21), phosphorylated mammalian target of rapamycin (p-mTOR), and arginase 1 (Arg1); low levels of phosphatase and tensin homolog (PTEN); and more extensive liver fibrosis. For cultured cells, arsenite-induced miR-21, p-mTOR, and Arg1; decreased PTEN; and promoted M2 polarization of macrophages derived from THP-1 monocytes (THP-M), which caused secretion of fibrogenic cytokines, including transforming growth factor-β1. Coculture of arsenite-treated, THP-M with LX-2 cells induced α-SMA and collagen I in the LX-2 cells and resulted in the activation of these cells. Downregulation of miR-21 in THP-M inhibited arsenite-induced M2 polarization and activation of LX-2 cells, but cotransfection with PTEN siRNA or a miR-21 inhibitor reversed this inhibition. Moreover, knockout of miR-21 in mice attenuated liver fibrosis and M2 polarization compared with WT mice exposed to arsenite. Additionally, LN, PCIII, and HA levels were higher in patients with higher hair arsenic levels, and levels of miR-21 were higher than controls and positively correlated with PCIII, LN, and HA levels. Thus, arsenite induces the M2 polarization of macrophages via miR-21 regulation of PTEN, which is involved in the activation of hepatic stellate cells and hepatic fibrosis. The results establish a previously unknown mechanism for arsenicosis-induced fibrosis.
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http://dx.doi.org/10.1002/jcp.30288DOI Listing
January 2021

CoQ10 protects against acetaminophen-induced liver injury by enhancing mitophagy.

Toxicol Appl Pharmacol 2021 01 30;410:115355. Epub 2020 Nov 30.

Department of Nutrition, School of Public Health, Guangdong Medical University, People's Republic of China; Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, People's Republic of China. Electronic address:

Coenzyme Q10 (CoQ10), which is a key cofactor of the electron transport chain in the mitochondria has shown many beneficial effects on liver diseases. However, the mechanisms of CoQ10 protective role on the acetaminophen (APAP)-induced liver injury are elusive and unclear. In this study, we further investigated the CoQ10 therapeutic effects on APAP-overdose liver injury. C57BL/6 J mice were intraperitoneally treated with APAP to induce liver injury. CoQ10 (5 mg/kg) was given to mice at 1.5 h after APAP treatment. The results showed that hepatic CoQ10 levels were decreased during the APAP-induced hepatotoxicity and preceded serum ALT elevation. Treatment of CoQ10 significantly improved the liver injury induced by APAP. Moreover, CoQ10 treatment decreased the ROS levels and promoted the antioxidative related gene expression in APAP overdose mice. Importantly, results showed that even though CoQ10 had no effects on the mtDNA copy number and the expression of genes related to mitochondrial biogenesis, it significantly improved the mitochondrial complex I and V activities and promoted the mitophagy in APAP-overdose mice. To further authenticate mitophagy role in CoQ10-mediated improved liver injury in vivo, we administrated APAP-overdose mice with chloroquine 1 h prior to APAP treatment and found that chloroquine treatment functionally abrogated the CoQ10 protective role on APAP overdose mice. To conclude, this study provides evidence that CoQ10 activates mitophagy to protect against APAP-induced liver injury. Therefore, CoQ10 may represent a novel therapeutic option for the prevention and treatment of drug-induced liver injury.
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http://dx.doi.org/10.1016/j.taap.2020.115355DOI Listing
January 2021

LncRNA H19-mediated M2 polarization of macrophages promotes myofibroblast differentiation in pulmonary fibrosis induced by arsenic exposure.

Environ Pollut 2021 Jan 27;268(Pt A):115810. Epub 2020 Oct 27.

Center for Global Health, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, People's Republic of China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, People's Republic of China. Electronic address:

Arsenic is a potent toxicant, and long-term exposure to inorganic arsenic causes lung damage. M2 macrophages play an important role in the pathogenesis of pulmonary fibrosis. However, the potential connections between arsenic and M2 macrophages in the development of pulmonary fibrosis are elusive. C57BL/6 mice were fed with drinking water containing 0, 10 and 20 ppm arsenite for 12 months. We have found that, in lung tissues of mice, arsenite, a biologically active form of arsenic, elevated H19, c-Myc, and Arg1; decreased let-7a; and caused pulmonary fibrosis. For THP-1 macrophages (THP-M) and bone-marrow-derived macrophages (BMDMs), 8 μM arsenite increased H19, c-Myc, and Arg1; decreased let-7a; and induced M2 polarization of macrophages, which caused secretion of the fibrogenic cytokine, TGF-β1. Down-regulation of H19 or up-regulation of let-7a reversed the arsenite-induced M2 polarization of macrophages. Arsenite-treated THP-M and BMDMs co-cultured with MRC-5 cells or primary lung fibroblasts (PLFs) elevated levels of p-SMAD2/3, SMAD4, α-SMA, and collagen I in lung fibroblasts and resulted in the activation of lung fibroblasts. Knockout of H19 or up-regulation of let-7a in macrophages reversed the effects. The results indicated that H19 functioned as an miRNA sponge for let-7a, which was involved in arsenite-induced M2 polarization of macrophages and induced the myofibroblast differentiation phenotype by regulation of c-Myc. In the sera of arseniasis patients, levels of hydroxyproline and H19 were higher, and levels of let-7a were lower than levels in the controls. These observations elucidate a possible mechanism for arsenic exposure-induced pulmonary fibrosis.
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http://dx.doi.org/10.1016/j.envpol.2020.115810DOI Listing
January 2021

The mycobiome in murine intestine is more perturbed by food arsenic exposure than in excreted feces.

Sci Total Environ 2021 Jan 21;753:141871. Epub 2020 Aug 21.

Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan 523808, China. Electronic address:

Arsenic is a global pollutant that can accumulate in rice and has been confirmed to disturb the gut microbiome. By contrast, the influence on the gut mycobiome is seldom concerned because fungi comprise a numerically small proportion of the whole gut microcommunity. To expand the detection of the mycobiome in different gut sections of mammals and investigate the influence of food arsenic on the gut mycobiome in the digestive tract, we treated mice with feeds containing different compositions of arsenic species (7.3% sodium arsenate, 72.7% sodium arsenite, 1.0% sodium monomethylarsonate, and 19.0% sodium dimethylarsinate) in rice at a total arsenic dose of 30 mg/kg. After 60 days of exposure, the feces of four different sites, the ileum, cecum, colon, and excreted feces, were collected and analyzed by internal transcribed spacer gene sequencing. Among the samples, the major fungal phyla were Ascomycota, Basidiomycota, and Zygomycota; the top 10 fungal genera were Aspergillus, Verticillium, Penicillium, Cladosporium, Alternaria, Fusarium, Ophiocordyceps, Trametes, Mucor, and Nigrospora. In control mice, along the murine digestive tract, the mycobial richness and composition were significantly changed; Aspergillus and Penicillium possessed the higher ability to be stabilized in the murine gut, and larger proportions of positive correlations were observed among the major fungi. After arsenic exposure, the fungal composition was more disturbed in the intestinal tract than in feces. Along the digestive tract, arsenic can trigger larger mycobial variations, and the sensitivities of major fungi to arsenic were changed. Thus, the murine intestinal spatial mycobiota are more perturbed than excreted fecal mycobiota after food arsenic exposure. Feces are insufficient to be selected as a representative of the gut mycobiota in arsenic exposure studies.
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http://dx.doi.org/10.1016/j.scitotenv.2020.141871DOI Listing
January 2021

Triphenyl phosphate permeates the blood brain barrier and induces neurotoxicity in mouse brain.

Chemosphere 2020 Aug 16;252:126470. Epub 2020 Mar 16.

School of Public Health, Dongguan Key Laboratory of Environmental Medicine, Guangdong Medical University, Guangdong, 523-808, China. Electronic address:

Concerns have been raised over the neurotoxicity of triphenyl phosphate (TPP), but there have been few studies of the neurotoxic effects of TPP on mammals and the underlying mechanisms. In this study, weaned male mice (C57/BL6) were used and exposed to 0, 50, or 150 mg/kg TPP daily by oral gavage for 30 days. The blood brain barrier (BBB) permeability of TPP and its metabolite diphenyl phosphate (DPP) in the brain, and TPP induced metabolomic and transcriptomic changes of the brain were investigated. The results showed that TPP and DPP can cross the BBB of mice. Histopathological examination of the brain revealed abnormalities in the hippocampus, cortex and thalamus, and mice treated with high doses showed a potential inflammation in the thalamus and hippocampus. Untargeted metabolomic results revealed that the changed level of glutamic acid, N-acetyl CoA metabolites, and organic acid in the brain of treated mice, suggest that amino acid and lipid metabolism was interfered. RNA-seq data indicated that neuronal transcription processes and cell apoptosis pathway (forkhead box (FOXO), and mitogen-activated protein kinase (MAPK) signaling pathways) were significantly affected by TPP exposure. RT-PCR showed proinflammation cytokine tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6)) levels were increased, while antioxidant genes including nuclear factor-E2-related factor 2 (Nrf2), heme oxygenase1 (HO-1) and superoxide dismutase (SOD1) decreased. These results suggest that TPP could cause a degree of neurotoxicity by inducing neuroinflammation and neuronal apoptosis, which are related to oxidative stress. The potential implications for neurophysiology and behavioral regulation cannot be ignored.
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http://dx.doi.org/10.1016/j.chemosphere.2020.126470DOI Listing
August 2020

Development of a Pulsed Xenon Ultraviolet Disinfection Device for Real-Time Air Disinfection in Ambulances.

J Healthc Eng 2020 24;2020:6053065. Epub 2020 Feb 24.

Department of Environmental and Occupational Health, Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan 523808, China.

Objectives: We have developed a pulsed xenon ultraviolet light-based real-time air disinfection system with rapid and effective disinfection by using high-intensity pulse germicidal UV. Disinfection of the ambulance's environment is critical in the prevention of infectious cross contamination.

Methods: In this study, a pulsed xenon ultraviolet light-based air disinfection system was established for real-time air disinfection in ambulances. In this system, a pulsed xenon ultraviolet (PX-UV) was used to generate broad-spectrum (200-320 nm), high-intensity ultraviolet light to deactivate and kill bacteria and viruses. The results showed that the use of PX-UV could be effective in reducing , , and environmental pathogens level in ambulances (≥90% reduction in 30 mins).

Results: This device was relatively simple and easy to use and does not leave chemical residues or risk exposing patients and workers to toxic chemicals.

Conclusions: This appears to be a practical alternative technology to achieve automated air disinfection in ambulances.
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http://dx.doi.org/10.1155/2020/6053065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060415PMC
February 2020

Smad4 promotes diabetic nephropathy by modulating glycolysis and OXPHOS.

EMBO Rep 2020 02 9;21(2):e48781. Epub 2020 Jan 9.

Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China.

Diabetic nephropathy (DN) is the leading cause of end-stage kidney disease. TGF-β1/Smad3 signalling plays a major pathological role in DN; however, the contribution of Smad4 has not been examined. Smad4 depletion in the kidney using anti-Smad4 locked nucleic acid halted progressive podocyte damage and glomerulosclerosis in mouse type 2 DN, suggesting a pathogenic role of Smad4 in podocytes. Smad4 is upregulated in human and mouse podocytes during DN. Conditional Smad4 deletion in podocytes protects mice from type 2 DN, independent of obesity. Mechanistically, hyperglycaemia induces Smad4 localization to mitochondria in podocytes, resulting in reduced glycolysis and oxidative phosphorylation and increased production of reactive oxygen species. This operates, in part, via direct binding of Smad4 to the glycolytic enzyme PKM2 and reducing the active tetrameric form of PKM2. In addition, Smad4 interacts with ATPIF1, causing a reduction in ATPIF1 degradation. In conclusion, we have discovered a mitochondrial mechanism by which Smad4 causes diabetic podocyte injury.
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http://dx.doi.org/10.15252/embr.201948781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001498PMC
February 2020

Optimization and Identification of Antioxidant Peptide from Underutilized : Extraction, Gastrointestinal Digestion, and Fractionation.

Biomed Res Int 2019 20;2019:6424651. Epub 2019 Aug 20.

Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan 523808, China.

DPPH• scavenging peptides (<3kDa) from underutilized protein were obtained by the following successive treatment, i.e., ultrasound extraction, simulated gastrointestinal digestion hydrolyzation, and membrane ultrafiltration classification. The optimal condition for ultrasound-assisted extraction was an ultrasound wave with 800 W of power treating a mixture of 60 mL of 1.0 mol L NaOH and 2 g algae powder for 15 min. A high correlation (r=0.8146) between DPPH• scavenging activity and yield of the intact peptides showed their antioxidant capacity. Simulated digestion assay resulted in excellent DPPH• scavenging activity of the total peptide, amounting to (86.5 ± 10.1)%, comparing with the nondigestion samples at (46.8 ± 6.5)%. After fractionation, the 500-1000 Da fraction exhibited the highest DPPH• scavenging activity (81.2 ± 4.0)%, increasing 1.5 times due to digestion. Then, the 500-1000 Da fraction was analyzed by RPLC-Q Exactive HF mass spectrometer, and 4 novel peptides, i.e., Ile-Leu-Thr-Lys-Ala-Ala-Ile-Glu-Gly-Lys, Ile-Ile-Tyr-Phe-Gln-Gly-Lys, Asn-Asp-Pro-Ser-Thr-Val-Lys, and Thr-Val-Arg-Pro-Pro-Gln-Arg, were identified. From these amino acid sequences, hydrophobic residues accounted for 56%, which indicated their high antioxidant property. The results indicated that underutilized protein of could be a potential source of antioxidative peptides through simulated gastrointestinal digestion.
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http://dx.doi.org/10.1155/2019/6424651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6720044PMC
February 2020

Andrographolide antagonizes the cigarette smoke-induced epithelial-mesenchymal transition and pulmonary dysfunction through anti-inflammatory inhibiting HOTAIR.

Toxicology 2019 06 23;422:84-94. Epub 2019 May 23.

Center for Global Health, China International Cooperation Center for Environment and Human Health, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, People's Republic of China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, People's Republic of China. Electronic address:

In cells of the lung surface, cigarette smoke (CS) induces inflammatory and epithelial-mesenchymal transition (EMT), effects that are related to pulmonary dysfunction and Chronic obstructive pulmonary disease (COPD). However, the molecular mechanisms involved remain largely unknown, and potential therapeutic approaches are under development. In the present study, with cell culture and animal studies, we showed that CS exposure causes pulmonary dysfunction and airway remodeling with inflammatory cell infiltration. Consistent with these pulmonary lesions, the inflammatory factors interleukin-6 (IL-6) and interleukin-8 (IL-8) were increased in mice exposed to CS for 4 days. Accordingly, downstream signal transducer and activator of transcription 3 (STAT3) was activated, which up-regulated expression of the lncRNA HOTAIR, and enhancer of zeste homolog 2 (EZH2). In addition, CS exposure led to decreased levels of E-cadherin and to increased N-cadherin, vimentin, and α-SMA, indicating that the EMT was induced in mouse lung tissues. These effects, including increases of IL-6 and HOTAIR, were confirmed in human bronchial epithelial (HBE) cells treated with cigarette smoke extract (CSE). Finally, we established that, in HBE cells, andrographolide reversed the CSE-induced EMT via decreasing IL-6 levels and, in an animal model, prevented CS-induced lung inflammation and small airway remodeling, indicating that it has potential clinical application for CS-induced pulmonary dysfunction and COPD.
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http://dx.doi.org/10.1016/j.tox.2019.05.009DOI Listing
June 2019

Protective Effects of Aqueous Extracts of against Hydroquinone-Induced Toxicity in Hepatic L02 Cells.

Oxid Med Cell Longev 2018 18;2018:4528581. Epub 2018 Nov 18.

Department of Preventive Medicine, Gannan Medical University, 1 Yixueyuan Road, Ganzhou, 341000 Jiangxi, China.

Hydroquinone (HQ) is widely used in food stuffs and is an occupational and environmental pollutant. Although the hepatotoxicity of HQ has been demonstrated both in vitro and in vivo, the prevention of HQ-induced hepatotoxicity has yet to be elucidated. In this study, we focused on the intervention effect of aqueous extracts of (FLJ) on HQ-induced cytotoxicity. We demonstrated that HQ reduced cell viability in a concentration-dependent manner by administering 160 mol/L HQ for 12 h as the positive control of cytotoxicity. The aqueous FLJ extracts significantly increased cell viability and decreased LDH release, ALT, and AST in a concentration-dependent manner compared with the corresponding HQ-treated groups in hepatic L02 cells. This result indicated that aqueous FLJ extracts could protect the cytotoxicity induced by HQ. HQ increased intracellular MDA and LPO and decreased the activities of GSH, GSH-Px, and SOD in hepatic L02 cells. In addition, aqueous FLJ extracts significantly suppressed HQ-stimulated oxidative damage. Moreover, HQ promoted DNA double-strand breaks (DSBs) and the level of 8-hydroxy-2'-deoxyguanosine and apoptosis. However, aqueous FLJ extracts reversed HQ-induced DNA damage and apoptosis in a concentration-dependent manner. Overall, our results demonstrated that the toxicity of HQ was mediated by intracellular oxidative stress, which activated DNA damage and apoptosis. The findings also proved that aqueous FLJ extracts exerted protective effects against HQ-induced cytotoxicity in hepatic L02 cells.
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http://dx.doi.org/10.1155/2018/4528581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6276457PMC
January 2019

Benzene-induced mouse hematotoxicity is regulated by a protein phosphatase 2A complex that stimulates transcription of .

J Biol Chem 2019 02 19;294(7):2486-2499. Epub 2018 Dec 19.

From the Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080,

Chronic benzene exposure is associated with hematotoxicity and the development of aplastic anemia and leukemia. However, the signaling pathways underlying benzene-induced hematotoxicity remain to be defined. Here, we investigated the role of protein phosphatase 2A (PP2A) in the regulation of benzene-induced hematotoxicity in a murine model. Male mice with a hepatocyte-specific homozygous deletion of the gene (encoding PP2A Aα subunit) (HO) and matched wildtype (WT) mice were exposed to benzene via inhalation at doses of 1, 10, and 100 ppm for 28 days. Peripheral white blood cell counts and activation of bone marrow progenitors were attenuated in the HO mice, indicating that deletion protects against benzene-induced hematotoxicity. Moreover, elevation of urinary -phenyl mercapturic acid, a benzene metabolite, was much greater in WT mice than in HO mice. Real-time exhalation analysis revealed more exhaled benzene but fewer benzene metabolites in HO mice than in WT mice, possibly because of the down-regulation of Cyp2e1, encoding cytochrome P4502E1, in hepatocytes of the HO mice. Loss-of-function screening disclosed that PP2A complexes containing the B56α subunit participate in regulating Cyp2e1 expression. Notably, PP2A-B56α suppression in HepG2 cells resulted in persistent β-catenin phosphorylation at Ser-Ser-Thr in response to CYP2E1 agonists. In parallel, nuclear translocation of β-catenin was inhibited, concomitant with a remarkable decrease of Cyp2e1 expression. These findings support the notion that a regulatory cascade comprising PP2A-B56α, β-catenin, and Cyp2e1 is involved in benzene-induced hematotoxicity, providing critical insight into the role of PP2A in responses to the environmental chemicals.
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http://dx.doi.org/10.1074/jbc.RA118.006319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6378973PMC
February 2019

The effects of Nrf2 knockout on regulation of benzene-induced mouse hematotoxicity.

Toxicol Appl Pharmacol 2018 11 6;358:56-67. Epub 2018 Sep 6.

Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, China. Electronic address:

Previous studies have demonstrated that oxidative stress is implicated in benzene-induced hematotoxicity. However, the low dose-response effects and the mechanism underlying perturbation of hematopoiesis remain to be defined. This study aims to address the role of Nrf2 pathway in mediating benzene-induced hematotoxicity. Nrf2 (wildtype, Nrf2-WT) and Nrf2 (knockout, Nrf2-KO) mice were administrated with benzene at doses of 0.1, 1.0, 10.0, 100.0 mg/kg by oral gavage for a consecutive 4 weeks (6 times/week). As a result, benzene exposure caused a decline of WBC and lymphocyte counts in a dose-dependent manner at a dose range from 1.0 to 100.0 mg/kg, while low dose benzene induced hormesis effects. Interestingly, Nrf2 deficiency seemed to relieve the decline of peripheral blood cell counts upon benzene exposure, indicating the involvement of Nrf2 in regulation of benzene-induced hematotoxicity. The suppression of phase II enzyme expression in Nrf2-KO mice resulted in considerable reduction in detoxification indicated by the decrease of urinary S-phenylmercapturic acid (SPMA), a metabolite of benzene. Ex vivo assay revealed enhanced cytotoxicity and oxidative stress were induced by benzene in Nrf2-KO mice. Notably, the depletion of Nrf2 triggered the proliferation and differentiation of hematopoietic cells, but induced aberrant morphological changes in periphery erythrocytes and bone marrow cells, implicating the compensatory effects carried on at the expense of induction of dysfunctional blood cells. Our findings provide a new insight into a low dose-response towards benzene-induced hematotoxicity and uncover the critical role of Nrf2 pathway in mediating abnormal hematopoiesis in response to oxidative stress.
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http://dx.doi.org/10.1016/j.taap.2018.09.002DOI Listing
November 2018

Circ008913, via miR-889 regulation of DAB2IP/ZEB1, is involved in the arsenite-induced acquisition of CSC-like properties by human keratinocytes in carcinogenesis.

Metallomics 2018 09;10(9):1328-1338

Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China.

Arsenic is a known human carcinogen and the mechanisms underlying arsenic-induced tumorigenesis remain elusive. Circular RNAs (circRNAs) are involved in the development of cancers, generally acting as sponges for microRNAs (miRNAs). Here, we screened the circRNA expression profiles of HaCaT cells, which are immortalized human keratinocytes, and arsenite-transformed HaCaT cells (T-HaCaT). The presence of has_circRNA-008913 (circ008913) was confirmed in HaCaT cells. Among the circRNAs down-regulated in T-HaCaT cells, circ008913 showed the greatest decrease and was chosen for further research. In HaCaT cells, arsenite induced increases of mRNA levels of the genes for cell-surface markers (k5 and CD34) of skin stem cells, decreases of DAB2IP, and increases of ZEB1. MicroRNA (miR)-889 suppressed the expression of DAB2IP and was involved in regulation of cancer stem cells (CSCs). Moreover, overexpression of circ008913 with pLCDH-circ008913 or transfection with an miR-889 inhibitor reduced the capacity of T-HaCaT cells for colony formation, invasion, migration, and the sizes of tumors in nude mice, effects that were reversed by co-transfection with an miR-889 mimic. These results suggest that, in HaCaT cells, arsenite decreases circ008913 levels, which act as a sponge for miR-889 and down-regulate the miR-889 target, DAB2IP, which, in turn, up-regulates ZEB1, increases mRNA levels of the cell-surface markers of skin stem cells, and is involved in arsenite-induced acquisition of CSC-like properties that lead to malignant transformation. The results also indicate that circ008913 functions as a competing endogenous RNA (ceRNA) for miR-889, which is involved in the arsenite-induced acquisition of CSC-like properties by regulation of DAB2IP and elucidate a previously unknown mechanism between arsenite-induced acquisition of CSC-like properties and carcinogenesis.
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http://dx.doi.org/10.1039/c8mt00207jDOI Listing
September 2018

Luteoloside Inhibits Proliferation and Promotes Intrinsic and Extrinsic Pathway-Mediated Apoptosis Involving MAPK and mTOR Signaling Pathways in Human Cervical Cancer Cells.

Int J Mol Sci 2018 Jun 5;19(6). Epub 2018 Jun 5.

Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan 523808, China.

Cervical cancer is a common gynecological malignancy with high incidence and mortality. Drugs commonly used in chemotherapy are often accompanied by strong side-effects. To find an anti-cervical cancer drug with high effects and low toxicity, luteoloside was used to treat the cervical cancer cell line Hela to investigate its effects on cell morphology, proliferation, apoptosis, and related proteins. The study demonstrated that luteoloside could inhibit proliferation remarkably; promote apoptosis and cytochrome C release; decrease the mitochondrial membrane potential and reactive oxygen species level; upregulate the expression of Fas, Bax, p53, phospho-p38, phospho-JNK, and cleaved PARP; downregulate the expression of Bcl-2 and phospho-mTOR; activate caspase-3 and caspase-8; change the nuclear morphology, and fragmentate DNA in Hela cells. These results strongly suggest that luteoloside can significantly inhibit the proliferation and trigger apoptosis in Hela cells. In contrast, luteoloside had less proliferation inhibiting effects on the normal cell lines HUVEC12 and LO2, and minor apoptosis promoting effects on HUVEC12 cells. Furthermore, the luteoloside-induced apoptosis in Hela cells is mediated by both intrinsic and extrinsic pathways and the effects of luteoloside may be regulated by the mitogen-activated protein kinases and mTOR signaling pathways via p53.
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http://dx.doi.org/10.3390/ijms19061664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6032149PMC
June 2018

The profiles and networks of miRNA, lncRNA, mRNA, and circRNA in benzo(a)pyrene-transformed bronchial epithelial cells.

J Toxicol Sci 2018 ;43(4):281-289

Our aim was to demonstrate the significance of miRNA, lncRNA, and circRNA in the transformation of human bronchial epithelial cells induced by benzo(a)pyrene (BaP), and to investigate their regulatory networks. Hierarchical clustering, gene ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and network regulation analysis were used to analyze the high-throughput sequencing results of human bronchial epithelial cell line BEAS-2B and BaP-transformed BEAS-2B cells (BEAS-2B-T). 76,191,786 and 3,431differentially-expressed miRNA, lncRNA, mRNA and circRNA were detected, respectively; 43 miRNA, 48 lncRNA, 438 mRNA and 2,079 circRNA were up-regulated; 33 miRNA, 143 lncRNA, 348 mRNA and 1,352 circRNA were down-regulated. Through GO analysis, 257 biological process (BP) terms, 12 cell composition (CC) terms and 49 molecular function (MF) terms were found in differentially-expressed lncRNA; 143 BP terms, 32 CC terms, and 48 MF terms were found in differentially-expressed circRNA. Pathways of KEGG analysis of lncRNA and circRNA could be classified into the categories "human diseases" and "organism systems". From miRNA-circRNA, circRNA-mRNA, and lncRNA-circRNA networks analysis, we found that mir-137, circ-RPS5, circ-ZNF292, circ-ERBB2IP, circ-SEMA3C, circ-IGF1R, circ-RTN4, APOC1, and CDKN2A may be of great significance for cell transformation. From the analysis of miRNA, lncRNA, mRNA, and circRNA networks, we found that PDGFRB, lncRNA RGMB-AS1, circ-ZNF292 are associated with miR-138-5p. Our study shows that miRNA, lncRNA, and circRNA have a significant regulatory role in the transformation of human bronchial epithelial cell induced by BaP.
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http://dx.doi.org/10.2131/jts.43.281DOI Listing
August 2018

miR-7-5p overexpression suppresses cell proliferation and promotes apoptosis through inhibiting the ability of DNA damage repair of PARP-1 and BRCA1 in TK6 cells exposed to hydroquinone.

Chem Biol Interact 2018 Mar 5;283:84-90. Epub 2018 Feb 5.

Department of Environmental and Occupational Health, Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan, China. Electronic address:

Hydroquinone (HQ), one of the major metabolic products of benzene, is a carcinogen, which induces apoptosis and inhibit proliferation in lymphoma cells. microRNA-7-5p (miR-7-5p), a tumor suppressor, participates in various biological processes including cell proliferation and apoptosis regulation by repressing expression of specific oncogenic target genes. To explore whether miR-7-5p is involved in HQ-induced cell proliferation and apoptosis, we assessed the effect of miR-7-5p overexpression on induction of apoptosis analyzed by FACSCalibur flow cytometer in transfection of TK6 cells with miR-7-5p mimic (TK6- miR-7-5p). We observed an increased apoptosis by 25.43% and decreased proliferation by 28.30% in TK6-miR-7-5p cells compared to those negative control cells (TK6-shNC) in response to HQ treatment. Furthermore, HQ might active the apoptotic pathway via partly downregulation the expression of BRCA1 and PARP-1, followed by p53 activation, in TK6-miR-7-5p cells. In contrast, attenuated p53 and BRCA1 expression was observed in shPARP-1 cells than in NC cells after HQ treatment. Therefore, we conclude that HQ may activate apoptotic signals via inhibiting the tumor suppressive effects of miR-7-5p, which may be mediated partly by upregulating the expression of PARP-1 and BRCA1 in control cells. The increase of miR-7-5p expression further intensified downregulation of PARP-1 and BRCA1 in TK6-miR-7-5p cells, resulting in an increase of apoptosis and proliferation inhibited.
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http://dx.doi.org/10.1016/j.cbi.2018.01.019DOI Listing
March 2018

Differently expressed long noncoding RNAs and mRNAs in TK6 cells exposed to low dose hydroquinone.

Oncotarget 2017 Nov 4;8(56):95554-95567. Epub 2017 Oct 4.

Department of Environmental and Occupational Health, Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan, 523808, China.

Previous studies have shown that long noncoding RNAs (lncRNAs) were related to human carcinogenesis and might be designated as diagnosis and prognosis biomarkers. Hydroquinone (HQ), as one of the metabolites of benzene, was closely relevant to occupational benzene poisoning and occupational leukemia. Using high-throughput sequencing technology, we investigated differences in lncRNA and mRNA expression profiles between experimental group (HQ 20 μmol/L) and control group (PBS). Compared to control group, a total of 65 lncRNAs and 186 mRNAs were previously identified to be aberrantly expressed more than two fold change in experimental group. To validate the sequencing results, we selected 10 lncRNAs and 10 mRNAs for quantitative real-time PCR (qRT-PCR). Through GO annotation and KEGG pathway analysis, we obtained 3 mainly signaling pathways, including P53 signaling pathway, which plays an important role in tumorigenesis and progression. After that, 25 lncRNAs and 32 mRNAs formed the lncRNA-mRNA co-expression network were implemented to play biological functions of the dysregulated lncRNAs transcripts by regulating gene expression. The lncRNAs target genes prediction provided a new idea for the study of lncRNAs. Finally, we have another important discovery, which is screened out 11 new lncRNAs without annotated. All these results uncovered that lncRNA and mRNA expression profiles in TK6 cells exposed to low dose HQ were different from control group, helping to further study the toxicity mechanisms of HQ and providing a new direction for the therapy of leukemia.
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http://dx.doi.org/10.18632/oncotarget.21481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5707042PMC
November 2017

Enhanced H3K4me3 modifications are involved in the transactivation of DNA damage responsive genes in workers exposed to low-level benzene.

Environ Pollut 2018 Mar 22;234:127-135. Epub 2017 Nov 22.

Guangzhou Key Laboratory of Environmental Pollution and Health Risk Assessment, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, China. Electronic address:

In this study, we explore whether altered global histone modifications respond to low-level benzene exposure as well as their association with the hematotoxicity. We recruited 147 low-level benzene-exposed workers and 122 control workers from a petrochemical factory in Maoming City, Guangdong Province, China. The internal exposure marker level, urinary S-phenylmercapturic acid (SPMA), in benzene-exposed workers was 1.81-fold higher than that of the controls (P < 0.001). ELISA method was established to examine the specific histone modifications in human peripheral blood lymphocytes (PBLCs) of workers. A decrease in the counts of white blood cells (WBC), neutrophils, lymphocytes, and monocytes appeared in the benzene-exposed group (all P < 0.05) compared to the control group. Global trimethylated histone 3 lysine 4 (H3K4me3) modification was enhanced in the benzene-exposed group (P < 0.05) and was positively associated with the concentration of urinary SPMA (β = 0.103, P = 0.045) and the extent of DNA damage (% Tail DNA: β = 0.181, P = 0.022), but was negatively associated with the leukocyte count (WBC: β = -0.038, P = 0.023). The in vitro study revealed that H3K4me3 mark was enriched in the promoters of several DNA damage responsive (DDR) genes including CRY1, ERCC2, and TP53 in primary human lymphocytes treated with hydroquinone. Particularly, H3K4me3 modification was positively correlated with the expression of CRY1 in the PBLCs of benzene-exposed workers. These observations indicate that H3K4me3 modification might mediate the transcriptional regulation of DDR genes in response to low-dose benzene exposure.
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http://dx.doi.org/10.1016/j.envpol.2017.11.042DOI Listing
March 2018

PARP‑1 may be involved in hydroquinone‑induced apoptosis by poly ADP‑ribosylation of ZO‑2.

Mol Med Rep 2017 Dec 27;16(6):8076-8084. Epub 2017 Sep 27.

Department of Environmental and Occupational Health, Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan, Guangdong 523808, P.R. China.

Hydroquinone (HQ), a major reactive metabolite of benzene, contributes to benzene‑induced leukemia. The molecular mechanisms that underlie this activity remain to be elucidated. Poly ADP‑ribosylation (PARylation) is a type of reversible posttranslational modification that is performed by enzymes in the PAR polymerase (PARP) family and mediates different biological processes, including apoptosis. Zona occludens 2 (ZO‑2) is a tight junction scaffold protein, which is involved in cell proliferation and apoptosis. The present study investigated the activity and mechanisms regulated by PARP‑1 during HQ‑induced apoptosis using TK6 lymphoblastoid cells and PARP‑1‑silenced TK6 cells. The results revealed that exposure to 10 µM HQ for 72 h induced apoptosis in TK6 cells and that apoptosis was attenuated in PARP‑1‑silenced TK6 cells. In cells treated with HQ, inhibition of PARP‑1 increased the expression of B cell leukemia/lymphoma 2 (Bcl‑2), increased ATP production and reduced reactive oxygen species (ROS) production relative to the levels observed in cells treated with HQ alone. Co‑localization of ZO‑2 and PAR (or PARP‑1 protein) was determined using immunofluorescence confocal microscopy. The findings of the present study revealed that ZO‑2 was PARylated via an interaction with PARP‑1, which was consistent with an analysis of protein expression that was performed using western blot analysis, which determined that ZO‑2 protein expression was upregulated in HQ‑treated control cells and downregulated in HQ‑treated PARP‑1‑silenced TK6 cells. These findings indicated that prolonged exposure to a low dose of HQ induced TK6 cells to undergo apoptosis, whereas inhibiting PARP‑1 attenuates cellular apoptosis by activating Bcl‑2 and energy‑saving processes and reducing ROS. The present study determined that PARP‑1 was involved in HQ‑induced apoptosis by PARylation of ZO‑2.
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http://dx.doi.org/10.3892/mmr.2017.7643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5779892PMC
December 2017

Combination of betulinic acid and chidamide synergistically inhibits Epstein-Barr virus replication through over-generation of reactive oxygen species.

Oncotarget 2017 Sep 27;8(37):61646-61661. Epub 2017 Jun 27.

School of Public Health, Guangdong Medical University, Dongguan 523808, PR China.

Epstein-Barr virus (EBV) has widely infected more than 90% of human populations. Currently, there is no efficient way to remove the virus because the EBV carriers are usually in a latent stage that allows them to escape the immune system and common antiviral drugs. In the effort to develop an efficient strategy for the removal of the EBV virus, we have shown that betulinic acid (BA) slightly suppresses EBV replication through SOD2 suppression with subsequent reactive oxygen species (ROS) generation and DNA damage in EBV-transformed LCL (lymphoblastoid cell line) cells. Chidamide (CDM, CS055), a novel histone deacetylase inhibitor (HDACi), could significantly switch EBV from the latent stage to the lytic stage with increased gene expression of BZLF1 and BMRF1, but has a small effect on EBV replication due to the suppression effect of CDM-mediated ROS generation. Interestingly, a combination of BA and CDM synergistically inhibits EBV replication with ROS over-generation and subsequent DNA damage and apoptosis. Overexpression of SOD2 diminishes this effect, while SOD2 knockdown mimics this effect. An xenograft tumor development study with the tail vein injection of EBV-transformed LCL cells in nude mice proves that the combination of BA and CDM synergistically increases superoxide anion release in tumor tissues and suppresses EBV replication and tumor growth, and significantly prolongs mouse survival. We conclude that the combination of BA and CDM could be an efficient strategy for clinical EBV removal.
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http://dx.doi.org/10.18632/oncotarget.18661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5617453PMC
September 2017

Bcl-2 protects TK6 cells against hydroquinone-induced apoptosis through PARP-1 cytoplasm translocation and stabilizing mitochondrial membrane potential.

Environ Mol Mutagen 2018 01 26;59(1):49-59. Epub 2017 Aug 26.

Department of Environmental and Occupational Health, Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan, 523808, China.

B cell leukemia/lymphoma-2 (Bcl-2) suppresses apoptosis by binding the BH3 domain of proapoptotic factors and thereby regulating mitochondrial membrane potential (MMP). This study aimed to investigate the role of Bcl-2 in controlling the mitochondrial pathway of apoptosis during hydroquinone (HQ)-induced TK6 cytotoxicity. In this study, HQ, one metabolite of benzene, decreased the MMP in a concentration-dependent manner and induced the generation of reactive oxygen species (ROS), the activation of the DNA damage marker γ-H2AX, and production of the DNA damage-responsive enzyme poly(ADP-ribose)polymerase-1 (PARP-1). Exposure of TK6 cells to HQ leads to an increase in Bcl-2 and co-localization with PARP-1 in the cytoplasm. Inhibition of Bcl-2 using the BH3 mimetic, ABT-737, suppressed the PARP-1 nuclear to cytoplasm translocation and sensitized TK6 cells to HQ-induced apoptosis through depolarization of the MMP. Western blot analysis indicated that ABT-737 combined with HQ increased the levels of cleaved PARP and γ-H2AX, but significantly decreased the level of P53. Thus, ABT-737 can influence PARP-1 translocation and induce apoptosis via mitochondria-mediated apoptotic pathway, independently of P53. In addition, we found that knockdown of PARP-1 attenuated the HQ-induced production of cleaved PARP and P53. These results identify Bcl-2 as a protective mediator of HQ-induced apoptosis and show that upregulation of Bcl-2 helps to localize PARP-1 to the cytoplasm and stabilize MMP. Environ. Mol. Mutagen. 59:49-59, 2018. © 2017 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/em.22126DOI Listing
January 2018

Long non-coding RNAs: The novel diagnostic biomarkers for leukemia.

Environ Toxicol Pharmacol 2017 Oct 18;55:81-86. Epub 2017 Aug 18.

Department of Environmental and Occupational Health, Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan, 523808, China. Electronic address:

Long non-coding RNAs (LncRNAs) are a category of non-coding RNAs (ncRNAs) with a length of 200nt-100kb lacking a significant open reading frame. The study of lncRNAs is a newly established field, due in part to their capability to act as the novel biomarkers in disease. A growing body of research shows that lncRNAs may not only useful as biomarkers for the diagnosis and clinical typing and prognosis of cancers, but also as potential targets for novel therapies. Differential expression of lncRNAs has been found in leukemia in the last two years, however, the majority of the lncRNAs described here are transcripts of unknown function and their role in leukemogenesis is still unclear. Here, we summarize the lncRNAs associated with leukemia in order to find a potential classification tool for leukemia, and a new field of research is being explored.
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http://dx.doi.org/10.1016/j.etap.2017.08.014DOI Listing
October 2017

Down-regulation of miRNA-451a and miRNA-486-5p involved in benzene-induced inhibition on erythroid cell differentiation in vitro and in vivo.

Arch Toxicol 2018 Jan 21;92(1):259-272. Epub 2017 Jul 21.

Guangzhou Key Laboratory of Environmental Pollution and Health Risk Assessment, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, China.

Exposure to high-dose benzene leads to the inhibition of erythroid differentiation. However, whether lower doses of benzene exposure resemble high-dose effects in erythroid differentiation, as well as the underlying mechanisms, remains largely unknown. To identify the microRNAs (miRNAs) specifically responsible for benzene exposure and their regulatory role in erythroid differentiation, we performed miRNA microarray in CD34 hematopoietic progenitor cells isolated from human umbilical cord blood after treatment with hydroquinone (HQ), a metabolite of benzene at concentrations of 0, 1.0, 2.5, and 5.0 μM. As a result, HQ treatment inhibited erythroid differentiation in a dose-response manner. miRNA microarray analysis revealed that miRNA-451a, miRNA-486-5p and miRNA-126-3p expression were significantly lower in HQ-treated CD34 hematopoietic progenitor cells. In vitro studies showed that miRNA-451a and miRNA-486-5p were up-regulated during erythroid differentiation both in CD34 hematopoietic progenitor cells and K562 cells. The increase in the percentage of benzidine-positive cells and the expression of γ-globin in K562 cells transfected with either miRNA-451a or miRNA-486-5p mimic indicated that both miRNAs played a role in the promotion of erythroid cell differentiation. Overexpression of either miRNA-451a or miRNA-486-5p attenuated the inhibitory effects on erythroid differentiation in HQ-treated K562 cells. In vivo study showed a decreasing count of peripheral red blood cell (RBC) in C57BL/6J male mice treated with aerosol benzene at concentrations of 0, 1, 5, 25 ppm (time weight average, TWA). In addition, the expression of miRNA-451a or miRNA-486-5p was negatively correlated with the concentration of benzene inhalation on erythroid toxicity of C57BL/6J mice. Particularly, the decline in miRNA-451a and miRNA-486-5p expression appeared in male chronic benzene poisoning patients, and was correlated with a constant decrease in their RBC counts over the first 3 months after being diagnosed. These findings indicate that the suppression of miRNA-451a or miRNA-486-5p might be associated with the benzene-induced perturbation of erythroid cell differentiation.
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http://dx.doi.org/10.1007/s00204-017-2033-7DOI Listing
January 2018

Dichloroacetonitrile induces cytotoxicity through oxidative stress-mediated and p53-dependent apoptosis pathway in LO2 cells.

Toxicol Mech Methods 2017 Oct 7;27(8):575-581. Epub 2017 Jul 7.

a Department of Environmental and Occupational Health, Dongguan Key Laboratory of Environmental Medicine, School of Public Health , Guangdong Medical University , Dongguan , China.

Dichloroacetonitrile (DCAN), one of the disinfection byproducts of water chlorination, induces cell proliferation and apoptosis; however, the detailed mechanism remains unclear. Oxidative stress participates in various biological processes, including DNA damage and cytotoxicity. To explore whether oxidative stress mediated DCAN-induced cell proliferation and apoptosis, we assessed the effect of redox imbalance and apoptosis in LO2 cells. We observed increase of reactive oxygen species and malondialdehyde and increased apoptosis by 13.6% in 500 μM DCAN compared with the control group. We also observed a decrease of antioxidant ability damage including glutathione, superoxide dismutase, and total antioxidant capacity depletion. Furthermore, DCAN might activate oxidative stress-mediated apoptosis pathway via up-regulation of p53 expression and caspase-3 activity. Therefore, we conclude that DCAN may activate apoptotic signals via p53 up-regulation and oxidative stress-mediated apoptosis in LO2 cells.
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http://dx.doi.org/10.1080/15376516.2017.1337257DOI Listing
October 2017

Corrigendum to "Inhibition of autophagy enhances hydroquinone-induced TK6 cell death" [Toxicol. in Vitro 41 (2017) 123-132].

Toxicol In Vitro 2017 08 13;42:358. Epub 2017 May 13.

School of Public Health, Guangdong Medical University, PR-523808 Dongguan, Guangdong, China; Dongguan Key Laboratory of Environmental Medicine, PR-523808 Dongguan, Guangdong, China. Electronic address:

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http://dx.doi.org/10.1016/j.tiv.2017.05.004DOI Listing
August 2017

Hydroquinone induces TK6 cell growth arrest and apoptosis through PARP-1/p53 regulatory pathway.

Environ Toxicol 2017 Sep 26;32(9):2163-2171. Epub 2017 Apr 26.

Department of Environmental and Occupational Health, Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan, China.

Hydroquinone (HQ), one of the most important metabolites derived from benzene, induces cell cycle arrest and apoptosis. Poly(ADP-ribose) polymerase-1 (PARP-1) participates in various biological processes, including DNA repair and cell cycle regulation. To explore whether PARP-1 regulatory pathway mediated HQ-induced cell cycle arrest and apoptosis, we assessed the effect of PARP-1 suppression on induction of apoptosis analyzed by FACSCalibur flow cytometer in PARP-1 deficientTK6 cells (TK6-shPARP-1). We observed an increase in the fraction of cells in G1 phase by 7.6% and increased apoptosis by 4.5% in PARP-1-deficient TK6 cells (TK6-shPARP-1) compared to those negative control cells (TK6-shNC cells) in response to HQ treatment. Furthermore, HQ might activate the extrinsic pathways of apoptosis via up-regulation of Fas expression, followed by caspase-3 activation, apoptotic body, and sub G1 accumulation. Enhanced p53 expression was observed in TK6-shPARP-1 cells than in TK6-shNC cells after HQ treatment. In contrast, Fas expression was lower in TK6-shPARP-1 cells than in TK6-shNC cells. Therefore, we conclude that HQ may activate apoptotic signals via Fas up-regulation and p53-mediated apoptosis in TK6-shNC cells. The reduction of PARP-1 expression further intensified up-regulation of p53 in TK6-shPARP-1 cells, resulting in an increased G1→S phase cell arrest and apoptosis in TK6-shPARP-1 cells compared to TK6-shNC cells.
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http://dx.doi.org/10.1002/tox.22429DOI Listing
September 2017

LincRNa-p21: function and mechanism in cancer.

Med Oncol 2017 May 19;34(5):98. Epub 2017 Apr 19.

Department of Environmental and Occupational Health, Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan, 523808, China.

In view of the rapid development of gene chips and high-throughput sequencing technology, noncoding RNAs (ncRNas) form a high percentage of the mammalian genome. Two major subgroups of ncRNAs that have been identified are the long ncRNAs (lncRNas) and the microRNAs. A number of studies in the past few years have showed crucial functions for lncRNas in cancer. LincRNa-p21 as a p53-dependent transcriptional target gene and a potential diagnostic marker is involved in proliferation, cell cycle, metabolism and reprogramming. In addition, more researches revealed that lincRNa-p21 is associated with cancer progression and contributed to the treatment and prognosis of cancer. In this review, we briefly summarize the function and molecular mechanisms of lincRNa-p21 in cancer and its regulation for the genes expression .
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http://dx.doi.org/10.1007/s12032-017-0959-5DOI Listing
May 2017