Publications by authors named "Yuan-Hua Chen"

103 Publications

Tauroursodeoxycholic acid alleviates pulmonary endoplasmic reticulum stress and epithelial-mesenchymal transition in bleomycin-induced lung fibrosis.

BMC Pulm Med 2021 May 5;21(1):149. Epub 2021 May 5.

Second Affiliated Hospital, Anhui Medical University, Hefei, 230032, China.

Background: Several studies demonstrate that endoplasmic reticulum (ER) stress-mediated epithelial-mesenchymal transition (EMT) is involved in the process of bleomycin (BLM)-induced pulmonary fibrosis. Tauroursodeoxycholic acid (TUDCA), a bile acid with chaperone properties, is an inhibitor of ER stress. This study aimed to investigate the preventive effects of TUDCA on BLM-induced EMT and lung fibrosis.

Methods: The model of lung fibrosis was established by intratracheal injection with a single dose of BLM (3.0 mg/kg). In TUDCA + BLM group, mice were intraperitoneally injected with TUDCA (250 mg/kg) daily.

Results: BLM-induced alveolar septal destruction and inflammatory cell infiltration were alleviated by TUDCA. BLM-induced interstitial collagen deposition, as determined by Sirius Red staining, was attenuated by TUDCA. BLM-induced elevation of pulmonary α-smooth muscle actin (α-SMA) and reduction of pulmonary E-cadherin were attenuated by TUDCA. BLM-induced pulmonary Smad2/3 phosphorylation was suppressed by TUDCA. BLM-induced elevation of Ki67 and PCNA was inhibited by TUDCA in mice lungs. In addition, BLM-induced elevation of HO-1 (heme oxygenase-1) and 3-NT (3-nitrotyrosine) was alleviated by TUDCA. Finally, BLM-induced upregulation of pulmonary GRP78 and CHOP was attenuated by TUDCA.

Conclusions: These results provide evidence that TUDCA pretreatment inhibits Smad2/3-medited EMT and subsequent lung fibrosis partially through suppressing BLM-induced ER stress and oxidative stress.
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http://dx.doi.org/10.1186/s12890-021-01514-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097922PMC
May 2021

Microcystin-LR inhibits testosterone synthesis via reactive oxygen species-mediated GCN2/eIF2α pathway in mouse testes.

Sci Total Environ 2021 Aug 25;781:146730. Epub 2021 Mar 25.

Department of Toxicology & Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University, Hefei 230032, China. Electronic address:

Previous studies demonstrated that microcystin-leucine-arginine (MC-LR) disrupted testosterone (T) synthesis, but the underlying mechanisms are not entirely elucidated. This study aims to explore the role of reactive oxygen species (ROS)-mediated GCN2/eIF2α activation on MC-LR-induced disruption of testicular T synthesis. Male mice were intraperitoneally injected with MC-LR (0 or 20 μg/kg) daily for 5 weeks. Serum T was decreased in MC-LR-exposed mice (0.626 ± 0.122 vs 24.565 ± 8.486 ng/ml, P < 0.01), so did testicular T (0.667 ± 0.15 vs 8.317 ± 1.387 ng/mg protein, P < 0.01). Steroidogenic proteins including StAR, CYP11A1 and CYP17A1 were downregulated in MC-LR-exposed mouse testes and TM3 cells. Mechanistically, p-GCN2 and p-eIF2α were elevated in MC-LR-exposed TM3 cells. GCN2iB attenuated MC-LR-induced GCN2 and eIF2α phosphorylation in TM3 cells. Moreover, GCN2iB attenuated MC-LR-induced downregulation of steroidogenic proteins in TM3 cells. Further analysis found that cellular ROS were elevated and HO-1 was upregulated in MC-LR-exposed TM3 cells. PBN rescued MC-LR-induced activation of GCN2/eIF2α signaling in TM3 cells. Additionally, pretreatment with PBN attenuated MC-LR induced downregulation of steroidogenic proteins and synthases in TM3 cells. These results suggest that ROS-mediated GCN2/eIF2α activation contributes partially to MC-LR-caused downregulation of steroidogenic proteins and synthases. The present study provides a new clue for understanding the mechanism of MC-LR-induced endocrine disruption.
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http://dx.doi.org/10.1016/j.scitotenv.2021.146730DOI Listing
August 2021

Supplementation with high-dose cholecalciferol throughout pregnancy induces fetal growth restriction through inhibiting placental proliferation and trophoblast epithelial-mesenchymal transition.

J Nutr Biochem 2021 05 3;91:108601. Epub 2021 Feb 3.

Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University, Hefei, China. Electronic address:

Vitamin D deficiency has been associated with adverse pregnant outcomes. Several studies investigated the effects of maternal vitamin D3 supplementation on fetal development with inconsistent results. The aim of this study was to investigate the effects of maternal supplementation with different doses of vitamin D3 on fetal development. Pregnant mice were administered with different doses of cholecalciferol (0, 2,000, 10,000, 40,000 IU/kg/day) by gavage throughout pregnancy. Fetal weight and crown-rump length were measured. Placental proliferation and mesenchymal characteristics were detected. HTR-8/SVneo cells were incubated in the absence or presence of calcitriol (500 nmol/L) to evaluate the effects of active vitamin D3 on migration and invasion of human trophoblast cells. Although a low dose of cholecalciferol was safe, fetal weight and crown-rump length were decreased in dams treated with high-dose cholecalciferol throughout pregnancy. Placental weight and labyrinth thickness were reduced in mice administered with high-dose cholecalciferol. An obvious calcification was observed in placentae of mice administered with high-dose cholecalciferol. Ki67-positive cells, a marker of placental proliferation, were reduced in mice administered with high-dose cholecalciferol. N-cadherin and vimentin, two mesenchymal markers, were decreased in cholecalciferol-treated mouse placentae and calcitriol-treated human trophoblast cells. MMP-2 and MMP-9, two matrix metalloproteinases, were downregulated in cholecalciferol-treated mouse placentae and calcitriol-treated human trophoblast cells. In addition, trophoblast migration and invasion were suppressed by calcitriol. Supplementation with high-dose cholecalciferol induces fetal growth restriction partially through inhibiting placental proliferation and trophoblast epithelial-mesenchymal transition.
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http://dx.doi.org/10.1016/j.jnutbio.2021.108601DOI Listing
May 2021

Di-(2-ethylhexyl) phthalate induces testicular endoplasmic reticulum stress and germ cell apoptosis in adolescent mice.

Environ Sci Pollut Res Int 2021 May 7;28(17):21696-21705. Epub 2021 Jan 7.

Department of Toxicology, Anhui Medical University, Hefei, 230032, China.

Di-(2-ethylhexyl) phthalate (DEHP) is a male reproductive toxicant. This research is aimed at investigating the effect of pubertal DEHP exposure on testicular endoplasmic reticulum (ER) stress and germ cell apoptosis. Five-week-old male mice were orally administered with DEHP (0, 0.5, 50, or 500 mg/kg/day) for 35 days. Testis weight and sperm count were reduced in mice exposed to 500 mg/kg/day DEHP. The number of seminiferous tubules in stages VII-VIII, mature seminiferous tubules, was reduced and the number of seminiferous tubules in stages IX-XII, immature seminiferous tubules, was elevated in mice treated with 500 mg/kg/day DEHP. Numerous apoptotic germ cells were observed in mouse seminiferous tubules exposed to 50 and 500 mg/kg/day DEHP. Moreover, cleaved caspase-3 was elevated in mouse testes exposed to 500 mg/kg/day DEHP. In addition, Bcl-2 was reduced and Bax/Bcl-2 was elevated in mouse testes exposed to 500 mg/kg/day DEHP. Additional experiment showed that GRP78, an ER molecular chaperone, was downregulated in mouse testes exposed to 500 mg/kg/day DEHP. Testicular p-IRE-1α, p-JNK, and CHOP, three markers of ER stress, were upregulated in mice exposed to 500 mg/kg/day DEHP. These results suggest that pubertal exposure to high doses of DEHP induces germ cell apoptosis partially through initiating ER stress in testes.
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http://dx.doi.org/10.1007/s11356-020-12210-zDOI Listing
May 2021

Low Vitamin D Status Is Associated with Inflammation in Patients with Chronic Obstructive Pulmonary Disease.

J Immunol 2021 Feb 23;206(3):515-523. Epub 2020 Dec 23.

Department of Toxicology, Anhui Medical University, Hefei 230032, China; and

Vitamin D deficiency is associated with increased risks of chronic obstructive pulmonary disease (COPD). Nevertheless, the mechanisms remain unknown. This study analyzed the correlations between vitamin D levels and inflammation in COPD patients. One hundred and one patients with COPD and 202 control subjects were enrolled. Serum 25(OH)D level and inflammatory cytokines were detected. Serum 25(OH)D was decreased and inflammatory cytokines were increased in COPD patients. According to forced expiratory volume in 1 s, COPD patients were divided into three grades. Furthermore, serum 25(OH)D was gradually decreased in COPD patients ranging from grade 1-2 to 4. Serum 25(OH)D was inversely associated with inflammatory cytokines in COPD patients. Further analysis found that NF-κB and AP-1 signaling were activated in COPD patients. Besides, inflammatory signaling was gradually increased in parallel with the severity of COPD. By contrast, pulmonary nuclear vitamin D receptor was decreased in COPD patients. In vitro experiments showed that 1,25(OH)D inhibited LPS-activated inflammatory signaling in A549 cells (human lung adenocarcinoma cell). Mechanically, 1,25(OH)D reinforced physical interactions between vitamin D receptor with NF-κB p65 and c-Jun. Our results indicate that vitamin D is inversely correlated with inflammatory signaling in COPD patients. Inflammation may be a vital mediator of COPD progress in patients with low vitamin D levels.
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http://dx.doi.org/10.4049/jimmunol.2000964DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812059PMC
February 2021

Signal Decoding for Glutamate Modulating Egg Laying Oppositely in under Varied Environmental Conditions.

iScience 2020 Oct 19;23(10):101588. Epub 2020 Sep 19.

Key Laboratory of Molecular Biophysics of Ministry of Education, Institute of Biophysics and Biochemistry, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.

Animals' ability to sense environmental cues and to integrate this information to control fecundity is vital for continuing the species lineage. In this study, we observed that the sensory neurons Amphid neuron (ASHs and ADLs) differentially regulate egg-laying behavior in under varied environmental conditions via distinct neuronal circuits. Under standard culture conditions, ASHs tonically release a small amount of glutamate and inhibit Hermaphrodite specific motor neuron (HSN) activities and egg laying via a highly sensitive Glutamate receptor (GLR)-5 receptor. In contrast, under Cu stimulation, ASHs and ADLs may release a large amount of glutamate and inhibit Amphid interneuron (AIA) interneurons via low-sensitivity Glutamate-gated chloride channel (GLC)-3 receptor, thus removing the inhibitory roles of AIAs on HSN activity and egg laying. However, directly measuring the amount of glutamate released by sensory neurons under different conditions and assaying the binding kinetics of receptors with the neurotransmitter are still required to support this study directly.
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http://dx.doi.org/10.1016/j.isci.2020.101588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567941PMC
October 2020

Prevalence and risk factors of intrahepatic cholestasis of pregnancy in a Chinese population.

Sci Rep 2020 10 1;10(1):16307. Epub 2020 Oct 1.

Department of Histology and Embryology, Anhui Medical University, No. 81 Meishan Road, Shushan District, Hefei, 230032, Anhui, People's Republic of China.

Studies on the risk factors for intrahepatic cholestasis of pregnancy (ICP) in a population-based cohort are lacking. We assess the prevalence and risk factors of ICP in a Chinese population. In this study, a cohort study was conducted that included 12,200 eligible pregnant women. The overall incidence of ICP in this cohort was 6.06%. With increasing maternal age, the incidence of ICP decreased in women younger than 30 years of age but increased in those older than 30. With increasing pre-pregnancy BMI, the incidence of ICP decreased if the pre-pregnancy BMI was less than 23 kg/m but increased if it was 23 kg/m or higher. Further analysis showed that the risk of ICP increased when maternal age was < 25 years (Adjusted RR  2.01; 95% CI 1.64-2.47) or ≥ 35 years (Adjusted RR  1.34; 95% CI 1.02-1.76). Furthermore, an increased risk of ICP was associated with pre-pregnancy underweight (adjusted RR  1.27; 95% CI 1.04-1.56), inadequate gestational weight gain (GWG) (adjusted RR  1.58; 95% CI 1.28-1.96), lower maternal education (adjusted RR  2.96; 95% CI 2.35-3.74), multiparity (adjusted RR  1.54; 95% CI 1.23-1.93), and twin/multiple pregnancies (adjusted RR  2.12; 95% CI 1.25-3.58). Maternal age (< 25 or ≥ 35 years), underweight, inadequate GWG, lower maternal education, multiparity, and twin/multiple pregnancies were identified as risk factors of ICP.
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http://dx.doi.org/10.1038/s41598-020-73378-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530728PMC
October 2020

Long-term vitamin D deficiency promotes renal fibrosis and functional impairment in middle-aged male mice.

Br J Nutr 2021 Apr 19;125(8):841-850. Epub 2020 Aug 19.

Department of Toxicology, School of Public Health, Anhui Medical University, Hefei230032, People's Republic of China.

Renal fibrosis is common especially in the elderly population. Recently, we found that vitamin D deficiency caused prostatic hyperplasia. This study aimed to investigate whether vitamin D deficiency promotes renal fibrosis and functional impairment. All mice except controls were fed with vitamin D-deficient (VDD) diets, beginning from their early life. The absolute and relative kidney weights on postnatal week 20 were decreased in VDD diet-fed male pups but not in female pups. A mild pathological damage was observed in VDD diet-fed male pups but not in females. Further analysis showed that VDD-induced pathological damage was aggravated, accompanied by renal dysfunction in 40-week-old male pups. An obvious collagen deposition was observed in VDD diet-fed 40-week-old male pups. Moreover, renal α-smooth muscle actin (α-SMA), a marker of epithelial-mesenchymal transition (EMT), and Tgf-β mRNA were up-regulated. The in vitro experiment showed that 1,25-dihydroxyvitamin D3 alleviated transforming growth factor-β1 (TGF-β1)-mediated down-regulation of E-cadherin and inhibited TGF-β1-evoked up-regulation of N-cadherin, vimentin and α-SMA in renal epithelial HK-2 cells. Moreover, 1,25-dihydroxyvitamin D3 suppressed TGF-β1-evoked Smad2/3 phosphorylation in HK-2 cells. These results provide experimental evidence that long-term vitamin D deficiency promotes renal fibrosis and functional impairment, at least partially, through aggravating TGF-β/Smad2/3-mediated EMT in middle-aged male mice.
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http://dx.doi.org/10.1017/S0007114520003232DOI Listing
April 2021

Gestational vitamin D deficiency causes placental insufficiency and fetal intrauterine growth restriction partially through inducing placental inflammation.

J Steroid Biochem Mol Biol 2020 10 9;203:105733. Epub 2020 Aug 9.

Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Department of Toxicology, Anhui Medical University, Hefei, 230032, China. Electronic address:

Several epidemiological studies suggest an association between vitamin D deficiency (VDD) and fetal intrauterine growth restriction (IUGR). Here, we explored the mechanism through which VDD induced fetal IUGR. Pregnant mice were fed with VDD diet to establish VDD model. Cyp27b1 mice were generated to develop a model of active vitamin D3 deficiency. Cyp27b1 mice were injected with either 1α,25(OH)D or vehicle once a day throughout pregnancy. As expected, fetal weight and crown-rump length were reduced in VDD diet-fed mice. Correspondingly, fetal weight and crown-rump length were lower in cyp27b1 mice. 1α,25(OH)D elevated fetal weight and crown-rump length, and protected cyp27b1 mice from fetal IUGR. Further analysis found that placental proliferation was inhibited and placental weight was decreased in VDD diet-fed mice. Several growth factors and nutrient transfer pumps were downregulated in the placentas of VDD diet-fed mice. Mechanistically, several inflammatory cytokines were upregulated and placental NF-κB was activated not only in VDD diet-fed mice but also in VDD pregnant women. Interestingly, 1α,25(OH)D inhibited the downregulated of placental nutrient transfer pumps and the upregulated of placental inflammatory cytokines in Cyp27b1+/- mice. These results provide experimental evidence that gestational VDD causes placental insufficiency and fetal IUGR may be through inducing placental inflammation.
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http://dx.doi.org/10.1016/j.jsbmb.2020.105733DOI Listing
October 2020

Environmental exposure to cadmium impairs fetal growth and placental angiogenesis via GCN-2-mediated mitochondrial stress.

J Hazard Mater 2021 01 8;401:123438. Epub 2020 Jul 8.

Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China. Electronic address:

Cadmium (Cd), a well-known environmental pollutant, can lead to placental insufficiency and fetal growth restriction. However, the underlying mechanism is unknown. The purpose of our study is to explore the effect of Cd on placental angiogenesis and its mechanism using in vitro and in vivo models. Results found that gestational Cd exposure obviously decreased placental weight and impaired placental vascular development in mice. Correspondingly, Cd exposure evidently downregulated the expression of VEGF-A protein (a key indicator of angiogenesis) and progesterone receptor (PR) in placental trophoblasts. Further experiment showed that lentivirus PR overexpression reversed Cd-caused the reduction of VEGF-A level in human placental trophoblasts. In addition, Cd significantly reduced progesterone level, down-regulated the expression of key progesterone synthase (StAR, CYP11A1), and activated mitochondrial stress response and GCN-2/p-eIF2α signaling in placental trophoblasts. Additional experiment showed that GCN-2 siRNA pretreatment markedly alleviated Cd-activated mitochondrial stress response, restored Cd-downregulated the expression of CYP11A1, reversed Cd-reduced the level of progesterone and VEGF-A in human placental trophoblasts. Finally, our case-control study confirmed that impaired placental angiogenesis and reduced progesterone level occurred in all-cause small for gestational age placenta. Taken together, environmental exposure to Cd impairs fetal growth and placental angiogenesis via GCN-2-mediated mitochondrial stress.
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http://dx.doi.org/10.1016/j.jhazmat.2020.123438DOI Listing
January 2021

Continuous association of total bile acid levels with the risk of small for gestational age infants.

Sci Rep 2020 06 9;10(1):9257. Epub 2020 Jun 9.

School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China.

The association between maternal serum total bile acid (TBA) levels and small-for-gestational-age (SGA) infants is unclear. We investigated the association between various degrees of serum TBA levels and the risk of SGA infants in a Chinese population. The current study performed a cohort study among 11811 mothers with singleton pregnancy. Subjects were divided into seven categories according to maternal serum TBA levels. Interestingly, birth sizes were reduced, whereas the rate of SGA infants was increased across increasing categories of serum TBA. Compared to category 1, adjusted ORs (95%CI) for SGA infants were 0.99 (0.82-1.21) in category 2, 1.22 (0.97-1.53) in category 3, 1.99 (1.53-2.58) in category 4, 2.91 (2.16-3.93) in category 5, 4.29 (3.33-5.54) in category 6, and 9.01 (5.99-13.53) in category 7, respectively. Furthermore, adjusted ORs (95%CI) for SGA infants for each 1-SD increase in serum TBA levels were 1.36 (1.29-1.43) among all subjects, 2.40 (1.82-3.45) among subjects without cholestasis, and 1.13 (1.06-1.22) among subjects with cholestasis, respectively. These results suggest that gestational cholestasis increases the risk of SGA infants. Additionally, our results indicate strong, continuous associations of serum TBA levels below those diagnostic of cholestasis with a decreased birth sizes and an increased risk of SGA infants.
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http://dx.doi.org/10.1038/s41598-020-66138-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283485PMC
June 2020

Gestational vitamin D deficiency impairs fetal lung development through suppressing type II pneumocyte differentiation.

Reprod Toxicol 2020 06 21;94:40-47. Epub 2020 Apr 21.

Department of Toxicology, Anhui Medical University, Hefei, 230032, China; Laboratory of Environmental Toxicology, Anhui Medical University, Hefei, 230032, China. Electronic address:

Gestational vitamin D deficiency is associated with pulmonary diseases. This study aimed to investigate the effect of gestational vitamin D deficiency on fetal lung development in mice. Absolute and relative weights of fetal lungs were reduced in vitamin D deficient (VDD) group. Incrassate mesenchyme, measured by septal wall thickness, accompanied by lessened saccular space, was shown in VDD group. Numerous immature type II pneumocytes, as determined by PAS staining, were observed in VDD group. Moreover, increased Ki67-positive cells, a marker of cell proliferation, was detected in VDD group. The additional experiments showed that Sftpa, Sftpb, Sftpc and Sftpd, four surfactant genes, were downregulated and pro-surfactant protein B was reduced in VDD group. FoxA1, FoxA2 and TTF-1, three transcription factors that regulate surfactant genes, and VEGF, a key regulator for pulmonary maturation, were downregulated in VDD group. These results suggest that gestational vitamin D deficiency impairs fetal lung development partially through suppressing type II pneumocyte differentiation.
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http://dx.doi.org/10.1016/j.reprotox.2020.03.008DOI Listing
June 2020

Association among placental 11β-HSD2, PPAR-γ, and NF-κB p65 in small-for-gestational-age infants: A nested case-control study.

Am J Reprod Immunol 2020 05 12;83(5):e13231. Epub 2020 Apr 12.

Department of Toxicology, Anhui Medical University, Hefei, China.

Problem: 11β-Hydroxysteroid dehydrogenase 2 (11β-HSD2) catalyzes active glucocorticoids into their inactive products, preventing the passage of glucocorticoids into the fetus from maternal circulation. Peroxisome proliferator-activated receptor (PPAR)γ is a member of the nuclear receptor superfamily that regulates the expression of placental 11β-HSD2. Nuclear factor-kappa B (NF-κB) is a transcription factor that regulates inflammatory signaling. This study aimed to investigate the association among 11β-HSD2, PPAR-γ, and NF-κB p65 in small-for-gestational-age (SGA) infants.

Method Of Study: Forty-six SGA and 46 appropriate-for-gestational-age (AGA) infants were enrolled in this study. Both newborns and placentas were weighed. Placental 11β-HSD2 levels were measured using Western blotting. Placental PPAR-γ and NF-κB p65 were detected by immunohistochemistry. Placental inflammatory cytokines were evaluated by real-time RT-PCR.

Results: 11β-HSD2 levels were lower in SGA placentas than those in AGA placentas. Placental PPAR-γ-positive nuclei were less in SGA than those in AGA. By contrast, placental NF-κB p65-positive nuclei were more in SGA than those in AGA. The levels of CRP, TNF-α, IL-8, and IL-1β, several inflammatory cytokines, were higher in SGA placentas. Correlation analysis showed that neonatal weight was positively associated with PPAR-γ and 11β-HSD2 in SGA placentas. By contrast, neonatal weight was inversely correlated with NF-κB p65 in SGA placentas. 11β-HSD2 was positively correlated with PPAR-γ in SGA placentas.

Conclusions: Inflammation-associated downregulation of placental PPAR-γ and 11β-HSD2 may be involved in SGA.
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http://dx.doi.org/10.1111/aji.13231DOI Listing
May 2020

Long-term 1-nitropyrene exposure induces endoplasmic reticulum stress and inhibits steroidogenesis in mice testes.

Chemosphere 2020 Jul 27;251:126336. Epub 2020 Feb 27.

Department of Toxicology & Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University, Hefei, 230032, China. Electronic address:

1-Nitropyrene (1-NP) is a representative nitro-polycyclic aromatic hydrocarbon from diesel exhaust. Recently, we found that maternal 1-NP exposure caused fetal growth retardation and disturbed cognitive development in adolescent female offspring. To investigate long-term 1-NP exposure on spermatogenesis and steroidogenesis, male mice were exposed to 1-NP (1.0 mg/kg/day) by gavage for 70 days. There was no significant difference on relative testicular weight, number of testicular apoptotic cells and epididymal sperm count between 1-NP-exposed mice and controls. Although long-term 1-NP exposure did not influence number of Leydig cells, steroidogenic genes and enzymes, including STAR, P450scc, P45017α and 17β-HD, were downregulated in 1-NP-expoed mouse testes. Correspondingly, serum and testicular testosterone (T) levels were reduced in 1-NP-exposed mice. Additional experiment showed that testicular GRP78 mRNA and protein were upregulated by 1-NP. Testicular phospho-IRE1α and sliced xbp-1 mRNA, a downstream molecule of IRE1α, were elevated in 1-NP-exposed mice. Testicular phospho-PERK and phospho-eIF2α, a downstream molecule of PERK pathway, were increased in 1-NP-exposed mice. Testicular NOX4, a subunit of NAPDH oxidase, and HO-1, MDA, two oxidative stress markers, were increased in 1-NP-exposed mice. Testicular GSH and GSH/GSSG were decreased in 1-NP-exposed mice. These results suggest that long-term 1-NP exposure induces reactive oxygen species-evoked ER stress and disrupts steroidogenesis in mouse testes.
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http://dx.doi.org/10.1016/j.chemosphere.2020.126336DOI Listing
July 2020

Obeticholic Acid Protects against Gestational Cholestasis-Induced Fetal Intrauterine Growth Restriction in Mice.

Oxid Med Cell Longev 2019 15;2019:7419249. Epub 2019 Nov 15.

Department of Histology and Embryology, Anhui Medical University, Hefei, China.

Gestational cholestasis is a common disease and is associated with adverse pregnancy outcomes. However, there are still no effective treatments. We investigated the effects of obeticholic acid (OCA) on fetal intrauterine growth restriction (IUGR) during 17-ethynylestradiol- (E2-) induced gestational cholestasis in mice. All pregnant mice except controls were subcutaneously injected with E2 (0.625 mg/kg) daily from gestational day (GD) 13 to GD17. Some pregnant mice were orally administered with OCA (5 mg/kg) daily from GD12 to GD17. As expected, OCA activated placental, maternal, and fetal hepatic FXR signaling. Additionally, exposure with E2 during late pregnancy induced cholestasis, whereas OCA alleviated E2-induced cholestasis. Gestational cholestasis caused reduction of fetal weight and crown-rump length and elevated the incidence of IUGR. OCA decreased the incidence of IUGR during cholestasis. Interestingly, OCA attenuated reduction of blood sinusoid area in placental labyrinth layer and inhibited downregulation of placental sodium-coupled neutral amino acid transporter- (SNAT-) 2 during cholestasis. Additional experiment found that OCA attenuated glutathione depletion and lipid peroxidation in placenta and fetal liver and placental protein nitration during cholestasis. Moreover, OCA inhibited the upregulation of placental NADPH oxidase-4 and antioxidant genes during cholestasis. OCA activated antioxidant Nrf2 signaling during cholestasis. Overall, we demonstrated that OCA treatment protected against gestational cholestasis-induced placental dysfunction and IUGR through suppressing placental oxidative stress and maintaining bile acid homeostasis.
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http://dx.doi.org/10.1155/2019/7419249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6885290PMC
May 2020

Vitamin D deficiency exacerbates bleomycin-induced pulmonary fibrosis partially through aggravating TGF-β/Smad2/3-mediated epithelial-mesenchymal transition.

Respir Res 2019 Nov 27;20(1):266. Epub 2019 Nov 27.

Department of Toxicology, Anhui Medical University, 81 Meishan Road, Hefei, 230032, China.

Background: Our earlier report indicated that active vitamin D3 inhibited epithelial-mesenchymal transition (EMT) in bleomycin (BLM)-induced pulmonary fibrosis. The objective of this study was to further investigate whether vitamin D deficiency exacerbates BLM-induced pulmonary fibrosis.

Methods: This study consists of two independent experiments. Experiment 1, male mice were fed with vitamin D deficient (VDD) fodder. Experiment 2, Cyp27b1, Cyp27b1 and Cyp27b1 mice were fed with standard diet. For pulmonary fibrosis, mice were intratracheally instilled with a single dose of BLM (1.5 mg/kg). Serum 25(OH) D level was measured. Pulmonary collagen deposition was assessed by Sirius red staining. EMT was measured and transforming growth factor-beta (TGF-β)/Smad3 signaling was evaluated in the lungs of BLM-treated mice.

Results: The relative weight of lungs was elevated in BLM-treated mice. Col1α1 and Col1α2, two collagen protein genes, were upregulated, and collagen deposition, as determined by Sirius red staining, was observed in the lungs of BLM-treated mice. E-cadherin, an epithelial marker, was downregulated. By contrast, vimentin and α-SMA, two EMT markers, were upregulated in the lungs of BLM-treated mice. Pulmonary TGF-β/Smad3 signaling was activated in BLM-induced lung fibrosis. Further analysis showed that feeding VDD diet, leading to vitamin D deficiency, aggravated elevation of BLM-induced relative lung weight. Moreover, feeding VDD diet aggravated BLM-induced TGF-β/Smad3 activation and subsequent EMT in the lungs. In addition, feeding VDD diet exacerbated BLM-induced pulmonary fibrosis. Additional experiment showed that Cyp27b1 gene knockout, leading to active vitamin D3 deficiency, exacerbated BLM-induced pulmonary fibrosis. Moreover, Cyp27b1 gene knockout aggravated pulmonary TGF-β/Smad2/3 activation and subsequent EMT in BLM-induced lung fibrosis.

Conclusion: Vitamin D deficiency exacerbates BLM-induced pulmonary fibrosis partially through aggravating TGF-β/Smad2/3-mediated EMT in the lungs.
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http://dx.doi.org/10.1186/s12931-019-1232-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6882226PMC
November 2019

Maternal 1-nitropyrene exposure during pregnancy increases susceptibility of allergic asthma in adolescent offspring.

Chemosphere 2020 Mar 12;243:125356. Epub 2019 Nov 12.

Department of Toxicology & Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University, Hefei, 230032, China. Electronic address:

1-nitropyrene (1-NP) is widespread in the environment, as a typical nitrated polycyclic aromatic hydrocarbon. The purpose of this research was to explore the effects of gestational 1-NP exposure on susceptibility of allergic asthma in offspring. Maternal mice were exposed to 1-NP (100 μg kg) by gavage throughout the whole pregnancy. Pups were sensitized by injecting with ovalbumin (OVA) on postnatal day (PND)23, 29, and 36, respectively. At 7 days following the last injection, sensitized mice were exposed to aerosol OVA. As expected, there were quite a few inflammatory cells in the lungs of OVA-sensitized pups, accompanied by bronchial wall thickening and hyperemia. Elevated goblet cells and overproduced mucus were observed in the airways of OVA-sensitized pups. Interestingly, gestational 1-NP exposure aggravated infiltration of inflammatory cells, mainly eosinophils, in OVA-sensitized offspring. Although it had little effect on airway smooth muscle layer thickening and basement membrane fibrosis, gestational 1-NP exposure aggravated goblet cell hyperplasia, Muc5ac mRNA upregulation, and mucus secretion in the airways of OVA-sensitized and challenged offspring. Mechanistically, gestational 1-NP exposure aggravated elevation of pulmonary IL-5 in OVA-sensitized pups. These findings suggest that gestational 1-NP exposure increases susceptibility of allergic asthma in offspring.
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http://dx.doi.org/10.1016/j.chemosphere.2019.125356DOI Listing
March 2020

Maternal cadmium exposure during late pregnancy causes fetal growth restriction via inhibiting placental progesterone synthesis.

Ecotoxicol Environ Saf 2020 Jan 31;187:109879. Epub 2019 Oct 31.

Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China. Electronic address:

Cadmium (Cd) is a major environmental pollutant. Maternal Cd exposure throughout pregnancy caused fetal growth restriction (FGR). However, the pivotal time window of Cd-evoked FGR and its mechanism are unknown. Here, we will establish a murine model to explore the effects of maternal Cd exposure at different stages of gestation on fetal growth and placental progesterone biosynthesis. Pregnant mice were randomly divided into four groups. For Cd groups, mice were given with CdCl (150 mg/L) through drinking water at early (GD0-GD6), middle (GD7-GD12) and late (GD13-GD17) gestation, respectively. The controls received reverses osmosis (RO) water. Results showed that maternal cadmium exposure only in late gestation lowered fetal weight and length. Correspondingly, placental Cd level in late gestational Cd exposure is the highest among three different gestational stages. Although gestational Cd exposure had few adverse effects in the weight and diameter of mouse placenta, placental vascular development, as determined by H&E staining and cluster of differentiation-34 (CD-34) immunostaining, was impaired in mice exposed to Cd during late pregnancy. Additionally, late gestational exposure to cadmium markedly reduced progesterone level in maternal serum and placenta. In line, the expression of key progesterone synthetases, including steroidogenic acute regulatory protein (StAR) and 3β-hydroxyl steroid dehydrogenase (3β-HSD), was obviously downregulated in placenta from mice was exposed Cd during late pregnancy. These data suggest that maternal Cd exposure during late pregnancy, but not early and middle pregnancy, induces fetal growth restriction partially via inhibiting placental progesterone synthesis.
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http://dx.doi.org/10.1016/j.ecoenv.2019.109879DOI Listing
January 2020

Pre-pregnancy underweight and obesity are positively associated with small-for-gestational-age infants in a Chinese population.

Sci Rep 2019 10 29;9(1):15544. Epub 2019 Oct 29.

School of Public Health, Anhui Medical University, Hefei, 230032, China.

The association between suboptimal pre-pregnancy body mass index (BMI) and small-for-gestational-age (SGA) infants is not well defined. We investigated the association between pre-pregnancy BMI and the risk of SGA infants in a Chinese population. We performed a cohort study among 12029 mothers with a pregnancy. This cohort consisted of pregnant women that were: normal-weight (62.02%), underweight (17.09%), overweight (17.77%) and obese (3.12%). Birth sizes were reduced in the underweight and obese groups compared with the normal-weight group. Linear regression analysis indicated that birth size was positively associated with BMI in both the underweight and normal-weight groups. Further analysis showed that 12.74% of neonates were SGA infants in the underweight group, higher than 7.43% of neonates reported in the normal-weight group (adjusted RR = 1.92; 95% CI: 1.61, 2.30). Unexpectedly, 17.60% of neonates were SGA infants in the obese group, much higher than the normal-weight group (adjusted RR = 2.17; 95% CI: 1.57, 3.00). Additionally, 18.40% of neonates were large-for-gestational-age (LGA) infants in the obese group, higher than 7.26% of neonates reported in the normal-weight group (adjusted RR = 3.00; 95% CI: 2.21, 4.06). These results suggest that pre-pregnancy underweight increases the risk of SGA infants, whereas obesity increases the risks of not only LGA infants, but also SGA infants.
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http://dx.doi.org/10.1038/s41598-019-52018-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820714PMC
October 2019

Activation of autophagy inhibits cadmium-triggered apoptosis in human placental trophoblasts and mouse placenta.

Environ Pollut 2019 Nov 5;254(Pt A):112991. Epub 2019 Aug 5.

Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China. Electronic address:

Cadmium (Cd), a ubiquitous environmental pollutant, is known to impair placental development. However, the underlying mechanisms remain unclear. The present study used in vivo and in vitro models to investigate the effects of Cd on apoptosis and autophagy in placental trophoblasts and its mechanism. Pregnant mice were exposed to CdCl (4.5 mg/kg) on gestational day (GD) 9. Human JEG-3 cells were exposed to CdCl (0-40 μM) for different time points. Gestational Cd exposure obviously lowered the weight and diameter of mouse placentas. Number of TUNEL-positive cells was markedly elevated in Cd-administered mouse placentas and JEG-3 cells. Correspondingly, Cd significantly up-regulated cleaved caspase-3 protein level, a key indicator of apoptosis, in murine placentas and JEG-3 cells. Simultaneously, Cd also triggered autophagy, as determined by an elevation of LC3B-II and p62 protein, and accumulation of LC3-positive puncta, in placental trophoblasts. Chloroquine an autophagy inhibitor, obviously aggravated Cd-induced apoptosis in JEG-3 cells. By contrast, rapamycin, a specific autophagy inducer, significantly alleviated Cd-triggered apoptosis in JEG-3 cells. Mechanistically, autophagy inhibited Cd-induced apoptosis mainly via degrading caspase-9. Co-localizations of p62, a classical autophagic receptor, and caspase-9 were observed in Cd-stimulated human JEG-3 cells. Moreover, p62 siRNAs pretreatment markedly blocked the degradation of caspase 9 proteins via Cd-activated autophagy in JEG-3 cells. Collectively, our data suggest that activation of autophagy inhibits Cd-induced apoptosis via p62-mediated caspase-9 degradation in placental trophoblasts. These findings provide a new mechanistic insight into Cd-induced impairments of placental and fetal development.
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http://dx.doi.org/10.1016/j.envpol.2019.112991DOI Listing
November 2019

Lipopolysaccharide Downregulates 11β-Hydroxysteroid Dehydrogenase 2 Expression through Inhibiting Peroxisome Proliferator-Activated Receptor-γ in Placental Trophoblasts.

J Immunol 2019 09 17;203(5):1198-1207. Epub 2019 Jul 17.

Department of Toxicology, Anhui Medical University, Hefei 230032, China;

It is increasingly recognized that excessive glucocorticoids induce fetal intrauterine growth restriction (IUGR). Placental 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2), a glucocorticoid-catalyzing enzyme, prevents active glucocorticoids from maternal circulation into the fetus, thus protecting against IUGR. Previous studies demonstrated gestational LPS exposure caused fetal IUGR. The aim of the current study was to investigate the effects of LPS on 11β-HSD2 in mice placentas and human placental trophoblasts. Pregnant ICR(CD-1) mice were i.p. injected with LPS (200 μg/kg) on gestational day 16. As expected, gestational LPS exposure downregulated 11β-HSD2 in mice placentas. In vitro, LPS downregulated 11β-HSD2 in human placental trophoblasts. Additional experiment showed that LPS, which activated NF-κB, suppressed rosiglitazone-induced activation of peroxisome proliferator-activated receptor-γ (PPARγ) in mice placentas and human placental trophoblasts. Moreover, NF-κB p65 knockdown and specific NF-κB inhibitor attenuated LPS-induced suppression of PPARγ nuclear translocation in human placental trophoblasts. In addition, NF-κB p65 knockdown attenuated LPS-induced downregulation of 11β-HSD2 in human placental trophoblasts. Mechanically, LPS promoted physical interaction between NF-κB p65 and PPARγ in the cytoplasm and nucleus of placental trophoblasts. Finally, pretreatment with rosiglitazone, a PPARγ agonist, partially alleviated LPS-induced reduction of fetal weight and crown-rump length. Taken together, these results suggest that LPS downregulates 11β-HSD2 through suppressing PPARγ in placental trophoblasts. Placental 11β-HSD2 downregulation may contribute partially to LPS-induced fetal IUGR.
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http://dx.doi.org/10.4049/jimmunol.1900132DOI Listing
September 2019

The correlation between low vitamin D status and renal interleukin-6/STAT3 hyper-activation in patients with clear cell renal cell carcinoma.

Steroids 2019 10 8;150:108445. Epub 2019 Jul 8.

Department of Toxicology, School of Public Health, Anhui Medical University, Hefei 230032, China. Electronic address:

Low vitamin D status has been associated with increased risks of renal cell carcinoma (RCC). This study aimed to analyze the link between low vitamin D status and interleukin (IL)-6/STAT3 hyper-activation in clear cell RCC (ccRCC) patients. Forty-three newly diagnosed ccRCC patients and 86 age- and sex-matched controls were recruited. The association between low vitamin D status and IL-6/STAT3 hyper-activation was analyzed. Proliferation makersand STAT3 signal were evaluated. As expected, serum IL-6 level was higher in ccRCC patients than in controls. Moreover, serum IL-6 level was reversely correlated with serum 25(OH)D in ccRCC patients but not in controls. In addition, STAT3 signaling was hyper-activated in cancerous tissue. CcRCC patients were divided into three groups according to serum 25(OH)D level: vitamin D sufficiency (VitD-S, ≥30 ng/ml), vitamin D insufficiency (VitD-I, ≥20 and <30 ng/ml) or vitamin D deficiency (VitD-D, <20 ng/ml). Serum IL-6 was higher in ccRCC patients with VitD-D than those with VitD-S/VitD-I. Cancerous pSTAT3 level was higher in ccRCC patients with VitD-D than those with VitD-S/VitD-I. The number of pSTAT3 nuclei in cancerous tissue was more in ccRCC patients with VitD-D than those with VitD-S/VitD-I. The expressions of cancerous PCNA, cyclin D1 and Ki-67, three markers of proliferation, were higher in ccRCC patients with VitD-D than those with VitD-S/VitD-I. The in vitro experiments showed that active vitamin D3 inhibited LPS-induced STAT3 phosphorylation in ACHN cells. Our results provide evidence that low vitamin D status is correlated with hyper-activation of cancerous IL-6/STAT3 and proliferation in ccRCC patients.
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http://dx.doi.org/10.1016/j.steroids.2019.108445DOI Listing
October 2019

miRNA-10a promotes cancer cell proliferation in oral squamous cell carcinoma by upregulating GLUT1 and promoting glucose metabolism.

Oncol Lett 2019 Jun 16;17(6):5441-5446. Epub 2019 Apr 16.

Department of Dental Implantation, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210008, P.R. China.

MicroRNA-10a (miRNA-10a) promotes lung cancer; however, to the best of our knowledge, its involvement in other cancer types is unknown. The present study aimed to investigate the role of miRNA-10a in oral cancer. Expression levels of miRNA-10a and glucose transporter 1 (GLUT1) in tumor tissues and adjacent healthy tissues obtained from patients with oral squamous cell carcinoma (OSCC) were detected by reverse transcription-quantitative polymerase chain reaction. Correlation analysis between the expression levels of miRNA-10a and GLUT1 was performed using Pearson's correlation coefficient. It was identified that miRNA-10a and GLUT1 were upregulated in tumor tissues compared with adjacent healthy tissues of patients with OSCC. Expression levels of miRNA-10a and GLUT1 were positively correlated in tumor tissues but not in adjacent healthy tissues. In addition, miRNA-10a overexpression promoted glucose uptake and upregulated GLUT1 in OSCC cells. Furthermore, GLUT1 overexpression promoted glucose uptake; however, no significant increase in the expression level of miRNA-10a in OSCC cells was detected. Overexpression of miRNA-10a and GLUT1 promoted OSCC cell proliferation, while GLUT1-knockdown inhibited OSCC cell proliferation. GLUT1-knockdown also attenuated the enhancing effect of miRNA-10a overexpression on cancer cell proliferation. Therefore, miRNA-10a may promote cancer cell proliferation in OSCC by upregulating GLUT1 and promoting glucose metabolism.
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http://dx.doi.org/10.3892/ol.2019.10257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6507447PMC
June 2019

Pretreatment with Cholecalciferol Alleviates Renal Cellular Stress Response during Ischemia/Reperfusion-Induced Acute Kidney Injury.

Oxid Med Cell Longev 2019 25;2019:1897316. Epub 2019 Mar 25.

Department of Toxicology, Anhui Medical University, Hefei, China.

Background: Cellular stress is involved in ischemia/reperfusion- (I/R-) induced acute kidney injury (AKI). This study is aimed at investigating the effects of pretreatment with cholecalciferol on renal oxidative stress and endoplasmic reticulum (ER) stress during I/R-induced AKI.

Methods: I/R-induced AKI was established by cross-clamping renal pedicles for 90 minutes and then reperfusion. In the Chol + I/R group, mice were orally administered with three doses of cholecalciferol (25 g/kg) at 1, 24, and 48 h before ischemia. Renal cellular stress and kidney injury were measured at different time points after reperfusion.

Results: I/R-induced AKI was alleviated in mice pretreated with cholecalciferol. In addition, I/R-induced renal cell apoptosis, as determined by TUNEL, was suppressed by cholecalciferol. Additional experiment showed that I/R-induced upregulation of renal GRP78 and CHOP was inhibited by cholecalciferol. I/R-induced renal IRE1 and eIF2 phosphorylation was attenuated by cholecalciferol. Moreover, I/R-induced renal GSH depletion, lipid peroxidation, and protein nitration were blocked in mice pretreated with cholecalciferol. I/R-induced upregulation of renal NADPH oxidases, such as , , and , was inhibited by cholecalciferol. I/R-induced upregulation of heme oxygenase- (HO-) 1, and , was attenuated in mice pretreated with cholecalciferol.

Conclusions: Pretreatment with cholecalciferol protects against I/R-induced AKI partially through suppressing renal cellular stress response.
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http://dx.doi.org/10.1155/2019/1897316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6452543PMC
August 2019

Oral cholecalciferol supplementation alleviates lipopolysaccharide-induced preterm delivery partially through regulating placental steroid hormones and prostaglandins in mice.

Int Immunopharmacol 2019 Apr 7;69:235-244. Epub 2019 Feb 7.

Department of Toxicology, Anhui Medical University, Hefei 230032, China; Key Laboratory of Environmental Toxicology, Anhui Higher Education Institutes, Anhui Medical University, Hefei 230032, China; Anhui Provincial Key Laboratory of Population Health & Aristogenics, Hefei 230032, China. Electronic address:

Several epidemiological reports demonstrated that vitamin D deficiency elevated risk of preterm delivery. We investigate the effects of oral cholecalciferol (VD3) supplementation on lipopolysaccharide (LPS)-induced preterm delivery. Pregnant mice were randomly assigned to either oral VD3 (25 μg/kg) or corn oil once daily from gestational day (GD)13 to GD15, and were intraperitoneally injected with either LPS (200 μg/kg) or normal saline on GD15. As expected, LPS was effective in inducing preterm delivery and fetal death. LPS-induced preterm delivery and fetal death were alleviated in VD3-pretreated mice. LPS-induced down-regulation of genes for placental progesterone biosynthetic enzymes was blocked in VD3-pretreated mice. LPS-induced reduction of serum progesterone was correspondingly attenuated by VD3. Although oral VD3 had no effect on estradiol production, it attenuated LPS-induced up-regulation of placental ERβ in mice. LPS-induced placental COX-2 up-regulation and serum PGF2α elevation were alleviated in VD3-pretreated mice. Additionally, LPS-evoked elevations of the placental Tnfα, Il1β, Mcp1 and Mip2 mRNAs were attenuated by VD3. VD3 promoted placental vitamin D receptor nuclear translocation and simultaneously alleviated LPS-induced nuclear translocation of NF-κB p65 and p50 subunits. These results provide evidence that oral VD3 supplementation alleviates LPS-induced preterm delivery and fetal demise partially through regulating placental steroid hormones and prostaglandins.
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http://dx.doi.org/10.1016/j.intimp.2019.01.052DOI Listing
April 2019

Obeticholic acid alleviate lipopolysaccharide-induced acute lung injury via its anti-inflammatory effects in mice.

Int Immunopharmacol 2019 Jan 20;66:177-184. Epub 2018 Nov 20.

Second Affiliated Hospital, Anhui Medical University, Hefei 230032, China; Anhui Center for Surveillance of Bacterial Resistance, Hefei 230032, China. Electronic address:

Acute lung injury (ALI) is a common disease that may result in acute respiratory failure and death. However, there are still no effective treatments for ALI. Several studies have shown that farnesoid X receptor (FXR) has an anti-inflammatory effect. We investigated the effects of obeticholic acid (OCA), an agonist of FXR, on Lipopolysaccharide (LPS)-induced ALI in mice. Sixty male mice were randomly divided into six groups, and orally administered with or without OCA once daily for 3 consecutive days before LPS (1.0 mg/kg). Animals were sacrificed at 0 h, 2 h or 6 h after LPS. As expected, OCA enhanced pulmonary FXR activity. OCA prevented LPS-induced ALI. Additional experiment showed that OCA alleviated LPS-induced up-regulation of pulmonary pro-inflammatory and chemokine genes. Moreover, OCA also repressed LPS-induced the release of TNF-α and KC in serum and bronchoalveolar lavage fluid. In contrast, OCA further up-regulated LPS-induced the expression of Il-10, an anti-inflammatory cytokine. Further study showed that OCA inhibited LPS-evoked NF-κB signaling in the lungs. OCA attenuated LPS-induced ERK1/2, JNK, p38 and Akt phosphorylation in the lungs. Overall, these results suggest that OCA prevent LPS-induced ALI may be through enhancing pulmonary FXR activity and then blockading several inflammatory signaling pathways.
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http://dx.doi.org/10.1016/j.intimp.2018.11.005DOI Listing
January 2019

Differential effects of high-fat diets before pregnancy and/or during pregnancy on fetal growth development.

Life Sci 2018 Nov 6;212:241-250. Epub 2018 Oct 6.

Department of Toxicology, Anhui Medical University, Hefei 230032, China; Anhui Provincial Key Laboratory of Population Health & Aristogenics, Hefei 230032, China. Electronic address:

Aims: The aim of the study was to investigate the effects of high-fat diets before pregnancy and/or during pregnancy on fetal development.

Main Methods: Female mice were fed with standard diets (SD) or high-fat diets (HFD). After 12 weeks, females were mated. In the SD + SD and HFD + SD groups, pregnant mice were fed with standard diets. In the SD + HFD and HFD + HFD groups, pregnant mice were fed with high-fat diets. All pregnant mice were sacrificed on gestational day (GD) 16.

Key Findings: Fetal weight and crown-rump length were increased in SD + HFD-fed mice, whereas were decreased in HFD + SD-fed mice. The levels of CRP and TNF-α in maternal serum and amniotic fluid were elevated in all HFD-fed mice. Placenta weight was elevated in SD + HFD-fed but not in HFD + SD-fed mice. Blood sinusoid areas, and the number of Ki67-positive cells, a marker of cell proliferation, were elevated in placental labyrinth layer of SD + HFD-fed mice, but decreased in HFD + SD-fed mice. Finally, placental Fatp1, a fatty acid transporter gene, was up-regulated in SD + HFD-fed mice. By contrary, placental Fatp1, and Snat2, an amino acid transporter, were down-regulated in HFD + SD-fed mice. Moreover, the levels of placental FATP4 and SNAT2 were up-regulated in SD + HFD-fed mice.

Significance: HFD before pregnancy and HFD during pregnancy differentially disturb fetal growth development. HFD before pregnancy-induced fetal SGA might be partially attributed to inflammatory cytokines and mediators derived from maternal adipose tissue. By contrary, HFD during pregnancy-induced fetal overweight may be partially attributed to the increase of placental nutrient transport capacity.
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http://dx.doi.org/10.1016/j.lfs.2018.10.008DOI Listing
November 2018

Farnesoid X receptor agonist obeticholic acid inhibits renal inflammation and oxidative stress during lipopolysaccharide-induced acute kidney injury.

Eur J Pharmacol 2018 Nov 6;838:60-68. Epub 2018 Sep 6.

Department of Toxicology, Anhui Medical University, Hefei, China; Laboratory of Environmental Toxicology, Hefei, China. Electronic address:

It is increasingly recognized that farnesoid X receptor (FXR) has anti-inflammatory and antioxidant activities. The present study investigated the effects of obeticholic acid (OCA), a novel synthetic FXR agonist, on renal inflammation and oxidative stress in a model of sepsis-induced acute kidney injury. All mice except controls were intraperitoneally injected with lipopolysaccharide (LPS, 2.0 mg/kg). In the OCA + LPS group, mice were orally pretreated with three doses of OCA (5 mg/kg) at 48, 24 and 1 h before LPS injection. Interestingly, OCA pretreatment alleviated LPS-induced renal dysfunction and pathological damage. Moreover, OCA pretreatment repressed renal inflammatory cytokines and chemokines during LPS-induced acute kidney injury. In addition, OCA blocked nuclear translocation of nuclear factor kappa B (NF-κB) p65 and p50 subunits in tubular epithelial cells of renal cortex. Additional experiment showed that OCA pretreatment attenuated LPS-induced renal glutathione depletion, lipid peroxidation and protein nitration. Moreover, OCA pretreatment inhibited the upregulation of renal NADPH oxidase and inos genes during LPS-induced acute kidney injury. In conclusion, OCA pretreatment protects against sepsis-induced acute kidney injury through inhibiting renal inflammation and oxidative stress. These results provide evidence for roles of FXR as an important regulator of inflammation and oxidative stress in the kidney.
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http://dx.doi.org/10.1016/j.ejphar.2018.09.009DOI Listing
November 2018

Chronic folate deficiency induces glucose and lipid metabolism disorders and subsequent cognitive dysfunction in mice.

PLoS One 2018 28;13(8):e0202910. Epub 2018 Aug 28.

Anhui Provincial Key Laboratory of Population Health & Aristogenics, Hefei, China.

Previous studies have shown that folate levels were decreased in patients with type 2 diabetes (T2D) and further lowered in T2D patients with cognitive impairment. However, whether folate deficiency could cause T2D and subsequent cognitive dysfunction is still unknown. The present study aimed to explore the effects of chronic folate deficiency (CFD) on glucose and lipid metabolism and cognitive function in mice. Seven-week-old mice were fed with either a CFD or control diet for 25 weeks. Serum folate was significantly reduced, whereas serum total homocysteine was significantly increased in the CFD group. Moreover, CFD induced obesity after a 6-week diet treatment, glucose intolerance and insulin resistance after a 16-week-diet treatment. In addition, CFD reduced the hepatic p-Akt/Akt ratio in response to acute insulin administration. Moreover, CFD increased serum triglyceride levels, upregulated hepatic Acc1 and Fasn mRNA expression, and downregulated hepatic Cd36 and ApoB mRNA expression. After a 24-week diet treatment, CFD induced anxiety-related activities and impairment of spatial learning and memory performance. This study demonstrates that folate deficiency could induce obesity, glucose and lipid metabolism disorders and subsequent cognitive dysfunction.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0202910PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6112663PMC
February 2019

Cadmium induces inflammatory cytokines through activating Akt signaling in mouse placenta and human trophoblast cells.

Placenta 2018 05 28;65:7-14. Epub 2018 Mar 28.

Department of Toxicology, School of Public Health, Anhui Medical University, Hefei, China; Laboratory of Environmental Toxicology, Anhui Medical University, Hefei, China. Electronic address:

Introduction: Several reports demonstrated that cadmium (Cd) had proinflammatory activities. The present study aimed to investigate whether Cd induces inflammatory cytokines in mouse placenta and human trophoblast cells.

Methods: Human JEG-3 cells were treated with different concentration of CdCl (0-50 μM) or CdCl (25 μM) for different times. The pregnant mice were administered with CdCl (3.0 mg/kg, i.p.) on GD15.

Results: TNF-α, IL-8 and IL-6 mRNAs were elevated in CdCl-treated JEG-3 cells. Several inflammatory cytokines were up-regulated in Cd-treated placenta of mice. Moreover, keratinocyte chemokine (KC), a functional analogue of human IL-8, was increased in maternal serum and amniotic fluid from CdCl-exposed mice. Additional experiment showed that gestational Cd exposure activated Akt signaling in mouse placenta. Co-culture with CdCl elevated pAkt level in JEG-3 cells in concentration- and time-dependent manners. LY294002, a specific inhibitor of PI3K, blocked CdCl-evoked Akt phosphorylation in JEG-3 cells. Concomitantly, LY294002 inhibited CdCl-induced IL-8 in JEG-3 cells. N-acetylcysteine (NAC), an antioxidant and a glutathione precursor, blocked CdCl-evoked Akt phosphorylation in mouse placenta and human trophoblast cells. Additionally, NAC attenuated Cd-induced up-regulation of KC in amniotic fluid.

Discussion: Cd induces inflammatory cytokines partially through activating Akt signaling in mouse placenta and human trophoblast cells. NAC may be exploited for prevention of Cd-induced placental inflammation.
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http://dx.doi.org/10.1016/j.placenta.2018.03.008DOI Listing
May 2018