Publications by authors named "Zhengping Yu"

114 Publications

Rapamycin antagonizes cadmium-induced breast cancer cell proliferation and metastasis through directly modulating ACSS2.

Ecotoxicol Environ Saf 2021 Aug 16;224:112626. Epub 2021 Aug 16.

School of Medicine, Guangxi University, Nanning, Guangxi Zhuang Autonomous Region, China; Department of Environmental Medicine, School of Public Health, and Department of Emergency Medicine, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. Electronic address:

Cadmium (Cd) is a carcinogen that stimulates breast cancer (BC) progression. Rapamycin is a macrolide antibiotic produced by Streptomyces hygroscopicus that possesses a wide array of pharmacological activities, including anti-BC activity. However, the effects of rapamycin on Cd-increased BC progression and the underlying mechanism have not been fully elucidated. Here, we hypothesize that rapamycin antagonizes Cd-induced BC cell proliferation and metastasis by directly modulating ACSS2. In this study, we found that rapamycin efficiently inhibited Cd-induced proliferation, invasion and migration in MCF-7 and T47-D cells. Moreover, a surface plasmon resonance (SPR) assay confirmed that rapamycin directly binds to the ACSS2 protein with a calculated equilibrium dissociation constant (KD) of 18.3 μM. Molecular docking showed that there are three binding sites in the ACSS2 protein and that rapamycin binds at the coenzyme A (COA) binding site with a docking score of - 12.26 and a binding free energy of - 26.34 kcal/mol. More importantly, rapamycin suppresses Cd-induced BC progression by activating ACSS2. After cells were cotreated with an ACSS2 inhibitor, the effects of rapamycin were abolished. In conclusion, our findings suggest that rapamycin suppresses Cd-augmented BC progression by upregulating ACSS2, and ACSS2 may serve as a direct target of rapamycin for inhibiting xenobiotic (e.g., Cd)-mediated BC progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ecoenv.2021.112626DOI Listing
August 2021

NAC antagonizes arsenic-induced neurotoxicity through TMEM179 by inhibiting oxidative stress in Oli-neu cells.

Ecotoxicol Environ Saf 2021 Oct 28;223:112554. Epub 2021 Jul 28.

Department of Occupational Health, Army Medical University, 400038, Chongqing, People's Republic of China. Electronic address:

Arsenic is one of the most common environmental pollutants. Neurotoxicity induced by arsenic has become a major public health concern. However, the effects of arsenic-induced neurotoxicity in the brain and the underlying molecular mechanisms are not well understood. N-acetyl-cysteine (NAC) is a thiol-based antioxidant that can antagonize heavy metal-induced neurotoxicity by scavenging reactive oxygen species (ROS). Here, we used the mouse oligodendrocyte precursor cell (OPC) line Oli-neu to explore the neurotoxic effects of arsenic and the protective effects of NAC. We found that arsenic exposure decreased cell viability, increased oxidative stress, caused mitochondrial dysfunction, and led to apoptosis of Oli-neu cells. Furthermore, we revealed that NAC treatment reversed these neurotoxic effects of arsenic. TMEM179, a key membrane protein, was found highly expressed in OPCs and to be an important factor in maintaining mitochondrial functions. We found that TMEM179 played a critical role in mediating the neurotoxic effects of arsenic and the protective role of NAC. PKCβ is a downstream factor through which TMEM179 regulates the expression of apoptosis-related proteins. This study improves our understanding of the neurotoxic effects and mechanisms of arsenic exposure and the protective effects of NAC. It also identifies a potential molecular target, TMEM179, for the treatment of arsenic-induced neurotoxicity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ecoenv.2021.112554DOI Listing
October 2021

The prognostic value of sarcopenia combined with preoperative fibrinogen-albumin ratio in patients with intrahepatic cholangiocarcinoma after surgery: A multicenter, prospective study.

Cancer Med 2021 07 8;10(14):4768-4780. Epub 2021 Jun 8.

Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.

Background: To explore the prognostic value of the fibrinogen-albumin ratio (FAR) combined with sarcopenia in intrahepatic cholangiocarcinoma (ICC) patients after surgery and to develop a nomogram for predicting the survival of ICC patients.

Materials And Methods: In this prospective cohort study, 116 ICC patients who underwent radical surgery were enrolled as the discovery cohort and another independent cohort of 68 ICC patients was used as the validation cohort. Kaplan-Meier method was used to analyze prognosis. The independent predictor of overall survival (OS) and recurrence-free survival (RFS) was evaluated by univariable and multivariable Cox regression analyses, then developing nomograms. The performance of nomograms was evaluated by concordance index (C-index), calibration curve, receiver operating characteristic curve analysis (ROC), and decision curve analysis (DCA).

Results: Patients with high FAR had lower OS and RFS. FAR and sarcopenia were effective predictors of OS and RFS. Patients with high FAR and sarcopenia had a poorer prognosis than other patients. OS nomogram was constructed based on age, FAR, and sarcopenia. RFS nomogram was constructed based on FAR and sarcopenia. C-index for the nomograms of OS and RFS was 0.713 and 0.686. Calibration curves revealed great consistency between actual survival and nomogram prediction. The area under ROC curve (AUC) for the nomograms of OS and RFS was 0.796 and 0.791 in the discovery cohort, 0.823 and 0.726 in the validation cohort. The clinical value of nomograms was confirmed by the DCA.

Conclusions: ICC patients with high FAR and sarcopenia had a poor prognosis, the nomograms developed based on these two factors were accurate and clinically useful in ICC patients who underwent radical resection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cam4.4035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8290250PMC
July 2021

Histone hypoacetylation contributes to neurotoxicity induced by chronic nickel exposure in vivo and in vitro.

Sci Total Environ 2021 Aug 10;783:147014. Epub 2021 Apr 10.

Department of Occupational Health, Army Medical University, 400038 Chongqing, People's Republic of China. Electronic address:

Nickel (Ni) is a heavy metal that is both an environmental pollutant and a threat to human health. However, the effects of Ni on the central nervous system in susceptible populations have not been well established. In the present study, the neurotoxicity of Ni and its underlying mechanism were investigated in vivo and in vitro. Ni exposure through drinking water (10 mg Ni/L, 12 weeks) caused learning and memory impairment in mice. Reduced dendrite complexity was observed in both Ni-exposed mouse hippocampi and Ni-treated (200 μM, 72 h) primary cultured hippocampal neurons. The levels of histone acetylation, especially at histone H3 lysine 9 (H3K9ac), were reduced in Ni-exposed mouse hippocampi and cultured neurons. RNA sequencing and chromatin immunoprecipitation (ChIP) sequencing analyses revealed that H3K9ac-modulated gene expression were downregulated. Treatment with sodium butyrate, a histone deacetylase inhibitor, attenuated Ni-induced H3K9 hypoacetylation, neural gene downregulation and dendrite complexity reduction in cultured neurons. Sodium butyrate also restored Ni-induced memory impairment in mice. These results indicate that Ni-induced H3K9 hypoacetylation may be a contributor to the neurotoxicity of Ni. The finding that Ni disturbs histone acetylation in the nervous system may provide new insight into the health risk of chronic Ni exposure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.scitotenv.2021.147014DOI Listing
August 2021

Plasmalemma vesicle-associated protein promotes angiogenesis in cholangiocarcinoma via the DKK1/CKAP4/PI3K signaling pathway.

Oncogene 2021 Jun 2;40(25):4324-4337. Epub 2021 Jun 2.

Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.

Cholangiocarcinoma (CCA) is aggressive and has poor clinical outcomes because of typically delayed diagnosis and a lack of effective non-surgical therapeutic options. Recent studies have shown that plasmalemma vesicle-associated protein (PLVAP) is related to angiogenesis in various tumors, and in vivo PLVAP targeting therapy has been proven effective against hepatocellular carcinoma and pancreatic cancer. The goal of this study was to determine the potential therapeutic utility of targeting PLVAP and thus angiogenesis in CCA and explore the underlying molecular mechanisms. We found that the PLVAP expression levels were significantly higher in CCA tissues when compared with matched adjacent non-tumor tissues obtained from a total of 90 CCA patients; higher expression levels of PLVAP were associated with shorter overall survival of patients. In addition, overexpression of PLVAP was associated with higher micro-vessel density in CCA tissues. In a PLVAP overexpressing CCA patient-derived xenograft model, a novel humanized anti-PLVAP antibody in combination with Gemcitabine plus Cisplatin was significantly inhibited tumor growth. Molecular analysis of CCA cells co-cultured with human umbilical vascular endothelial cells or human hepatic sinusoidal endothelial cells showed that Dickkopf-related protein 1 (DKK1) secreted by CCA cells activated the PI3K/Akt pathway after binding to its receptor, cytoskeleton-associated protein 4 (CKAP4), resulting in the upregulation of PLVAP. Thus, CCA cells increased the angiogenic potency of endothelial cells in a paracrine fashion. Consistently, patients bearing CKAP4 and PLVAP overexpressing tumors had a poor prognosis. In conclusion, the DKK1/CKAP4/PI3K/PLVAP pathway increases angiogenesis in CCA and is therefore a potential anti-angiogenic target.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41388-021-01844-zDOI Listing
June 2021

8-Formylophiopogonanone B antagonizes doxorubicin-induced cardiotoxicity by suppressing heme oxygenase-1-dependent myocardial inflammation and fibrosis.

Biomed Pharmacother 2021 Aug 29;140:111779. Epub 2021 May 29.

Department of Cardiology, Affiliated Hospital of North Sichuan Medical College, No. 63, Wenhua Road, Shunqing District, Nanchong, Sichuan 637000, China; Academician Workstation, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, China. Electronic address:

Doxorubicin (DOX) is a widely used antitumor drug that causes severe cardiotoxicity in patients; no effective strategy yet exists to address this problem. We previously reported that 8-formylophiopogonanone B (8-FOB), a natural isoflavone in Ophiopogon japonicas, antagonizes paraquat-induced hepatotoxicity. Here, we explored the mechanisms underlying DOX-induced cardiotoxicity as well as whether 8-FOB can alleviate DOX-induced cardiotoxicity. Acute cardiotoxicity was established by injecting C57BL/6J mice with a single dose of DOX (20 mg/kg, intraperitoneal). To elucidate the mechanisms underlying DOX-induced cardiotoxicity, differentially expressed genes between hearts from DOX-treated and control mice were identified from the Gene Expression Omnibus (GEO) database via GEO2R. Using the Cytoscape software plugin cytoHubba, five hub genes associated with DOX-induced cardiotoxicity were identified: CD68, PTEN, SERPINE1, AIF1, and HMOX1. However, of these, only HMOX1 protein expression levels were significantly increased after DOX treatment. We also confirmed that HMOX1-dependent myocardial inflammation and fibrosis were closely associated with DOX-induced cardiotoxicity. More importantly, 8-FOB protected against DOX-cardiotoxicity by ameliorating cardiac injury and dysfunction, reducing cardiac fibrosis and inflammatory cytokine release, and inhibiting HMOX1 expression. In conclusion, our results suggest that inhibition of HMOX1-dependent myocardial inflammatory insults and fibrosis is essential for 8-FOB to ameliorate DOX-caused cardiotoxicity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biopha.2021.111779DOI Listing
August 2021

1800 MHz Radiofrequency Electromagnetic Field Impairs Neurite Outgrowth Through Inhibiting EPHA5 Signaling.

Front Cell Dev Biol 2021 12;9:657623. Epub 2021 Apr 12.

Department of Occupational Health, Third Military Medical University, Chongqing, China.

The increasing intensity of environmental radiofrequency electromagnetic fields (RF-EMF) has increased public concern about its health effects. Of particular concern are the influences of RF-EMF exposure on the development of the brain. The mechanisms of how RF-EMF acts on the developing brain are not fully understood. Here, based on high-throughput RNA sequencing techniques, we revealed that transcripts related to neurite development were significantly influenced by 1800 MHz RF-EMF exposure during neuronal differentiation. Exposure to RF-EMF remarkably decreased the total length of neurite and the number of branch points in neural stem cells-derived neurons and retinoic acid-induced Neuro-2A cells. The expression of Eph receptors 5 (EPHA5), which is required for neurite outgrowth, was inhibited remarkably after RF-EMF exposure. Enhancing EPHA5 signaling rescued the inhibitory effects of RF-EMF on neurite outgrowth. Besides, we identified that cAMP-response element-binding protein (CREB) and RhoA were critical downstream factors of EPHA5 signaling in mediating the inhibitory effects of RF-EMF on neurite outgrowth. Together, our finding revealed that RF-EMF exposure impaired neurite outgrowth through EPHA5 signaling. This finding explored the effects and key mechanisms of how RF-EMF exposure impaired neurite outgrowth and also provided a new clue to understanding the influences of RF-EMF on brain development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fcell.2021.657623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075058PMC
April 2021

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition).

Autophagy 2021 Jan 8;17(1):1-382. Epub 2021 Feb 8.

University of Crete, School of Medicine, Laboratory of Clinical Microbiology and Microbial Pathogenesis, Voutes, Heraklion, Crete, Greece; Foundation for Research and Technology, Institute of Molecular Biology and Biotechnology (IMBB), Heraklion, Crete, Greece.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/15548627.2020.1797280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996087PMC
January 2021

Cadmium exposure impairs pancreatic β-cell function and exaggerates diabetes by disrupting lipid metabolism.

Environ Int 2021 04 25;149:106406. Epub 2021 Jan 25.

Department of Environmental Medicine, and Department of Emergency Medicine of First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. Electronic address:

Cadmium is known as an environmental pollutant that contributes to pancreatic damage and the pathogenesis of diabetes. However, less attention has been devoted to elucidating the mechanisms underlying Cd-induced pancreatic β-cell dysfunction and the role of Cd toxicity in the development of diabetes. In this study, we demonstrated that exposure to Cd caused remarkable pancreatic β-cell dysfunction and death, both in vitro and in vivo. Lipidomic analysis of Cd-exposed pancreatic β-cells using high-resolution mass spectrometry revealed that Cd exposure altered the profile and abundance of lipids. Cd exposure induced intracellular lipid accumulation, promoted lipid biogenesis, elevated pro-inflammatory lipid contents and inhibited lipid degradation. Furthermore, Cd exposure upregulated the expression levels of TNF-α, IL-1β and IL-6 in pancreatic β-cells and elevated the TNF-α, IL1-β and IL-6 levels in the serum and pancreas. Taken together, the results of our study demonstrated that environmental relevant Cd exposure causes pro-inflammatory lipids elevation and insulin secretion dysfunction in β-cells and hence exaggerates diabetes development. Combined exposure to environmental hazardous chemicals might markedly increase the probability of developing diabetes in humans. This study provides new metabolic and pharmacological targets for antagonizing Cd toxicity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.envint.2021.106406DOI Listing
April 2021

Cadmium promotes breast cancer cell proliferation, migration and invasion by inhibiting ACSS2/ATG5-mediated autophagy.

Environ Pollut 2021 Jan 15;273:116504. Epub 2021 Jan 15.

School of Medicine, Guangxi University, Nanning, Guangxi Zhuang Autonomous Region, China; Department of Environmental Medicine, School of Public Health, And Department of Emergency Medicine, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. Electronic address:

Cadmium (Cd), which is considered a carcinogenic metal, promotes breast cancer (BC) progression, but the precise mechanism remains unclear. Herein, MCF-7 and T47-D cells were treated with 0.1, 1, and 10 μM cadmium chloride (CdCl) for 24, 48 and 72 h. In our study, Cd exposure significantly accelerated the proliferation, migration and invasion of MCF-7 and T47-D cells. Notably, Cd inhibited autophagic flux by suppressing ATG5-dependent autophagosome formation but had no significant effect on autophagosome-lysosome fusion and lysosomal function. The genetic enhancement of autophagy through ATG5 overexpression suppressed the Cd-mediated increases in proliferation, migration and invasion, which indicated a carcinogenic role of autophagy impairment in Cd-exposed BC cells. GSEA and GeneMANIA were utilized to demonstrate that the Cd-induced decrease in ACSS2 expression mechanistically inhibited ATG5-dependent autophagy in BC cells. Importantly, ACSS2 overexpression increased the level of H3K27 acetylation in the promoter region of ATG5, and this result maintained autophagic flux and abolished the Cd-induced increases in proliferation, migration and invasion. We also verified that the expression of ACSS2 in BC tissues was low and positively related to ATG5 expression. These findings indicated that the promoting effect of Cd on BC cell proliferation, migration and invasion through the impairment of ACSS2/ATG5-dependent autophagic flux suggests a new mechanism for BC cell proliferation and metastasis stimulated by Cd.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.envpol.2021.116504DOI Listing
January 2021

A novel five-lncRNA signature panel improves high-risk survival prediction in patients with cholangiocarcinoma.

Aging (Albany NY) 2021 01 20;13(2):2959-2981. Epub 2021 Jan 20.

Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.

Cholangiocarcinoma (CCA) is a fatal disease with dismal survival rates. Long non-coding RNA (lncRNA) expression profiling as potential prognostic biomarkers play critical roles in tumor initiation, development, and poor prognosis. Identifying specific lncRNA to predict the prognosis of CCA patients in the early stages is very important for improving a patient's survival. In the current study, we aimed to establish a novel risk-stratification lncRNA signature panel in CCA. The initial lncRNA discovery was identified in The Cancer Genome Atlas database (TCGA cohort). The Cox regression analysis was used to establish the lncRNA prognostic model and the receiver operating characteristic (ROC) curve analysis was performed to assess the specificity and sensitivity of the model. This was followed by independent validation of the lncRNA signature in the CCA patients from the First Affiliated Hospital of Wenzhou Medical University (WMU cohort). Furthermore, by using the Gene Ontology function and Kyoto Encyclopedia Gene and Genome pathway enrichment analysis, we explored the potential function of prognosis lncRNA. Finally, five lncRNA (HULC; AL359715.5; AC006504.8; AC090114.2; AP00943.4) were screened to establish the predictive model that significantly associated with poor overall survival(HR:4.879;95%CI,1.587-14.996;=0.006). This five-lncRNA signature model showed excellent accuracy in the TCGA cohort (AUC=0.938), and also robustly predicted survival in the validation WMU cohort(AUC=0.816). Functional enrichment analysis suggested prognostic lncRNA was primarily associated with CCA-related biological processes. Our data established a novel lncRNA signature model for CCA risk-stratification and robust identification of CCA patients with poor molecular genotypes. Moreover, it revealed new molecular mechanisms of CCA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/aging.202446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880389PMC
January 2021

ATP citrate lyase inhibitor triggers endoplasmic reticulum stress to induce hepatocellular carcinoma cell apoptosis via p-eIF2α/ATF4/CHOP axis.

J Cell Mol Med 2021 02 3;25(3):1468-1479. Epub 2021 Jan 3.

Departments of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.

ATP citrate lyase (ACLY), a key enzyme in the metabolic reprogramming of many cancers, is widely expressed in various mammalian tissues. This study aimed to evaluate the effects and mechanisms of ACLY and its inhibitor BMS-303141 on hepatocellular carcinoma (HCC). In this study, ACLY was highly expressed in HCC tissues, especially in HepG2 and Huh7 cells, but was down-regulated in Hep3B and HCC-LM3 cells. Besides, ACLY knockdown inhibited HepG2 proliferation and clone formation, while opposite result was noticed in HCC-LM3 cells with ACLY overexpression. Moreover, ACLY knockdown impeded the migration and invasion abilities of HepG2 cells. Similarly, BMS-303141 suppressed HepG2 and Huh-7 cell proliferation. The p-eIF2α, ATF4, CHOP p-IRE1α, sXBP1 and p-PERK were activated in HepG2 cells stimulated by BMS-303141. In cells where ER stress was induced, ATF4 was involved in BMS-303141-mediated cell death procession, and ATF4 knockdown reduced HCC cell apoptosis stimulated by BMS-303141. In a mouse xenograft model, combined treatment with BMS-303141 and sorafenib reduced HepG2 tumour volume and weight. In addition, ACLY expression was associated with HCC metastasis and tumour-node-metastases staging. Survival analysis and Cox proportional hazards regression model showed that overall survival was lower in HCC patients with high ACLY expression; AFP level, TNM staging, tumour size and ACLY expression level were independent risk factors affecting their overall survival. In conclusion, ACLY might represent a promising target in which BMS-303141 could induce ER stress and activate p-eIF2α/ATF4/CHOP axis to promote apoptosis of HCC cells, and synergized with sorafenib to enhance the efficacy of HCC treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jcmm.16235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875901PMC
February 2021

BIX-01294, a G9a inhibitor, suppresses cell proliferation by inhibiting autophagic flux in nasopharyngeal carcinoma cells.

Invest New Drugs 2021 Jun 2;39(3):686-696. Epub 2021 Jan 2.

Department of Otolaryngology Head and Neck Surgery, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China.

G9a, a histone methyltransferase, has been found to be upregulated in a range of tumor tissues, and contributes to tumor growth and metastasis. However, the impact of G9a inhibition as a potential therapeutic target in nasopharyngeal carcinoma (NPC) is unclear. In the present study we aimed to investigate the anti-proliferative effect of G9a inhibition in the NPC cell lines CNE1 and CNE2, and to further elucidate the molecular mechanisms underlying these effects. The expression of G9a in NPC tumor tissues was significantly higher than that in normal nasopharyngeal tissues. The pharmacological inhibition of G9a by BIX-01294 (BIX) inhibited proliferation and induced caspase-independent apoptosis in NPC cells in vitro. Treatment with BIX induced autophagosome accumulation, which exacerbated the cytotoxic activity of BIX in NPC cells. Mechanistic studies have found that BIX impairs autophagosomes by initiating autophagy in a Beclin-1-independent way, and impairs autophagic degradation by inhibiting lysosomal cathepsin D activation, leading to lysosomal dysfunction. BIX was able to suppress tumor growth, possibly by inhibiting autophagic flux; it might therefore constitute a promising candidate for NPC therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10637-020-01053-7DOI Listing
June 2021

Bisphenol A promotes breast cancer cell proliferation by driving miR-381-3p-PTTG1-dependent cell cycle progression.

Chemosphere 2021 Apr 15;268:129221. Epub 2020 Dec 15.

Department of Environmental Medicine, School of Public Health, and Department of Emergency Medicine, First Affiliated Hospital, School of Medicine, Zhejiang University, China. Electronic address:

Bisphenol A (BPA) is a high-production-volume industrial chemical that facilitates the development of breast cancer. However, the molecular mechanism associated with BPA-induced breast cancer cell proliferation and migration remains elusive. In our study, we exposed MCF-7 cells to different concentrations of BPA (0.1, 1 and 10 μM) for 24, 48, or 72 h. We found that BPA exposure significantly promoted MCF-7 cell proliferation and migration but not invasion. To elucidate the mechanisms, the differentially expressed genes between the BPA and control groups were investigated with the Gene Expression Omnibus (GEO) database through GEO2R. Kyoto Encyclopedia of Genes and Genomes (KEGG) and pathway action network analyses demonstrated the important role of the cell cycle pathway in the effects of BPA exposure on MCF-7 cells. Importantly, analysis with the cytoHubba plugin of Cytoscape software coupled with analysis of enriched genes in the cell cycle pathway identified PTTG1 and CDC20 (two hub genes) as key targets associated with BPA-induced MCF-7 cell proliferation and migration. Interestingly, BPA significantly increased the protein expression levels of PTTG1 but not CDC20. Knockdown of PTTG1 inhibited the BPA-induced increase in proliferation and maintained cell cycle progression. In addition, we confirmed that the increased expression of PTTG1 upon BPA exposure was caused by miR-381-3p inhibition. Moreover, we verified that miR-381-3p expression was low and inversely correlated with PTTG1 expression in breast cancer tissues. Together, these findings demonstrate that BPA promotes high PTTG1 expression and alters the cell cycle to enhance MCF-7 cell proliferation by inhibiting miR-381-3p expression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.chemosphere.2020.129221DOI Listing
April 2021

Long-term bisphenol A exposure exacerbates diet-induced prediabetes via TLR4-dependent hypothalamic inflammation.

J Hazard Mater 2021 01 14;402:123926. Epub 2020 Sep 14.

Department of Environmental Medicine, and Department of Emergency Medicine of First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China. Electronic address:

Bisphenol A (BPA), an environmental endocrine-disrupting compound, has been revealed associated with metabolic disorders such as obesity, prediabetes, and type 2 diabetes (T2D). However, its underlying mechanisms are still not fully understood. Here, we provide new evidence that BPA is a risk factor for T2D from a case-control study. To explore the detailed mechanisms, we used two types of diet models, standard diet (SD) and high-fat diet (HFD), to study the effects of long-term BPA exposure on prediabetes in 4-week-old mice. We found that BPA exposure for 12 weeks exacerbated HFD-induced prediabetic symptoms. Female mice showed increased body mass, serum insulin level, and impaired glucose tolerance, while male mice only exhibited impaired glucose tolerance. No change was found in SD-fed mice. Besides, BPA exposure enhanced astrocyte-dependent hypothalamic inflammation in both male and female mice, which impaired proopiomelanocortin (POMC) neuron functions. Moreover, eliminating inflammation by toll-like receptor 4 (TLR4) knockout significantly abolished the effects of BPA on the hypothalamus and diet-induced prediabetes. Taken together, our data establish a key role for TLR4-dependent hypothalamic inflammation in regulating the effects of BPA on prediabetes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jhazmat.2020.123926DOI Listing
January 2021

Cadmium exposure induces endothelial dysfunction via disturbing lipid metabolism in human microvascular endothelial cells.

J Appl Toxicol 2021 05 17;41(5):775-788. Epub 2020 Nov 17.

Department of Cardiovasology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China.

Cadmium (Cd) is an occupational and environmental heavy metal pollutant derived from many sources that is linked to endothelial homeostasis. The endothelium is an important site of Cd deposition, while increasing evidence has revealed there is a close relationship between endothelial dysfunction and abnormal lipid metabolism. However, the effects of the alterations in lipid metabolism on endothelial cells (ECs) after Cd exposure still remain unclear. In our study, human microvascular endothelial cells (HMEC-1) were exposed to 40-μM Cd for 6, 12, or 24 h or 10-, 20-, or 40-μM Cd for 24 h, respectively. The Cd exposure accelerated the decomposition of triglyceride (TG) and resulted in the accumulation of free fatty acids (FFAs). These changes stimulated cytotoxicity, impaired fatty acid oxidation (FAO), induced reactive oxygen species (ROS) generation, altered the mitochondrial membrane potential (MMP), and decreased the ATP content, which eventually led to endothelial dysfunction and cell death. In summary, exposure to cadmium caused endothelial dysfunction by disrupting lipid metabolism in HMEC-1. These changes were mainly due to FFA accumulation and FAO inhibition, which further induced ROS generation and mitochondrial dysfunction. Moreover, our results provide novel insight into understanding the alterations of lipid metabolism induced by Cd exposure in ECs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jat.4115DOI Listing
May 2021

The prognostic value of sarcopenia combined with hepatolithiasis in intrahepatic cholangiocarcinoma patients after surgery: A prospective cohort study.

Eur J Surg Oncol 2021 03 6;47(3 Pt B):603-612. Epub 2020 Sep 6.

Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, PR China; Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, PR China. Electronic address:

Introduction: Intrahepatic Cholangiocarcinoma (ICC) is the second most common primary liver cancer with dismal survival rates. This study aimed to explore the prognostic value of sarcopenia combine with hepatolithiasis in surgically treated ICC patients and develop a prognostic nomogram to help make clinical decisions.

Materials And Methods: A prospective cohort study was conducted including patients who underwent hepatectomy for ICC between August 2012 and October 2019. The association between the sarcopenia combined with hepatolithiasis and survival, including overall survival (OS) and recurrence-free survival (RFS) was investigated using the Kaplan-Meier (K-M) method. Univariable and multivariable Cox regression analysis was performed to determine the independent prognostic factors and a nomogram establishment was undertaken based on the multivariable analysis.

Results: A total of 121 ICC patients were included in the study. K-M analysis revealed that ICC patients with sarcopenia and hepatolithiasis have worse OS and RFS than those without sarcopenias and/or hepatolithiasis (p < 0.01). Multivariable analysis showed that age, serum CEA, hepatolithiasis, sarcopenia and diabetes were independent prognostic factors for OS(p < 0.05). Finally, a nomogram with good performance in survival prediction was established (C-index was 0.721; the area under the curve of OS was 0.837). The stratified analysis based on the nomogram disclosed that the median OS was 11.9 months in high-risk patients and 51.2 months in low-risk patients (p < 0.001).

Conclusions: ICC patients with sarcopenia and hepatolithiasis have worse OS and RFS. The nomogram we developed is a practical tool that can provide a more individualized risk assessment for surgically treated ICC patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejso.2020.09.002DOI Listing
March 2021

Melatonin Antagonizes Nickel-Induced Aerobic Glycolysis by Blocking ROS-Mediated HIF-1/miR210/ISCU Axis Activation.

Oxid Med Cell Longev 2020 28;2020:5406284. Epub 2020 May 28.

Department of Occupational Health, Army Medical University, 400038 Chongqing, China.

Nickel and its compounds, which are well-documented carcinogens, induce the Warburg effect in normal cells by stabilizing hypoxia-inducible factor 1 (HIF-1). Melatonin has shown diverse anticancer properties for its reactive oxygen species- (ROS-) scavenging ability. Our aim was to explore how melatonin antagonized a nickel-induced increment in aerobic glycolysis. In the current work, a normal human bronchial epithelium cell line (BEAS-2B) was exposed to a series of nonlethal doses of NiCl, with or without 1 mM melatonin. Melatonin attenuated nickel-enhanced aerobic glycolysis. The inhibition effects on aerobic glycolysis were attributed to the capability of melatonin to suppress the regulatory axis comprising HIF-1, microRNA210 (miR210), and iron-sulfur cluster assembly scaffold protein (ISCU1/2). N-Acetylcysteine (NAC) manifested similar effects as melatonin in scavenging ROS, maintaining prolyl-hydroxylase activity, and mitigating HIF-1 transcriptional activity in nickel-exposed cells. Our results indicated that ROS generation contributed to nickel-caused HIF-1 stabilization and downstream signal activation. Melatonin could antagonize HIF-1-controlled aerobic glycolysis through ROS scavenging.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2020/5406284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275958PMC
January 2021

KIF5A-dependent axonal transport deficiency disrupts autophagic flux in trimethyltin chloride-induced neurotoxicity.

Autophagy 2021 04 30;17(4):903-924. Epub 2020 Mar 30.

Department of Environmental Medicine, and Department of Emergency Medicine of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Trimethyltin chloride (TMT) is widely used as a constituent of fungicides and plastic stabilizers in the industrial and agricultural fields, and is generally acknowledged to have potent neurotoxicity, especially in the hippocampus; however, the mechanism of induction of neurotoxicity by TMT remains elusive. Herein, we exposed Neuro-2a cells to different concentrations of TMT (2, 4, and 8 μM) for 24 h. Proteomic analysis, coupled with bioinformatics analysis, revealed the important role of macroautophagy/autophagy-lysosome machinery in TMT-induced neurotoxicity. Further analysis indicated significant impairment of autophagic flux by TMT via suppressed lysosomal function, such as by inhibiting lysosomal proteolysis and changing the lysosomal pH, thereby contributing to defects in autophagic clearance and subsequently leading to nerve cell death. Mechanistically, molecular interaction networks of Ingenuity Pathway Analysis identified a downregulated molecule, KIF5A (kinesin family member 5A), as a key target in TMT-impaired autophagic flux. TMT decreased KIF5A protein expression, disrupted the interaction between KIF5A and lysosome, and impaired lysosomal axonal transport. Moreover, overexpression restored axonal transport, increased lysosomal dysfunction, and antagonized TMT-induced neurotoxicity . Importantly, in TMT-administered mice with seizure symptoms and histomorphological injury in the hippocampus, TMT inhibited KIF5A expression in the hippocampus. Gene transfer of enhanced autophagic clearance in the hippocampus and alleviated TMT-induced neurotoxicity . Our results are the first to demonstrate KIF5A-dependent axonal transport deficiency to cause autophagic flux impairment via disturbance of lysosomal function in TMT-induced neurotoxicity; manipulation of KIF5A may be a therapeutic approach for antagonizing TMT-induced neurotoxicity.: 3-MA: 3-methyladenine; AAV: adeno-associated virus; ACTB: actin beta; AGC: automatic gain control; ATG: autophagy-related; ATP6V0D1: ATPase H transporting lysosomal V0 subunit D1; ATP6V1E1: ATPase H transporting lysosomal V1 subunit E1; CA: cornu ammonis; CQ: chloroquine; CTSB: cathepsin B; CTSD: cathepsin D; DCTN1: dynactin subunit 1; DG: dentate gyrus; DYNLL1: dynein light chain LC8-type 1; FBS: fetal bovine serum; GABARAP: GABA type A receptor-associated protein; GABARAPL1: GABA type A receptor associated protein like 1; GABARAPL2: GABA type A receptor associated protein like 2; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; IPA: Ingenuity Pathway Analysis; KEGG: Kyoto Encyclopedia of Genes and Genomes; KIF5A: kinesin family member 5A; LAMP: lysosomal-associated membrane protein; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; NBR1: NBR1 autophagy cargo receptor; OPTN: optineurin; PBS: phosphate-buffered saline; PFA: paraformaldehyde; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PRM: parallel reaction monitoring; siRNA: small interfering RNA; SQSTM1/p62: sequestosome 1; SYP: synaptophysin; TAX1BP1: Tax1 binding protein 1; TMT: trimethyltin chloride; TUB: tubulin.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/15548627.2020.1739444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078766PMC
April 2021

Association of TNFRSF12A Methylation With Prognosis in Hepatocellular Carcinoma With History of Alcohol Consumption.

Front Genet 2019 9;10:1299. Epub 2020 Jan 9.

Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer related death worldwide with a poor prognosis. Alcoholic liver disease accounts for approximately one-third of all HCC cases. Current evidence proved that aberrant over-expression of TNFRSF12A correlates with the severity of disease, making it a likely indicator of disease a more aggressive and worse prognosis outcome. Emerging studies have confirmed that epigenetic changes are critical events in the development and progression of liver cancer. The study to investigate the mechanisms by which alcohol abuse mediated changes in the methylation level of TNFRSF12A affect the occurrence, development and prognosis of HCC were under warranted. Thus, in this study we mined two publicly available datasets to detect the association between DNA methylation level of CpG sites in gene TNFRSF12A and the development of HCC in those with alcohol abuse history. Finally, we discovered that the hypomethylation of two methylation sites-cg00510447 and cg26808293-could identify HCC from other non-HCC liver diseases. Also, hypomethylation of these two sites could identify alcoholic cirrhosis from other non-hepatocellular carcinoma liver diseases. Most important, the prognostic analysis revealed that the hypomethylation of cg00510447 and cg26808293 in HCC patients with alcohol abuse history could predict poor prognosis. Further stratified analyses by gender discovered that in male HCC patients with alcohol abuse history, hypomethylation of cg26808293 signified poor prognosis. The further mechanism analysis revealed that the DNA methyltransferases DNMT3L might regulate TNFRSF12A methylation and affect the occurrence, development and prognosis of HCC, especially in patients with a history of alcohol abuse. These findings provide new insights into the role of epigenetic mechanisms in the transformation of alcoholic liver disease into HCC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fgene.2019.01299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6964049PMC
January 2020

Direct combustion of waste oil in domestic stove by an internal heat re-circulation atomization technology: Emission and performance analysis.

Waste Manag 2020 Mar 17;104:20-32. Epub 2020 Jan 17.

Shandong Sino-March Environmental Technology Co., Ltd., Yantai, Shandong Province 264006, China.

Direct use of waste oil as fuel to meet the residential energy demands, is very attractive due to its potentials to decrease fossil fuel consumption, reduce pollution and increase sustainability. This paper uses a domestic stove with an internal heat re-circulation and self-atomization technology to burn yellow waste cooking oil (WCO-1), brown waste cooking oil (WCO-2) and waste lubricant oil (WLO). Emission factors (EFs), energy efficiency and modified combustion efficiency (MCE) of this combined fuel/stove system were determined under space-heating and cooking modes. The results showed that EFs of CO, PM, total 16 PAHs and corresponding toxic equivalent quantity (TEQ) values ranged from 2.18 × 10 to 4.90 × 10 mg/MJ, 16.36-69.40 mg/MJ, 2.39-12.93 μg/MJ and 0.16-0.92 μg of TEQ/MJ. WCO-1 was verified to be the cleanest fuel with the highest energy efficiency (85.3 ± 3.3% and 90.4 ± 2.2%) and lowest emission levels, such as NO (53.75 ± 2.62 and 37.09 ± 5.41 mg/MJ), NO (82.40 ± 3.96 and 56.87 ± 8.29 mg/MJ) and PM (20.94 ± 6.55 and 16.35 ± 5.06 mg/MJ) compared to WCO-2 and WLO. The estimated total cost of using waste oil for each household in winter was much cheaper than some current available clean energy means, including only USD$ 400 of stove price and USD$ 250/ton of fuel per year. It is a promising candidate choice for replacing low-quality solid fuels in rural China and 2.62 million rural households would achieve environmental and economic benefits if promoting direct combustion of waste oil for daily heating and cooking.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.wasman.2020.01.007DOI Listing
March 2020

LncRNA RP11-422N16.3 Inhibits Cell Proliferation and EMT, and Induces Apoptosis in Hepatocellular Carcinoma Cells by Sponging miR-23b-3p.

Onco Targets Ther 2019 12;12:10943-10961. Epub 2019 Dec 12.

Departments of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, People's Republic of China.

Objective: This study investigated the mechanism of RP11-422N16.3 sponging miR-23b-3p in cell proliferation, apoptosis and epithelial-mesenchymal transition (EMT) in liver cancer.

Methods: Expressions of RP11-422N16.3, miR-23b-3p and dimethylglycine dehydrogenase (DMGDH) were determined in liver cancer tissues, adjacent normal tissues, hepatocellular carcinoma cell lines and normal liver epithelial cell line. Up-regulation of RP11-422N16.3 and down-regulation of miR-23b-3p were conducted in hepatocellular carcinoma cells. Bioinformatics analysis, luciferase reporter assay and RNA-pull down assay were performed to verify the relationship among miR-23b-3p, DMGDH, as well as RP11-422N16.3. Cell proliferation and cell apoptosis were determined by CCK-8 and Flow Cytometry analysis, respectively.

Results: Expressions of RP11-422N16.3 and DMGDH were down-regulated while that of miR-23b-3p were up-regulated in hepatocellular carcinoma cancer tissues and cells. RP11-422N16.3 localized in cytoplasm and competitively bound to miR-23b-3p. Up-regulation of RP11-422N16.3 and down-regulation of miR-23b-3p contributed to increased expressions of DMGDH and E-cadherin, and decreased expressions of miR-23b-3p, ZEB1, Snail and Vimentin, resulting in inhibiting cell proliferation and promoting cell apoptosis. Inhibition of RP11-422N16.3 or overexpression of miR-23b-3p accelerated cell proliferation and slowed down cell apoptosis. miR-23b-3p inhibited the expression of DMGDH.

Conclusion: Our data suggested that LncRNA RP11-422N16.3, by competitively binding to miR-23b-3p, promoted DMGDH expression, contributing to inhibit cell proliferation and EMT, and induce cell apoptosis in hepatocellular carcinoma cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/OTT.S232243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6913766PMC
December 2019

Transcriptomic insight into cadmium-induced neurotoxicity in embryonic neural stem/progenitor cells.

Toxicol In Vitro 2020 Feb 12;62:104686. Epub 2019 Oct 12.

Department of Environmental Medicine, School of Public Health, and Department of Emergency Medicine, First Affiliated Hospital, School of Medicine, Zhejiang University, China. Electronic address:

Cadmium exposure has raised great public concern. Extensive studies have revealed the neurotoxic effects of cadmium exposure during brain development. However, more evidence is still needed to reach a consistent conclusion and uncover the underlying mechanisms. Here, we used primary mouse embryonic neural stem/progenitor cells (NSPCs) as a cell model and exposed the cells to 0, 1, 2 or 4 μM cadmium. High-throughput mRNA-seq technology was used to explore the global transcriptome changes in NSPCs after exposure to 2 μM cadmium. We found that cadmium exposure remarkably influenced the expression of genes involved in cell growth, proliferation, cell cycle and survival. Pathway-Act-Network analysis revealed that these altered genes were targeted to the P53, PI3K-AKT, MAPK, calcium, and NF-kappa B signaling pathways. In vitro experiments using cultured NSPCs verified that cadmium exposure reduced cell viability, proliferation, neurosphere formation and caused cell cycle arrest at low concentrations (≤ 2 μM), while induced cell apoptosis at high concentrations (≥ 4 μM). Real-time PCR results confirmed the concentration-dependent effects of cadmium exposure on the expression of critical genes in the above signaling pathways. Together, our results provide transcriptomic insight into cadmium-induced developmental neurotoxic effects and the underlying mechanisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.tiv.2019.104686DOI Listing
February 2020

Long-term exercise prevents hepatic steatosis: a novel role of FABP1 in regulation of autophagy-lysosomal machinery.

FASEB J 2019 11 31;33(11):11870-11883. Epub 2019 Jul 31.

School of Aerospace Medicine, Fourth Military Medical University, Xi'an, China.

Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent diseases worldwide. Exercise is a first-line therapy and an important preventive measure for patients with NAFLD, but the underlying mechanisms are not clear. C57BL/6 mice were fed a high-fat diet (HFD) and subjected to 12 wk swimming exercise. Exercise protected against hepatic lipid accumulation and alleviated hepatocyte damage in HFD mice. Tandem mass tag-based quantitative proteomic analyses and ingenuity pathway analysis revealed that exercise down-regulated fatty acid-binding protein (FABP)1 signaling pathway, which was most closely associated with lipid metabolism. Moreover, exercise significantly decreased FABP1 expression, and liver-specific overexpression of FABP1 abolished the protective effect of exercise in NAFLD mice. Specifically, exercise significantly increased autophagic flux restoring lysosomal function, including lysosomal proteolysis and lysosomal acidification maintenance, contributing to enhancement in autophagic clearance and subsequently alleviation of hepatic steatosis. Conversely, overexpression in the mouse liver blocked the protective effect of exercise inhibiting autophagy flux. The present study identified FABP1 inhibition-mediated replenishment of the autophagy-lysosomal machinery as a novel endogenous mechanism whereby long-term exercise improves lipid homeostasis and ameliorates hepatic steatosis in NAFLD.-Pi, H., Liu, M., Xi, Y., Chen, M., Tian, L., Xie, J., Chen, M., Wang, Z., Yang, M., Yu, Z., Zhou, Z., Gao, F. Long-term exercise prevents hepatic steatosis: a novel role of FABP1 in regulation of autophagy-lysosomal machinery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1096/fj.201900812RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902714PMC
November 2019

Inhibition of SERPINA3N-dependent neuroinflammation is essential for melatonin to ameliorate trimethyltin chloride-induced neurotoxicity.

J Pineal Res 2019 Oct 6;67(3):e12596. Epub 2019 Aug 6.

Department of Environmental Medicine, and Department of Emergency Medicine of First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Trimethyltin chloride (TMT) is a potent neurotoxin that causes neuroinflammation and neuronal cell death. Melatonin is a well-known anti-inflammatory agent with significant neuroprotective activity. Male C57BL/6J mice were intraperitoneally injected with a single dose of melatonin (10 mg/kg) before exposure to TMT (2.8 mg/kg, ip). Thereafter, the mice received melatonin (10 mg/kg, ip) once a day for another three consecutive days. Melatonin dramatically alleviated TMT-induced neurotoxicity in mice by attenuating hippocampal neuron loss, inhibiting epilepsy-like seizures, and ameliorating memory deficits. Moreover, melatonin markedly suppressed TMT-induced neuroinflammatory responses and astrocyte activation, as shown by a decrease in inflammatory cytokine production as well as the downregulation of neurotoxic reactive astrocyte phenotype markers. Mechanistically, serine peptidase inhibitor clade A member 3N (SERPINA3N) was identified as playing a central role in the protective effects of melatonin based on quantitative proteome and bioinformatics analysis. Most importantly, melatonin significantly suppressed TMT-induced SERPINA3N upregulation at both the mRNA and protein levels. The overexpression of Serpina3n in the mouse hippocampus abolished the protective effects of melatonin on TMT-induced neuroinflammation and neurotoxicity. Melatonin protected cells against TMT-induced neurotoxicity by inhibiting SERPINA3N-mediated neuroinflammation. Melatonin may be a promising and practical agent for reducing TMT-induced neurotoxicity in clinical practice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jpi.12596DOI Listing
October 2019

SCD1 activation impedes foam cell formation by inducing lipophagy in oxLDL-treated human vascular smooth muscle cells.

J Cell Mol Med 2019 08 22;23(8):5259-5269. Epub 2019 May 22.

School of Aerospace Medicine, Fourth Military Medical University, Xi'an, China.

The formation of fat-laden foam cells, which contributes to the fatty streaks in the plaques of atheromas, is an important process in atherosclerosis. Vascular smooth muscle cells (VSMCs) are a critical origin of foam cells. However, the mechanisms that underlie VSMC foam cell formation are not yet completely understood. Here, we demonstrated that oxidized low-density lipoprotein (oxLDL) inhibited lipophagy by suppressing lipid droplet (LD)-lysosome fusion and increased VSMC foam cell formation. Moreover, although oxLDL treatment inhibited lysosomal biogenesis, it had no significant effect on lysosomal proteolysis and lysosomal pH. Notably, through TMT-based quantitative proteomic analysis and database searching, 94 differentially expressed proteins were identified, of which 54 were increased and 40 were decreased in the oxLDL group compared with those in the control group. Subsequently, SCD1, a protein of interest, was further investigated. SCD1 levels in the VSMCs were down-regulated by exposure to oxLDL in a time-dependent manner and the interaction between SCD1 and LDs was also disrupted by oxLDL. Importantly, SCD1 overexpression enhanced LD-lysosome fusion, increased lysosomal biogenesis and inhibited VSMC foam cell formation by activating TFEB nuclear translocation and its reporter activity. Modulation of the SCD1/TFEB-mediated lipophagy machinery may offer novel therapeutic approaches for the treatment of atherosclerosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jcmm.14401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6652860PMC
August 2019

LncRNA H19/miR-194/PFTK1 axis modulates the cell proliferation and migration of pancreatic cancer.

J Cell Biochem 2019 03 26;120(3):3874-3886. Epub 2018 Nov 26.

Department of Post-Anesthetic ICU, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.

Pancreatic ductal adenocarcinoma (PDAC) remains a huge challenge due to its high mortality and morbidity; gene therapy might be a promising treatment for PDAC. The critical role of Wnt-signaling pathway in cancer pathogenesis has been widely recognized; cyclin-dependent kinase 14 (CDK14, PFTK1)-induced low-density lipoprotein receptor-related proteins 5/6 (LRP5/6) phosphorylation is an important issue in Wnt-signaling activation. Long noncoding RNA (LncRNA)-microRNA (miRNA)-messenger RNA (mRNA) modulating the pathogenesis of cancers has been regarded as a major mechanism. In the current study, upregulated lncRNAs positively correlated with PFTK1 were analyzed and selected using The Cancer Genome Atlas (TCGA) database. Of them, lncRNA H19 can activate Wnt signaling in cancers. In PDAC tissues, the expression of H19 and PFTK1 were upregulated; H19 knockdown suppressed the cell proliferation and migration of PDAC, while PFTK1 overexpression partially attenuated the suppressive effect of H19 knockdown. As analyzed by TCGA and predicted by online tools, miR-194 was negatively correlated with PFTK1 and might bind to both H19 and PFTK1, which was further confirmed by luciferase reporter and RNA immunoprecipitation assays. Moreover, the effect of H19 knockdown on PFTK1 protein and the cell proliferation and migration could be partially reversed by miR-194 inhibition; H19/miR-194 axis modulated PDAC cell proliferation and migration through PFTK1 downstream Wnt signaling. Results suggested that rescuing miR-194 expression in PDAC can inhibit lncRNA H19 and PFTK1 expression, subsequently suppressing PDAC cell proliferation and migration. Due to the complexity of the lncRNA-miRNA-mRNA network, further in vivo experiments examining potential side effects are needed in future study to explore the clinical application of these findings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jcb.27669DOI Listing
March 2019

AKT inhibition-mediated dephosphorylation of TFE3 promotes overactive autophagy independent of MTORC1 in cadmium-exposed bone mesenchymal stem cells.

Autophagy 2019 04 20;15(4):565-582. Epub 2018 Oct 20.

a Department of Environmental Medicine, and Department of Critical Care Medicine of the First Affiliated Hospital , Zhejiang University School of Medicine , Hangzhou , China.

Cadmium (Cd) is a toxic metal that is widely found in numerous environmental matrices and induces serious adverse effects in various organs and tissues. Bone tissue seems to be a crucial target of Cd contamination. Macroautophagy/autophagy has been proposed to play a pivotal role in Cd-mediated bone toxicity. However, the mechanisms that underlie Cd-induced autophagy are not yet completely understood. We demonstrated that Cd treatment increased autophagic flux and inhibition of the autophagic process using Atg7 gene silencing blocked the Cd-induced mesenchymal stem cell death. Mechanistically, Cd activated nuclear translocation of TFE3 but not that of TFEB or MITF, which contributed to the expression of autophagy-related genes and lysosomal biogenesis. Specifically, Cd decreased expression of phospho-AKT (Ser473). The reduction in AKT activity led to dephosphorylation of cytosolic TFE3 at Ser565 and promoted TFE3 nuclear translocation independently of MTORC1. Notably, Cd treatment increased the activity of PPP3/calcineurin, and pharmacological inhibition of PPP3/calcineurin with FK506 suppressed AKT dephosphorylation and TFE3 activity. These results suggest that PPP3/calcineurin negatively regulates AKT phosphorylation and is involved in Cd-induced TFE3-dependent autophagy. Modulation of the PPP3/calcineurin-AKT-TFE3 autophagic-lysosomal machinery may offer novel therapeutic approaches for the treatment of Cd-induced bone damage. Abbreviations: ACTB: actin: beta; AKT: thymoma viral proto-oncogene; AMPK: AMP-activated protein kinase; ATG: autophagy related; Baf A1: bafilomycin A; Cd: cadmium; FOXO3: forkhead box O3; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MITF: melanogenesis associated transcription factor; MSC: mesenchymal stem sell; MTORC1: mechanistic target of rapamycin kinase complex 1; RPS6KB1: ribosomal protein S6 kinase: polypeptide 1; SGK1: serum/glucocorticoid regulated kinase 1; SQSTM1/p62: sequestosome 1;TFE3: transcription factor E3; TFEB: transcription factor EB; TFEC: transcription factor EC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/15548627.2018.1531198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6526814PMC
April 2019

Transcription factor E3 protects against cadmium-induced apoptosis by maintaining the lysosomal-mitochondrial axis but not autophagic flux in Neuro-2a cells.

Toxicol Lett 2018 Oct 17;295:335-350. Epub 2018 Jul 17.

Department of Environmental Medicine, and Department of Critical Care Medicine of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. Electronic address:

Cadmium (Cd), is a well-known environmental and occupational hazard with a potent neurotoxic action. However, the mechanism underlying cadmium-induced neurotoxicity remains unclear. Herein, we exposed Neuro-2a cells to different concentrations of cadmium chloride (CdCl) (12.5, 25 and 50 μM) for 24 h and found that Cd significantly induced lysosomal membrane permeabilization (LMP) with the release of cathepsin B (CTSB) to the cytosol, which in turn caused the release of mitochondrial cytochrome c (Cyt c) and eventually triggered caspase-dependent apoptosis. Interestingly, Cd decreased TFE3 expression but induced the nuclear translocation of TFE3 and TFE3 target-gene expression, which might be associated with lysosomal stress mediated by Cd. Notably, Tfe3 overexpression protected against Cd-induced neurotoxicity by maintaining the lysosomal-mitochondrial axis, and the protective effect of TFE3 is not dependent on the restoration of autophagic flux. In conclusion, our study demonstrated for the first time that lysosomal-mitochondrial axis dependent apoptosis, a neglected mechanism, may be the most important reason for Cd-induced neurotoxicity and that manipulation of TFE3 signaling may be a potential therapeutic approach for treatment of Cd-induced neurotoxicity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.toxlet.2018.07.015DOI Listing
October 2018

A novel nomogram for the prediction of intrahepatic cholangiocarcinoma in patients with intrahepatic lithiasis complicated by imagiologically diagnosed mass.

Cancer Manag Res 2018 23;10:847-856. Epub 2018 Apr 23.

Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.

Background: Accurate preoperative diagnosis of intrahepatic cholangiocarcinoma (ICC) among patients with imagiologically intrahepatic lithiasis (IHL) complicated by mass is crucial for timely and effective surgical intervention. The aim of the present study was to develop a nomogram to identify ICC associated with IHL (IHL-ICC).

Patients And Methods: Data were obtained from a total of 252 consecutive patients with IHL complicated by mass. Multivariate logistic regression analysis was conducted to identify the clinicopathologic and imagiological characteristics that were potentially associated with ICC. A nomogram was developed based on the results of the multivariate analysis, and the value for prediction of ICC was assessed.

Results: The study revealed six potential predictors for IHL-ICC, including comprehensive imagiological diagnosis, biliary tract operation history, fever, ascites, cancer antigen (CA) 19-9, and carcinoembryonic antigen (CEA). The optimal cutoff value was 3.75 μg/L for serum CEA and 143.15 U/mL for serum CA 19-9. The accuracy of the nomogram in predicting ICC was 78.5%. The Youden index provided a value of 0.348, corresponding to a cutoff of 95 points, with an area under the curve of 0.863.

Conclusion: The nomogram holds promise as a novel and accurate tool in identifying IHL-ICC for hepatectomy, and in the differentiation of benign occupying lesions in IHL patients, resulting in the avoidance of unnecessary surgical resection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/CMAR.S157506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5918625PMC
April 2018
-->