Publications by authors named "Xinhong Zhu"

36 Publications

KIN17 promotes tumor metastasis by activating EMT signaling in luminal-A breast cancer.

Thorac Cancer 2021 May 19. Epub 2021 May 19.

Laboratory Medicine Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China.

Background: Breast cancer (BC), the most common cause of cancer death in women, overtook lung cancer as the leading cause of cancer worldwide in 2020. Although many studies have proposed KIN17 as a biomarker of tumorigenesis in different cancer types, its role in tumor metastasis, particularly in BC metastasis, has been underexplored. This study aimed to explore the role of KIN17 in BC metastasis.

Methods: Survival analyses was performed to identify the association between KIN17 expression and BC patient survival in silico. Using lentivirus constructs, we developed bidirectional KIN17 expression (KD, knockdown; OE, overexpression) cellular models of luminal-A (Lum-A) breast cancer MCF-7 cells. We performed in vitro wound healing, transwell with and without Matrigel assays, and in vivo tail-vein metastasis assay to evaluate the migration and invasion abilities of MCF-7 with stable KIN17 knockdown or overexpression. Western blotting was performed to compare the changes in protein expression.

Results: We found that KIN17 expression was associated with poor overall survival (OS), relapse-free survival (RFS), distant metastasis-free survival (DMFS) and post-progression survival (PPS), particularly in Lum-A breast cancer patients. Later, we found that KIN17 knockdown inhibited migration and invasion of MCF-7 cells via regulating EMT-associated signaling pathways in vitro and decreases metastatic spread of the disease in vivo. In contrast, KIN17 overexpression promoted migration and invasion of MCF-7 cells in vitro and increased the metastatic spread of the disease in vivo.

Conclusions: Overall, our findings provide preliminary data which suggests KIN17 of importance to target in metastatic Lum-A patients.
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http://dx.doi.org/10.1111/1759-7714.14004DOI Listing
May 2021

Developmental neurotoxicity of antimony (Sb) in the early life stages of zebrafish.

Ecotoxicol Environ Saf 2021 May 8;218:112308. Epub 2021 May 8.

Key Laboratory for Biorheological Science and Technology of Ministry of Education, State and Local Joint Engineering Laboratory for Vascular Implants, Bioengineering College of Chongqing University, Chongqing 400030, China. Electronic address:

Accumulating studies have revealed the toxicity of antimony (Sb) to soil-dwelling and aquatic organisms at the individual level. However, little is known about the neurotoxic effects of antimony and its underlying mechanisms. To assess this issue, we investigated the neurotoxicity of antimony (0, 200, 400, 600 and 800 mg/L) in zebrafish embryos. After exposure, zebrafish embryos showed abnormal phenotypes such as a shortened body length, morphological malformations, and weakened heart function. Behavioral experiments indicated that antimony caused neurotoxicity in zebrafish embryos, manifested in a decreased spontaneous movement frequency, delayed response to touch, and reduced movement distance. We also showed that antimony caused a decrease in acetylcholinesterase (AChE) levels in zebrafish embryos, along with decreased expression of neurofunctional markers such as gfap, nestin, mbp, and shha. Additionally, antimony significantly increased reactive oxygen species levels and significantly reduced glutathione (GSH) and superoxide dismutase (SOD) activity. In summary, our findings indicated that antimony can induce developmental toxicity and neurotoxicity in zebrafish embryos by affecting neurotransmitter systems and oxidative stress, thus altering behavior. These outcomes will advance our understanding of antimony-induced neurotoxicity, environmental problems, and health hazards.
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http://dx.doi.org/10.1016/j.ecoenv.2021.112308DOI Listing
May 2021

Social support and coping style of Tongqi in China: A cross-sectional study.

Arch Psychiatr Nurs 2021 Jun 19;35(3):317-322. Epub 2020 Dec 19.

College of Nursing, Hubei University of Chinese Medicine, Wuhan, China. Electronic address:

Tongqi (gays' wives) in China were under tremendous distress and social pressure due to their special identities and were not clearly known. A sample of 179 Chinese Tongqi were recruited through online social media groups in 2017-2018. Their hidden lives, social support, and coping styles were analyzed. The results showed that the majority of Tongqi concealed their identities, had negative responses to cope with their tremendous distress, and did not have sufficient social support. Their social support was mainly from family members. Hidden identities obstructed Tongqi's access to extrafamilial social support that could alleviate their distress. Tongqi need more social support and protection.
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http://dx.doi.org/10.1016/j.apnu.2020.12.002DOI Listing
June 2021

Association of maternal pre-pregnancy low or increased body mass index with adverse pregnancy outcomes.

Sci Rep 2021 Feb 15;11(1):3831. Epub 2021 Feb 15.

Guangdong Institute of Family Planning Science and Technology, 17th Meidong Road, Yuexiu District, 510245, Guangzhou, People's Republic of China.

This study investigated the association between pre-pregnancy body mass index (BMI) and adverse pregnancy outcomes among women participated in the National Free Preconception Health Examination Project in Guangdong Province, China, and explored these associations according to maternal age. Pre-pregnancy BMI was classified into underweight (BMI < 18.5 kg/m), healthy weight (18.5-23.9 kg/m), overweight (24.0-27.9 kg/m), and obesity (≥ 28.0 kg/m) according to Chinese criteria. Outcomes were preterm birth (PTB, delivery before 37 weeks of gestation), large for gestational age (LGA, birthweight above the 90th percentile for gestational age by infants' sex), small for gestational age (SGA, birthweight below the 10th percentile for gestational age by infants' sex), primary caesarean delivery, shoulder dystocia or birth injury, and stillbirth. Adjusted incidence risk ratios (aIRR) were calculated for underweight, overweight and obesity, respectively. Compared with healthy weight, underweight was associated with increased risk of PTB (aIRR 1.06, 95%CI 1.04-1.09) and SGA (1.23, 1.22-1.26) but inversely associated with LGA (0.83, 0.82-0.85), primary caesarean delivery (0.88, 0.87-0.90) and stillbirth (0.73, 0.53-0.99). Overweight was associated with increased risk of LGA (1.17, 1.14-1.19), primary caesarean delivery (1.18, 1.16-1.20) and stillbirth (1.44, 1.03-2.06), but inversely associated with SGA (0.92, 0.90-0.95) and shoulder dystocia or birth injury (0.86, 0.79-0.93). Obesity was associated with increased risk of PTB (1.12, 1.05-1.20), LGA (1.32, 1.27-1.37), primary caesarean delivery (1.45, 1.40-1.50), but inversely associated with SGA (0.92, 0.87-0.97). The aIRRs for underweight, overweight and obesity in relation to these adverse pregnancy outcomes ranged from 0.65 to 1.52 according to maternal age. In Chinese population, maternal pre-pregnancy BMI was significantly associated with the risk of adverse pregnancy outcomes and the risk differs according to maternal age. Further investigation is warranted to determine whether and how counselling and interventions for women with low or increased BMI before pregnancy can reduce the risk of adverse pregnancy outcomes.
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http://dx.doi.org/10.1038/s41598-021-82064-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884680PMC
February 2021

Associations of pre-pregnancy impaired fasting glucose and body mass index among pregnant women without pre-existing diabetes with offspring being large for gestational age and preterm birth: a cohort study in China.

BMJ Open Diabetes Res Care 2021 Feb;9(1)

Department of Epidemiology, Family Planning Special Hospital of Guangdong, Guangzhou, China.

Introduction: Associations of pre-pregnancy impaired fasting glucose (IFG) and body mass index (BMI) with large for gestational age (LGA) and preterm birth (PTB) have been poorly understood. We aimed to investigate the associations of maternal BMI, separately and together with pre-pregnancy IFG, with LGA and PTB in Chinese population. We also aimed to quantify these associations by maternal age.

Research Design And Methods: This was a retrospective cohort study of women from the National Free Preconception Health Examination Project with singleton birth from 121 counties/districts in 21 cities of Guangdong Province, China, from January 1, 2013 to December 31, 2017. Women were included if they did not have pre-existing chronic diseases (diabetes, hypertension, etc). Participants were divided into eight groups according to their BMI (underweight (BMI <18.5 kg/m), normal weight (18.5-23.9 kg/m), overweight (24.0-27.9 kg/m), and obesity (≥28.0 kg/m)) and pre-pregnancy fasting glucose status (normoglycemia (fasting glucose concentration <6.1 mmol/L) and IFG (6.1-7.0 mmol/L)). Adjusted incidence risk ratios (aIRRs) and 95% CIs of LGA, severe LGA, PTB and early PTB were estimated.

Results: We included 634 030 women. The incidences of LGA, severe LGA, PTB and early PTB for the study population were 7.1%, 2.5%, 5.1% and 1.1%, respectively. Compared with normal weight mothers with normoglycemia, overweight and obese mothers irrespective of IFG had a higher risk of LGA (eg, obesity with IFG aIRR 1.85 (1.60-2.14)) and severe LGA (eg, obesity with IFG 2.19 (1.73-2.79)). The associations of BMI and pre-pregnancy fasting glucose status with LGA were similar found among women of all age groups. Underweight with normoglycemia had 6.0% higher risk of PTB (1.06 (1.03-1.09)) and 8.0% higher risk of early PTB (1.08 (1.02-1.17)), underweight with IFG had 14.0% higher risk of PTB (1.14 (1.02-1.27)), and obese mothers with IFG had 45.0% higher risk of PTB (1.45 (1.18-1.78)). The associations of BMI and pre-pregnancy fasting glucose status with PTB differed by maternal age.

Conclusion: Overweight and obesity regardless of IFG were associated with an increased risk of LGA, and these associations were similarly observed among mothers of all age groups. Underweight regardless of IFG, and obesity with IFG were associated with an increased risk of PTB, but the associations differed by maternal age. Findings from this study may have implications for risk assessment and counselling before pregnancy.
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http://dx.doi.org/10.1136/bmjdrc-2020-001641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878137PMC
February 2021

Field evaluation of two mosquito traps in Zhejiang Province, China.

Sci Rep 2021 01 11;11(1):294. Epub 2021 Jan 11.

Zhejiang Provincial Center for Disease Control and Prevention, 3399 Binsheng Road, Hangzhou City, Zhejiang Province, China.

Mosquito-borne Diseases are a common but severe public health threat. However, there is a lack of consensus on the effect of different mosquito trapping devices in China. This study firstly compared the BGM trap with the CDC light trap, commonly used in Chinese mosquito surveillance. Field trials of traps' efficiency were conducted in Yiwu city, China, from May 21st, 2018 to November 31st, 2018. Sixty-five comparisons were completed in five different biotopes (an urban residential area, a rural residential area, a park, a hospital, and a pig shelter). Concerning the number of mosquitoes per trap, the BGM trap outperformed three out of five biotopes. In contrast, the CDC light trap only showed better performance in the pig shelter. For specific species, the BGM trap outperformed in capturing Ae. albopictus, while the CDC light trap caught significantly more Cx. tritaeniorhynchus. Regarding Ae. albopictus and Cx. pipiens s.l. surveillance, the BGM trap is more suitable. The BGM trap shows significantly higher or similar efficiency than the CDC light trap in trapping common mosquito species in China, except in the pig shelter. Therefore, we recommend that Chinese researchers and public health practitioners use the BGM trap in future mosquito surveillance.
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http://dx.doi.org/10.1038/s41598-020-80618-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801727PMC
January 2021

Soluble epoxide hydrolase deficiency attenuates lipotoxic cardiomyopathy via upregulation of AMPK-mTORC mediated autophagy.

J Mol Cell Cardiol 2021 05 27;154:80-91. Epub 2020 Dec 27.

Guangdong Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Cardiology, RNA Biomedical Institute, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 107 Yanjiang Road, Guangzhou 510120, China; Department of Cardiology, The Eighth Affiliated Hospital of Sun Yat-sen University, 3025 Shennan Middle Road, Shen Zhen 518033, China. Electronic address:

Obesity-driven cardiac lipid accumulation can progress to lipotoxic cardiomyopathy. Soluble epoxide hydrolase (sEH) is the major enzyme that metabolizes epoxyeicosatrienoic acids (EETs), which have biological activity of regulating lipid metabolism. The current study explores the unknown role of sEH deficiency in lipotoxic cardiomyopathy and its underlying mechanism. Wild-type and Ephx2 knock out (sEH KO) C57BL/6 J mice were fed with high-fat diet (HFD) for 24 weeks to induce lipotoxic cardiomyopathy animal models. Palmitic acid (PA) was utilized to induce lipotoxicity to cardiomyocytes for in vitro study. We found sEH KO, independent of plasma lipid and blood pressures, significantly attenuated HFD-induced myocardial lipid accumulation and cardiac dysfunction in vivo. HFD-induced lipotoxic cardiomyopathy and dysfunction of adenosine 5'-monophosphate-activated protein kinase-mammalian target of rapamycin complex (AMPK-mTORC) signaling mediated lipid autophagy in heart were restored by sEH KO. In primary neonatal mouse cardiomyocytes, both sEH KO and sEH substrate EETs plus sEH inhibitor AUDA treatments attenuated PA-induced lipid accumulation. These effects were blocked by inhibition of AMPK or autophagy. The outcomes were supported by the results that sEH KO and EETs plus AUDA rescued HFD- and PA-induced impairment of autophagy upstream signaling of AMPK-mTORC, respectively. These findings revealed that sEH deficiency played an important role in attenuating myocardial lipid accumulation and provided new insights into treating lipotoxic cardiomyopathy. Regulation of autophagy via AMPK-mTORC signaling pathway is one of the underlying mechanisms.
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http://dx.doi.org/10.1016/j.yjmcc.2020.12.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068623PMC
May 2021

Case-based learning combined with science, technology, engineering and math (STEM) education concept to improve clinical thinking of undergraduate nursing students: A randomized experiment.

Nurs Open 2021 01 28;8(1):415-422. Epub 2020 Sep 28.

School of Nursing Hubei University of Chinese Medicine Wuhan China.

Aims: The present study was conducted to apply and examine case-based learning (CBL) and Science, Technology, Engineering, and Math (STEM) education concept in the training of nursing student's clinical thinking.

Design: A randomized experimental design with non-equivalent group pretest-posttest.

Methods: Participants were requested to participant in either of the two programmes: traditional education programme as a control group or CBL combined with STEM education concept (the STEM group). Questionnaires of critical thinking, self-directed learning, self-efficacy were administered before and after the experiment.

Results: Differences between the STEM group and control group were observed in critical thinking, self-directed learning, self-efficacy and career choice over one semester. Accordingly, CBL combined with STEM education concept enhanced the nursing student's clinical thinking.
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http://dx.doi.org/10.1002/nop2.642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7729541PMC
January 2021

I seeds irradiation inhibits tumor growth and induces apoptosis by Ki-67, P21, survivin, livin and caspase-9 expression in lung carcinoma xenografts.

Radiat Oncol 2020 Oct 15;15(1):238. Epub 2020 Oct 15.

Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Qingdao University, Qingdao, 266003, Shandong Province, China.

Background: Lung cancer is a fatal disease and a serious health problem worldwide. Patients are usually diagnosed at an advanced stage, and the effectiveness of chemotherapy for such patients is very limited. Iodine 125 seed (I) irradiation can be used as an important adjuvant treatment for lung carcinoma. The purpose of this study was to examine the role of irradiation by 125I seeds in human lung cancer xenograft model and to determine the underlying mechanisms involved, with a focus on apoptosis.

Methods: 40 mice with A549 lung adenocarcinoma xenografts were randomly divided into 4 groups: control group (n = 10), sham seed (0 mCi) implant group (n = 10), 125I seed (0.6 mCi) implant group (n = 10) and 125I seed (0.8 mCi) implant group (n = 10), respectively. The body weight and tumor volume, were recorded every 4 days until the end of the study. Apoptotic cells were checked by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and activities of caspase-3 and caspase-8 enzyme were tested. Expression of P21, survivin, livin, caspase-9 and proliferating cell nuclear antigen (Ki-67) was detected with immunohistochemical staining.

Results: The results of TUNEL staining assays showed that 125I seed irradiation suppresses the growth of lung cancer xenografts in nude mice and induced apoptosis. The activity of caspase-3 and caspase-8 was significantly higher. The expression levels Ki67, survivin and livin were substantially downregulated, while P21 and caspase-9 protein expression were significantly increased following 125I seed irradiation. This study revealed that 125I seed irradiation could significantly change apoptosis-related protein in human lung cancer xenografts.

Conclusions: Overall, our study demonstrates that radiation exposure by 125I seeds could be a new treatment option for lung cancer.
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http://dx.doi.org/10.1186/s13014-020-01682-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7559445PMC
October 2020

Utilization and professionalism toward social media among undergraduate nursing students.

Nurs Ethics 2021 Mar 25;28(2):297-310. Epub 2020 Sep 25.

240515Hubei University of Chinese Medicine, China.

Background: Social media has become an integrated part of nursing profession, requiring nursing students to develop confidentiality and professional fitness to practice. The aim of this study was to investigate nursing students' usage, professionalism and attitudes toward social media.

Methods: A cross-section study was conducted online among undergraduate nursing students (n = 654). Questionnaires of self-directed learning, self-efficacy and usage and views toward social media were administered.

Ethical Considerations: Ethical approval was obtained from the Hubei University of Chinese Medicine.

Results: All participants were social media users. QQ (93.2%) was the most frequently used. 74.5% respondents spent 2-6 h on social media daily. The majority held positive attitudes toward social media. Year group and gender had influence on perceptions and attitudes toward social media. Furthermore, 81.5% students believed that social media positively influenced self-directed learning. Self-directed learning and learning motivation acted as predictors of the attitudes toward social media. Meanwhile, 67.3% students had posted personal photos and videos online, and 82.4% of them did not have privacy setting on social media. In addition,13.8% students attacked others or posted improper photos online. 22.9% participants witnessed improper posts from schoolmates or teachers, such as complaints about schoolmates or teachers (22.2%), foul language (11.1%), violence (3.9%), sexually suggestive photos (2.6%) and patient confidentiality (0.7%). In all, 15.0% respondents accepted "friend request" from patients. A total of 58.2% students were not aware of professional standards of behavior online for health care providers. In addition, 52.3% participants insisted that it is essential to develop social media and professionalism course for nursing students.

Conclusion: Nursing students use social media extensively. Some students are at risk of carrying out unprofessional behavior which have detrimental effects on students' future opportunities. This suggests that best practices and training in nurse education should be implemented to help students to be informed of professionalism.
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http://dx.doi.org/10.1177/0969733020952105DOI Listing
March 2021

14,15-Epoxyeicosatrienoic Acid Alleviates Pathology in a Mouse Model of Alzheimer's Disease.

J Neurosci 2020 10 24;40(42):8188-8203. Epub 2020 Sep 24.

Institute of Mental Health, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, People's Republic of China

Alzheimer's disease (AD) is the leading cause of late-onset dementia, and there exists an unmet medical need for effective treatments for AD. The accumulation of neurotoxic amyloid-β (Aβ) plaques contributes to the pathophysiology of AD. encoding soluble epoxide hydrolase (sEH)-a key enzyme for epoxyeicosatrienoic acid (EET) signaling that is mainly expressed in lysosomes of astrocytes in the adult brain-is cosited at a locus associated with AD, but it is unclear whether and how it contributes to the pathophysiology of AD. In this report, we show that the pharmacologic inhibition of sEH with 1-trifluoromethoxyphenyl- 3-(1-propionylpiperidin-4-yl) urea (TPPU) or the genetic deletion of reduces Aβ deposition in the brains of both male and female familial Alzheimer's disease (5×FAD) model mice. The inhibition of sEH with TPPU or the genetic deletion of alleviated cognitive deficits and prevented astrocyte reactivation in the brains of 6-month-old male 5×FAD mice. 14,15-EET levels in the brains of these mice were also increased by sEH inhibition. In cultured adult astrocytes treated with TPPU or 14,15-EET, astrocyte Aβ clearance was increased through enhanced lysosomal biogenesis. Infusion of 14,15-EET into the hippocampus of 5×FAD mice prevented the aggregation of Aβ. Notably, a higher concentration of 14,15-EET (200 ng/ml) infusion into the hippocampus reversed Aβ deposition in the brains of 6-month-old male 5×FAD mice. These results indicate that EET signaling, especially 14,15-EET, plays a key role in the pathophysiology of AD, and that targeting this pathway is a potential therapeutic strategy for the treatment of AD. There are limited treatment options for Alzheimer's disease (AD). encoding soluble epoxide hydrolase (sEH) is located at a locus that is linked to late-onset AD, but its contribution to the pathophysiology of AD is unclear. Here, we demonstrate that sEH inhibition or deletion alleviates pathology in familial Alzheimer's disease (5×FAD) mice. Inhibiting sEH or increasing 14,15-epoxyeicosatrienoic acid (EET) enhanced lysosomal biogenesis and amyloid-β (Aβ) clearance in cultured adult astrocytes. Moreover, the infusion of 14,15-EET into the hippocampus of 5×FAD mice not only prevented the aggregation of Aβ, but also reversed the deposition of Aβ. Thus, 14,15-EET plays a key role in the pathophysiology of AD and therapeutic strategies that target this pathway may be an effective treatment.
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http://dx.doi.org/10.1523/JNEUROSCI.1246-20.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574654PMC
October 2020

Effects of Holothurian Glycosaminoglycan on the Sensitivity of Lung Cancer to Chemotherapy.

Integr Cancer Ther 2020 Jan-Dec;19:1534735420911430

Department of Respiratory & Critical Care Medicine, Affiliated Hospital of Qingdao University, Qingdao, Shandong, China.

Sea cucumber is a kind of food. Holothurian glycosaminoglycan (hGAG) is extracted from the body wall of the sea cucumber. Administration of hGAG and cisplatin (DDP) together to treat lung cancer was investigated. Lung adenocarcinoma A549 cells were cultured and divided into 4 groups: control group, hGAG 100 µg/mL group, DDP 3 µg/mL group, and hGAG 100 µg/mL + DDP 3 µg/mL group. Cell inhibition and apoptosis was evaluated by CCK8 and Hoechst33258 staining. Cell cycle was tested by Annexin V-FITC/PI (propidium iodide) double-staining and flow cytometry. The expression of mRNA and protein of Bcl-2, Bax, caspase-3, and survivin were detected by reverse transcriptase-polymerase chain reaction and Western blot, respectively. The results showed that hGAG combined with DDP enhanced the inhibitory effect of DDP on A549 lung cells through apoptosis pathway. The mechanism of apoptosis may be related to the reduction of Bcl-2 and survivin, as well as the ascension of Bax and caspase-3. hGAG could promote A549 cell cycle arrest in G1 and G2 phase and improve the DDP chemotherapy effects on A549 cells.
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http://dx.doi.org/10.1177/1534735420911430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7092648PMC
March 2021

Baicalein attenuates impairment of hepatic lysosomal acidification induced by high fat diet via maintaining V-ATPase assembly.

Food Chem Toxicol 2020 Feb 20;136:110990. Epub 2019 Nov 20.

Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China; Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China; Ministry of Education Key Laboratory of Environment, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.

Baicalein has been proved as a promising compound for non-alcoholic fatty liver disease (NAFLD); however, the molecular mechanisms underlying the progression of NAFLD and its intervention by baicalein remain largely obscure. Male C57BL/6J fed high-fat diet (HFD) and HepG2 cells stimulated with free fatty acid were treated with baicalein and various pharmacological reagents to explore the effect of signaling pathways involved in lysosomal acidification. Baicalein intake declined ALT and AST activities by 25.1% and 18.7%, respectively, compared with the HFD group. Moreover, baicalein markedly ameliorated the HFD-trigged lysosomal membrane permeabilization evidenced by declined cathepsin B release. Subsequent disorders, including cathepsin D maturation and mitochondrion membrane potential were also partially normalized by baicalein administration to HFD-fed mice. Meanwhile, an increase in V-ATPase V1 subunits expression in lysosomes, V-ATPase activity and the colocalization of cytosol V-ATPase V1 subunits and lysosomes was observed in baicalein-supplement mice. Bafilomycin A1 stimulation resulting in elevated lysosomal pH and triacylglycerol accumulation partially abolished the effect of baicalein. Furthermore, incubation with mTOR inhibitor rapamycin restored lysosomal pH and decreased cellular triacylglycerol content. Collectively, these findings demonstrate that hepatic lysosomal acidification is the main target of baicalein against NAFLD via maintaining lysosomal V-ATPase assembly through mTOR pathway.
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http://dx.doi.org/10.1016/j.fct.2019.110990DOI Listing
February 2020

The study of effect and mechanism of 630-nm laser on human lung adenocarcinoma cell xenograft model in nude mice mediated by hematoporphyrin derivatives.

Lasers Med Sci 2020 Jul 23;35(5):1085-1094. Epub 2019 Oct 23.

Department of International Medicine, Qingdao Municipal Hospital, Qingdao, 266071, China.

To investigate the effect and mechanism of 630-nm laser on human lung adenocarcinoma cell xenograft model in nude mice mediated by hematoporphyrin derivatives (HPD) and provide theoretical basis for clinical photodynamic therapy (PDT). Human lung adenocarcinoma cell xenograft model in nude mice was established and randomly divided into four groups: control group, pure photosensitizer group, pure irradiation group, and photodynamic treatment group. The tumor volume growth was compared, and the tumor growth inhibition rate was calculated. HE staining was used for routine pathological observation of tumor sections, and gross conditions of cells, interstitium, and blood vessels in several groups of tumor tissues were observed. TUNEL staining was used to observe and compare the apoptosis induced by photodynamic therapy. Real-time fluorescence quantitative reverse transcription polymerase chain reaction (RT-PCR) was used to detect the expression level of angiogenesis-related factors VEGF, HIF-1α and apoptosis-related factors Bax and Bcl-2 mRNA in the transplanted tumor tissues. Western blot was employed to detect the expression of angiogenesis-related proteins VEGF, HIF-1α and apoptosis-related proteins Bax, Caspase-3, and Bcl-2. Compared with the other three groups, the tumor growth inhibition rate of the photodynamic treatment group was significantly increased and the difference was statistically significant (P < 0.05). HE staining showed that the animal model of lung adenocarcinoma A549 was successfully established. TUNEL staining revealed that more apoptotic cells were found in the photodynamic treatment group, and the apoptosis index was calculated. Compared with the other three groups, the difference was statistically significant (P < 0.05). RT-PCR results showed that compared with the other three groups, the mRNA expressions of VEGF, HIF-1α, and Bcl-2 in the photodynamic treatment group decreased, while the expression of Bax mRNA increased(P < 0.05), and the differences were statistically significant. Western blot results showed that protein expressions of VEGF, HIF-1α, and Bcl-2 decreased in the photodynamic treatment group, while protein expression level of Bax and Caspase-3 increased (P < 0.05), indicating statistically significant differences. The 630-nm laser mediated by hematoporphyrin derivatives can significantly inhibit the growth of human lung adenocarcinoma xenograft tumor in nude mice, the mechanism of which is related to the inhibition of tumor angiogenesis by down-regulating VEGF and HIF-1α gene expression, and the promotion of tumor apoptosis by up-regulating Bax, Caspase-3, and down-regulating Bcl-2 gene expression.
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http://dx.doi.org/10.1007/s10103-019-02892-4DOI Listing
July 2020

The impact of maternal prepregnancy impaired fasting glucose on preterm birth and large for gestational age: a large population-based cohort study.

Am J Obstet Gynecol 2020 03 28;222(3):265.e1-265.e19. Epub 2019 Sep 28.

Guangdong Institute of Family Planning Science and Technology; Family Planning Special Hospital of Guangdong; National Health Committee of China (NHCC), Key Laboratory of Male Reproduction and Genetics. Electronic address:

Background: The impact of maternal prepregnancy impaired fasting glucose on preterm birth and large for gestational age has been poorly understood.

Objectives: We aimed to estimate the impact of prepregnancy impaired fasting glucose defined by the World Health Organization cut point on the risk of preterm birth and large for gestational age and to investigate whether the World Health Organization cut point of impaired fasting glucose was appropriate for identifying women at risk of preterm birth and large for gestational age among the Chinese population.

Study Design: This was a retrospective cohort study of women from the National Free Preconception Health Examination Project with singleton birth from 121 counties/districts in 21 cities of Guangdong Province, China, from Jan. 1, 2013, to Dec. 31, 2017. Women were included if their prepregnancy fasting glucose was less than 7.0 mmol/L. The primary outcomes were preterm birth (gestational age <37 weeks), early preterm birth (gestational age <34 weeks), large for gestational age (birthweight by gestational age >90th percentile based on the international standards in the International Fetal and Newborn Growth Consortium for the 21st Century study), and severe large for gestational age (birthweight by gestational age >97th percentile). We calculated the adjusted risk ratio for impaired fasting glucose and a 1 standard deviation increase in fasting glucose.

Results: We included 640,469 women. Of these, 31,006 (4.84%) met the World Health Organization cut point for impaired fasting glucose, 32,640 (5.10%) had preterm birth and 7201 (1.12%) had early preterm birth, 45,532 (7.11%) had large for gestational age birth, and 16,231 (2.53%) had severe large for gestational age birth. Compared with women with normoglycaemia, women with prepregnancy impaired fasting glucose had a 7.0% higher risk of preterm birth (adjusted risk ratio, 1.07, 95% confidence interval, 1.02-1.12), 10.0% had a higher risk of large for gestational age (adjusted risk ratio, 1.10, 95% confidence interval, 1.06-1.14), and 17.0% had a higher risk of severe large for gestational age (adjusted risk ratio, 1.17, 95% confidence interval, 1.10-1.26). No significant association of prepregnancy impaired fasting glucose with early preterm birth was found. The association of prepregnancy impaired fasting glucose with preterm birth and large for gestational age were similar in subgroups of women with various baseline characteristics. Adjusted risk ratio for preterm birth per standard deviation fasting glucose (0.7 mmol/L) was 0.99 (95% confidence interval, 0.98-1.00), for early preterm birth an adjusted risk ratio of 0.99 (confidence interval, 0.97-1.02), for large for gestational age an adjusted risk ratio of 1.04 (confidence interval, 1.03-1.05), and for severe large for gestational age an adjusted risk ratio of 1.03 (confidence interval, 1.01-1.04).

Conclusion: Our data suggest that maternal prepregnancy impaired fasting glucose increases the risk of preterm birth, large for gestational age, and severe large for gestational age. Data also suggest that the World Health Organization cut point of impaired fasting glucose is too restrictive, and lower levels of fasting glucose also increase the risk of large for gestational age and severe for severe gestational age in the Chinese population. Further investigation is warranted to determine whether and how counseling and interventions for women with prepregnancy impaired fasting glucose could reduce the risk of preterm birth and large for gestational age.
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http://dx.doi.org/10.1016/j.ajog.2019.09.037DOI Listing
March 2020

Migrant population is more vulnerable to the effect of air pollution on preterm birth: Results from a birth cohort study in seven Chinese cities.

Int J Hyg Environ Health 2019 08 16;222(7):1047-1053. Epub 2019 Jul 16.

Epidemiological Research Office of Key Laboratory of Male Reproduction and Genetics, Family Planning Research Institute of Guangdong Province, Guangzhou, China; Epidemiological Research Office of Key Laboratory of Male Reproduction and Genetics (National Health and Family Planning Commission), Family Planning Special Hospital of Guangdong Province, Guangzhou, China. Electronic address:

Background: Studies have reported that exposure to air pollution during pregnancy was associated with preterm birth (PTB). However, it remains unknown whether this association differs between local residents and migrants.

Objective: This study aimed to differentiate the associations between maternal air pollution exposure and PTB between local residents and migrants.

Methods: We established a retrospective birth cohort in seven Chinese cities in Pearl River Delta (PRD) region during 2015-2017. The mothers were included in the cohort at their first time of hospital visit for pregnancy, and the endpoint events were identified using the birth registry. The air pollution exposure was estimated based on the daily air pollution concentrations in the nearby air monitoring stations during different pregnancy periods. Cox proportional hazards models were utilized to estimate the associations between each air pollutant and PTB for different pregnancy periods.

Results: Our cohort included a total of 628,439 mother-and-live-birth pairs. Among them, 308,201 women were local residents, and 320,238 were migrants. We observed stronger effects of air pollutants among the migrants than the local residents. For the exposure during the entire pregnancy, the hazard ratio (HR) among the migrants and local residents were 1.56 (95% CI: 1.50, 1.63) and 0.98 (95% CI: 0.93, 1.02) for each 10 μg/m increase in PM, 1.32 (95% CI: 1.27, 1.39) and 1.18 (95% CI: 1.12, 1.23) for each 10 ppb increase in O, and 1.48 (95% CI: 1.40, 1.57) and 0.99 (95% CI: 0.93, 1.05) for each 10 μg/m increase in SO, respectively. Similarly higher effects were observed among the migrants for the exposures in different trimesters of pregnancy. However, the effects of NO were comparable between the two groups.

Conclusion: Our study suggests that maternal PM, O and SO exposures might be important risk factors of preterm birth, particularly among the migrants. More specific protective and education measures should be considered for the migrant pregnant women.
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http://dx.doi.org/10.1016/j.ijheh.2019.07.004DOI Listing
August 2019

ABAD/17β-HSD10 reduction contributes to the protective mechanism of huperzine a on the cerebral mitochondrial function in APP/PS1 mice.

Neurobiol Aging 2019 09 28;81:77-87. Epub 2019 May 28.

Department of Pharmacy, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China. Electronic address:

Huperzine A (HupA) is a kind of Lycopodium alkaloid with potential disease-modifying qualities that has been reported to protect against β-amyloid (Aβ)-mediated mitochondrial damage in Alzheimer's disease. However, the fundamental molecular mechanism underlying the protective action of HupA against Aβ-mediated mitochondrial malfunction is not completely understood. Recently, the mitochondrial enzyme amyloid-binding alcohol dehydrogenase (ABAD) protein has been reported to facilitate Aβ-induced mitochondrial damage, resulting in mitochondrial malfunction and cell death. Our study found that HupA, but not the acetylcholinesterase inhibitor tacrine, reduced the deposition of Aβ and the ABAD level, and further reduced Aβ-ABAD complexes, thereby improving cerebral mitochondrial function in APP/PS1 mice. This was accompanied by attenuated reactive oxygen species overload, as well as increases adenosine triphosphate levels. Moreover, HupA decreased the release of cytochrome-c from mitochondria and the level of cleaved caspase-3, thereby increasing dissociated brain cell viability in APP/PS1 mice. Thus, our study demonstrated that a reduction in ABAD was involved in the protective mechanism of HupA on the cerebral mitochondrial function in APP/PS1 mice.
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http://dx.doi.org/10.1016/j.neurobiolaging.2019.05.016DOI Listing
September 2019

The study of killing effect and inducing apoptosis of 630-nm laser on lung adenocarcinoma A549 cells mediated by hematoporphyrin derivatives in vitro.

Lasers Med Sci 2020 Feb 2;35(1):71-78. Epub 2019 May 2.

Department of Respiration, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China.

To investigate the killing effect and inducing apoptosis of 630-nm laser mediated by hematoporphyrin derivatives (HPD) on human lung adenocarcinoma A549 cells. The human lung adenocarcinoma A549 cells were incubated at random with different concentrations of HPD (5, 10, 12, 15, 20 μg/ml) for 4 h and then illuminated by 630-nm laser with different energy densities (25, 50, 75, 100 mW/cm). And, meanwhile, the simple photosensitizer group, laser irradiation group, and blank control group were established. Then, CCK8, Hoechst 33258 staining, RT-PCR, and Western blot were employed. HPD-PDT proved no killing effect on the lung adenocarcinoma A549 cells with photosensitizer or laser irradiation alone. With the combination, the killing effect was obvious. CCK8 showed that the A549 cell viability in 15 μg/ml and 20 μg/ml HPD group as well as 50 mW/cm, 75 mW/cm, and 100 mW/cm power density group decreased significantly compared with the control group. Hoechst 33258 staining showed that with the increase of HPD concentration, the cells presented chromatin fixation and hyperchromatic nuclei. The Annexin V-FITC/PI double staining was used to detect the apoptosis rate, and the difference was statistically significant. RT-PCR and Western blot showed that the expression of Caspase-3 and Bax were significantly up-regulated. However, the Bcl-2 and Survivin were significantly down-regulated in the HPD-PDT group, while those of the other three groups showed no significant changes. HPD-PDT has a significant effect on A549 cells. The mechanism of action may be related to the upregulation of the expression of Caspase-3, Bax, and downregulation of the expression of Bcl-2 and Survivin.
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http://dx.doi.org/10.1007/s10103-019-02794-5DOI Listing
February 2020

Astrocytic Epoxyeicosatrienoic Acid Signaling in the Medial Prefrontal Cortex Modulates Depressive-like Behaviors.

J Neurosci 2019 06 22;39(23):4606-4623. Epub 2019 Mar 22.

Institute of Mental Health, Southern Medical University, Guangzhou 510515, China,

Major depressive disorder is the most common mental illness. Mounting evidence indicates that astrocytes play a crucial role in the pathophysiology of depression; however, the underlying molecular mechanisms remain elusive. Compared with other neuronal cell types, astrocytes are enriched for arachidonic acid metabolism. Herein, we observed brain-region-specific alterations of epoxyeicosatrienoic acid (EET) signaling, which is an arachidonic acid metabolic pathway, in both a mouse model of depression and postmortem samples from patients with depression. The enzymatic activity of soluble epoxide hydrolase (sEH), the key enzyme in EET signaling, was selectively increased in the mPFC of susceptible mice after chronic social defeated stress and was negatively correlated with the social interaction ratio, which is an indicator of depressive-like behavior. The specific deletion of (encode sEH) in adult astrocytes induced resilience to stress, whereas the impaired EET signaling in the mPFC evoked depressive-like behaviors in response to stress. sEH was mainly expressed on lysosomes of astrocytes. Using pharmacological and genetic approaches performed on C57BL/6J background adult male mice, we found that EET signaling modulated astrocytic ATP release and Moreover, astrocytic ATP release was required for the antidepressant-like effect of deletion in adult astrocytes. In addition, sEH inhibitors produced rapid antidepressant-like effects in multiple animal models of depression, including chronic social defeated stress and chronic mild stress. Together, our results highlight that EET signaling in astrocytes in the mPFC is essential for behavioral adaptation in response to psychiatric stress. Astrocytes, the most abundant glial cells of the brain, play a vital role in the pathophysiology of depression. Astrocytes secrete adenosine ATP, which modulates depressive-like behaviors. Notably, astrocytes are enriched for arachidonic acid metabolism. In the present study, we explored the hypothesis that epoxyeicosatrienoic acid signaling, an arachidonic acid metabolic pathway, modulates astrocytic ATP release and the expression of depressive-like behaviors. Our work demonstrated that epoxyeicosatrienoic acid signaling in astrocytes in the mPFC is essential for behavioral homeostatic adaptation in response to stress, and the extent of astrocyte functioning is greater than expected based on earlier reports.
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http://dx.doi.org/10.1523/JNEUROSCI.3069-18.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6554635PMC
June 2019

Removal of hERG potassium channel affinity through introduction of an oxygen atom: Molecular insights from structure-activity relationships of strychnine and its analogs.

Toxicol Appl Pharmacol 2018 12 30;360:109-119. Epub 2018 Sep 30.

Key Laboratory of Mental Health of the Ministry of Education, Key Laboratory of Psychiatric Disorders of Guangdong Province, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China. Electronic address:

Nux vomica has been effectively used in Traditional Chinese Medicine. The processing of Nux vomica is necessary to reduce toxicity before it can be used in clinical practice. However, the mechanism for processing detoxification is unclear. hERG channels have been subjected to a routine test for compound cardiac toxicity in the drug development process. Therefore, we examined the effects and mechanisms of strychnine and brucine, two main ingredients of Nux vomica, and their N-oxides on hERG channels. Strychnine and brucine exhibited concentration-dependent inhibition of hERG channels with IC values of 25.9 μM and 44.18 μM, respectively. However, their nitrogen oxidative derivatives produced by processing of Nux vomica, strychnine N-oxide and brucine N-oxide, lost their activity on hERG channels. Compared to their parent compounds, only an oxygen atom was introduced in the nitrogen oxidative isoforms to compensate for the N - charge, suggesting that the protonated nitrogen is the key group for strychnine and brucine binding to hERG channel. Alanine-mutagenesis identified Y652 is the most important residue for strychnine and brucine binding to hERG channel. Y652A mutation increased the IC for strychnine and brucine by 21.64-fold and 29.78-fold that of WT I, respectively. Docking simulations suggested that the protonated nitrogen of strychnine and brucine formed a cation-π interaction with the aromatic ring of Y652. This study suggests that introduction of an oxygen to compensate for the N - charge could be a useful strategy for reducing hERG potency and increasing the safety margin of alkaloid-type compounds in drug development.
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http://dx.doi.org/10.1016/j.taap.2018.09.042DOI Listing
December 2018

Bidirectional association between nonalcoholic fatty liver disease and hypertension from the Dongfeng-Tongji cohort study.

J Am Soc Hypertens 2018 09 3;12(9):660-670. Epub 2018 Jul 3.

Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety and the Ministry of Education (MOE) Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. Electronic address:

The relation between nonalcoholic fatty liver disease (NAFLD) and hypertension is not fully understood. To examine the effect of the change in NAFLD status on the risk of incident hypertension, and vice versa, 6704 eligible hypertension-free subjects and 9328 NAFLD-free subjects from the Dongfeng-Tongji cohort study at baseline were enrolled in the study. Among the hypertension-free subjects, development and persistence of NAFLD were associated with an increased odds ratio (OR) for incident hypertension (OR: 1.49, 95% confidence interval [CI]: 1.26-1.76, P < .0001; OR: 1.50, 95% CI: 1.27-1.78, P < .0001). However, the resolution of NAFLD was not a risk factor for incident hypertension. Among the NAFLD-free subjects, the risk of new-emerging NAFLD was robust for hypertension status both in no-yes (OR: 1.45, CI: 1.23-1.71) and yes-yes (OR: 1.61, CI: 1.35-1.92). Moreover, stratified analysis by diabetes and overweight/obese for the risk of incident NAFLD showed that incident hypertension (no-yes) and persistent hypertension (yes-yes) were associated with risk of incident NAFLD in subjects without diabetes or overweight/obesity. In the overweight/obese participants, persistent hypertension (yes-yes) was a risk factor for incident NAFLD (OR: 1.29, 95% CI: 1.01-1.64, P = .0387). Conclusively, incidence and persistence of NAFLD are associated with increased risk of hypertension, and vice versa.
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http://dx.doi.org/10.1016/j.jash.2018.06.013DOI Listing
September 2018

Frataxin-Mediated PINK1-Parkin-Dependent Mitophagy in Hepatic Steatosis: The Protective Effects of Quercetin.

Mol Nutr Food Res 2018 08 26;62(16):e1800164. Epub 2018 Jul 26.

Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety and the Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Rd, Wuhan, 430030, Hubei, China.

Scope: Naturally occurring quercetin has been found to induce mitophagy and prevent nonalcoholic fatty liver disease (NAFLD). However, it still remains elusive whether frataxin upregulation by quercetin contributes to the beneficial effect through mitophagy or not.

Methods And Results: Adult male C57BL/J mice were fed a high-fat diet (HFD, 60% of energy from fat) with quercetin (100 mg kg body weight) or not for 10 weeks. Quercetin alleviated HFD-induced histopathological changes, disorders of lipid metabolism, and mitochondrial damage. Moreover, quercetin blocked mitophagy suppression by HFD based on the increased LC3II, PTEN-induced putative kinase 1 (PINK1) and Beclin1 expressions, as well as decreased p62 levels. Quercetin also improved the Parkin translocation to mitochondria confirmed by immunofluorescence. Specifically, frataxin was lowered in the liver of HFD-fed mice or HepG2 cell incubated with oleate/palmitate but restored by quercetin, and quercetin's regulation of frataxin may depend on p53. Furthermore, lentivirus-mediated stable knockdown of frataxin in HepG2 inhibited PINK1-Parkin-associated mitophagy and resulted in lipid accumulation. Frataxin was further decreased by free fatty acids in knockdown cells concomitantly with depressed PINK1-Parkin-associated mitophagy, which was partially normalized by quercetin.

Conclusion: Quercetin alleviated hepatic steatosis by enhancing frataxin-mediated PINK1/Parkin-dependent mitophagy, highlighting a promising preventive strategy and mechanism for NAFLD by quercetin.
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http://dx.doi.org/10.1002/mnfr.201800164DOI Listing
August 2018

CBX2 Inhibits Neurite Development by Regulating Neuron-Specific Genes Expression.

Front Mol Neurosci 2018 28;11:46. Epub 2018 Feb 28.

Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Guangzhou, China.

Polycomb group (PcG) proteins regulate the epigenetic status of transcription regulatory states during development. Progression from pluripotency to differentiation requires the sequential activation and repression of different PcG target genes, however, the relationship between early patterning signals, PcG expression, and the development of the central nervous system is still unclear. Using various models of neuronal differentiation, we provide evidence that CBX2 is a negative regulator of neuronal differentiation. Knock-down of CBX2 expression promotes neurite development, while overexpression of CBX2 inhibits neurite development. Further, we found that CBX2 is a direct target gene of miR-124. During neuronal differentiation, CBX2 was decreased while miR-124 was increased. Mechanistically, CBX2 directly interacts with the promoter region of several neuro-associated genes and regulates their expression. We found that the neuron-specific GAP-43 gene could contribute to the stimulating effect on neurite development associated with inhibition of CBX2.
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http://dx.doi.org/10.3389/fnmol.2018.00046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5835719PMC
February 2018

Quercetin ameliorates HFD-induced NAFLD by promoting hepatic VLDL assembly and lipophagy via the IRE1a/XBP1s pathway.

Food Chem Toxicol 2018 Apr 10;114:52-60. Epub 2018 Feb 10.

Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China; Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China; Ministry of Education Key Laboratory of Environment, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. Electronic address:

The consumption of a quercetin-rich diet has been well-established as a feasible method against non-alcoholic fatty liver disease (NAFLD); however, the molecular mechanisms underlying the progression of NAFLD and its intervention by quercetin remain largely obscure. Male Sprague-Dawley rats fed high-fat diet (HFD), and HepG2 cells stimulated with free fatty acid, were treated with quercetin and various pharmacological reagents to explore the effect of signaling pathways involved in endoplasmic reticulum stress on very low-density lipoprotein (VLDL) assembly and lipophagy. Quercetin intake decreased hepatic TG content by 39%, with a 1.5-fold increase in VLDL, and up-regulated spliced X-box binding protein 1 (XBP1s) expression compared with the HFD group. Thapsigargin or STF-083010 (an IRE1α endonuclease inhibitor) decreased VLDL content in a dose-dependent manner, partially counteracting the protective effects of quercetin, 4-PBA or APY-29 (an IRE1α endonuclease activator). Additionally, microsomal TG-transfer protein complex expression was increased with quercetin-treated and down-regulated by STF-083010. Moreover, quercetin increased co-localization of lysosomes with lipid droplets (LDs) accompanied by decreased p62 accumulation. STF-083010 partially abolished the effect of quercetin on LDs autophagy in an mTOR-independent manner. Collectively, these findings demonstrate that hepatic VLDL assembly and lipophagy are the main targets of quercetin against NAFLD via the IRE1a/XBP1s pathway.
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http://dx.doi.org/10.1016/j.fct.2018.02.019DOI Listing
April 2018

miR-124 and miR-9 mediated downregulation of HDAC5 promotes neurite development through activating MEF2C-GPM6A pathway.

J Cell Physiol 2018 Jan 19;233(1):673-687. Epub 2017 May 19.

Department of Neurobiology, Southern Medical University, Guangzhou, Guangdong Province, China.

The class IIa histone deacetylases (HDACs) play important roles in the central nervous system during diverse biological processes such as synaptic plasticity, axon regeneration, cell apoptosis, and neural differentiation. Although it is known that HDAC5 regulates neuronal differentiation, neither the physiological function nor the regulation of HDAC5 in neuronal differentiation is clear. Here, we identify HDAC5 as an inhibitor of neurite elongation and show that HDAC5 is regulated by the brain enriched microRNA miR-124 and miR-9. We discover that HDAC5 inhibits neurite extension both in differentiated P19 cells and primary neurons. We also show that the neuronal membrane glycoprotein GPM6A (M6a) is a direct target gene of HDAC5 regulated transcriptional factor MEF2C. HDAC5 inhibits neurite elongation, acting at least partially via a MEF2C/M6a signaling pathway. We also confirmed the miR-124/miR-9 regulated HDAC5-MEF2C-M6a pathway regulates neurite development in primary neurons. Thus, HDAC5 emerges as a cellular conductor of MEF2C and M6a activity and is regulated by miR-124 and miR-9 to control neurite development.
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http://dx.doi.org/10.1002/jcp.25927DOI Listing
January 2018

MicroRNA124 Regulated Neurite Elongation by Targeting OSBP.

Mol Neurobiol 2016 11 18;53(9):6388-6396. Epub 2015 Nov 18.

Key Laboratory of Psychiatric Disorders of Guangdong Province, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, People's Republic of China.

MicroRNA-124 (miR-124), a brain-specific miRNA molecule, has been implicated in stimulating neurite outgrowth and elongation during neuronal differentiation. However, the direct target genes and the mechanisms of miR-124-induced neurite outgrowth are poorly understood. In this study, we demonstrated that miR-124 directly targeted and downregulated the endogenous expression of oxysterol-binding protein (OSBP). A previous study found that the expression of miR-124 increased during brain development. In the present study, we demonstrated that the expression of OSBP decreased during the development of the C57BL/6 mouse cortex, which was negatively correlated with miR-124 expression. OSBP knockdown using specific shRNAs promoted neurite outgrowth and elongation in both Neuro-2a cells and primary cultured mouse cortical neurons. Conversely, OSBP overexpression strongly repressed the neurite elongation-enhancing effect of miR-124 in Neuro-2a cells. Our results suggested that OSBP may be a target and downstream effector of miR-124 for regulating neurite outgrowth and elongation.
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http://dx.doi.org/10.1007/s12035-015-9540-4DOI Listing
November 2016

Soluble Epoxide Hydrolase Deficiency or Inhibition Attenuates MPTP-Induced Parkinsonism.

Mol Neurobiol 2015 Aug 17;52(1):187-95. Epub 2014 Aug 17.

Department of Neurobiology, Southern Medical University, Guangzhou, Guangdong Province, China.

Soluble epoxide hydrolase (sEH) inhibition has been demonstrated to have beneficial effects on various diseases, such as hypertension, diabetes, and brain ischemia. However, whether sEH inhibition has therapeutic potential in Parkinson's disease is still unknown. In this paper, we found that sEH expression is increased in 1-methyl-4-phenyl-1,2,3,6-tetrahydro pyridine (MPTP)-treated mice, and sEH deficiency and inhibition significantly attenuated tyrosine hydroxylase (TH)-positive cell loss and improved rotarod performance. The substrate of sEH, 14,15-epoxyeicosatrienoic acid (14,15-EET), protected TH-positive cells and alleviated the rotarod performance deficits of wild-type mice but not sEH-knockout mice. Moreover, the 14,15-EET antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE) abolished the neuronal protective effects of sEH deficiency. In primary cultured cortical neurons, MPP(+) induced significant Akt inactivation in neurons from sEH wild-type mice, and this effect was not observed in neurons from knockout mice. Our data indicate that sEH deficiency and inhibition increased 14,15-EET in MPTP-treated mice, which activated the Akt-mediated protection of TH-positive neurons and behavioral functioning. We also found that sEH deficiency attenuated TH-positive cell loss in a paraquat-induced mouse model of Parkinson's. Our data suggest that sEH inhibition might be a powerful tool to protect dopaminergic neurons in Parkinson's disease.
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http://dx.doi.org/10.1007/s12035-014-8833-3DOI Listing
August 2015

High expression of NEDD9 predicts adverse outcomes of colorectal cancer patients.

Int J Clin Exp Pathol 2014 15;7(5):2565-70. Epub 2014 Apr 15.

Department of General Surgery, Qingdao Municipal Hospital, Qingdao University Medical College Qingdao, China.

NEDD9, a member of Crk-associated substrate (CAS) family, is highly expressed in multiple cancer types and involved cancer cell adhesion, migration, invasion. The prognostic value of NEDD9 has not been evaluated before. The aim of this study was to evaluate the association between NEDD9 expression and survival in colorectal cancer (CRC) patients. NEDD9 expression was analyzed by immunohistochemistry in 92 patients with CRC. Patients were followed-up annually by telephone or at outpatient clinic. The results revealed that high expression of NEDD9 in 68/92 CRC samples, compared with 12/92 normal tissues (P<0.01). Correlation analysis showed high level of expression of NEDD9 was significantly correlated with advanced TNM stage (P=0.014), pT grade (P=0.009), pN (P=0.013) and pM status (P=0.047). Patients with a higher NEDD9 expression had a significantly shorter overall survival (OS) (P<0.01). The multivariate analysis revealed that NEDD9 expression could serve as an independent predictive factor of OS. Our finding demonstrated the potential value of NEDD9 expression level as a prognostic molecular marker and a target for new therapies for CRC patients.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4069898PMC
February 2015

Deletion of soluble epoxide hydrolase attenuates cardiac hypertrophy via down-regulation of cardiac fibroblasts-derived fibroblast growth factor-2.

Crit Care Med 2014 May;42(5):e345-54

1Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, China. 2Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou, China. 3Department of Cardiology, Shenzhen Futian Hospital of Guangdong Medical College, Shenzhen, China. 4Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China. 5Department of Physiology, Georgia Regents University, Augusta, GA. 6Weil Institute of Critical Care Medicine, Rancho Mirage, CA.

Objective: Inhibition of soluble epoxide hydrolase (Ephx2) has been shown to play a protective role in cardiac hypertrophy, but the mechanism is not fully understood. We tested the hypothesis that deletion of soluble epoxide hydrolase attenuates cardiac hypertrophy via down-regulation of cardiac fibroblasts-derived fibroblast growth factor-2.

Design: Prospective, controlled, and randomized animal study.

Setting: University laboratory.

Subjects: Male wild-type C57BL/6 mice and Ephx2 (-/-) mice.

Interventions: Male wild-type or Ephx2 (-/-) mice were subjected to transverse aorta constriction surgery.

Measurements And Main Results: Four weeks after transverse aorta constriction, Ephx2 (-/-) mice did not develop significant cardiac hypertrophy as that of wild-type mice, indicated by no changes in the ratio of heart weight/body weight and ventricular wall thickness after transverse aorta constriction. Cardiac fibroblast growth factor-2 increased in wild-type-transverse aorta constriction group but this did not change in Ephx2 (-/-)-transverse aorta constriction group, and the serum level of fibroblast growth factor-2 did not change in both groups. In vitro, cardiac fibroblasts were stimulated by angiotensin II to analyze the expression of fibroblast growth factor-2. The effect of increased fibroblast growth factor-2 from cardiac fibroblasts induced by angiotensin II was attenuated by soluble epoxide hydrolase deletion. ERK1/2, p38, and AKT kinase were involved in fibroblast growth factor-2 expression regulated by angiotensin II, and soluble epoxide hydrolase deletion lowered the phosphorylation of ERK1/2 not p38 or AKT to mediate fibroblast growth factor-2 expression. In addition, soluble epoxide hydrolase deletion did not attenuate cardiomyocytes hypertrophy induced by exogenous fibroblast growth factor-2.

Conclusions: Our present data demonstrated that deletion of soluble epoxide hydrolase prevented cardiac hypertrophy not only directly to cardiomyocytes but also to cardiac fibroblasts by reducing expression of fibroblast growth factor-2.
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http://dx.doi.org/10.1097/CCM.0000000000000226DOI Listing
May 2014

Preparation of 5'-O-(1-Thiotriphosphate)-modified oligonucleotides using polymerase-endonuclease amplification reaction (PEAR).

PLoS One 2013 4;8(7):e67558. Epub 2013 Jul 4.

Department of Biotechnology, Ocean University of China, Qingdao, Shandong, People's Republic of China.

Antisense oligonucleotides (ASODNs) have been widely used as an important tool for regulating gene expression, and developed into therapeutics. Natural ODNs are susceptible to nuclease degradation, nucleic acid analogues, however, have less side effects, stronger stability and more potent activities. Large-scale de novo synthesis of a certain oligonucleotide has been very difficult and costly. In a previous preliminary study, we developed the polymerase-endonuclease amplification reaction (PEAR) for amplification and large-scale preparation of natural antisense ODNs. Here we extended the method in preparation of a widely used modified oligonucleotide with 5'-O-(1-Thiotriphosphate) modifications. Using electrospray ionization liquid chromatography mass spectrometry (ESI/LC/MS) detection, the purity of the PEAR product was measured as high as 100.0%. Using PEAR a large amount of a specific oligonucleotide can be produced starting from a small amount of synthetic seeds. It is suggested that PEAR can be a useful tool for large-scale production of modified oligonucleotides.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0067558PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3701678PMC
February 2014