Publications by authors named "Lijie Jiang"

44 Publications

A Giant Ruptured Noncoronary Sinus of Valsalva Aneurysm: A Case Report.

Heart Surg Forum 2021 02 19;24(1):E188-E190. Epub 2021 Feb 19.

Department of Cardiovascular Surgery at West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China.

The occurrence of a giant ruptured aneurysm originating from the noncoronary sinus of Valsalva in the right atrium is extremely rare. Herein, a case is presented of a giant ruptured noncoronary sinus of Valsalva aneurysm (SVA) that was protruding into the right atrium, which was almost completely occupied by an aneurysm. A 61-year-old female was referred to the hospital for exertional palpitation and dyspnea. While a surgical repair was performed by resection of the aneurysm and a sinus remodeling with a patch of fresh bovine pericardium, a very rare case was observed. It was a giant ruptured noncoronary sinus of aneurysm that completely occupied the right atrium, which was difficult to distinguish from the coronary aneurysm. It is also believed that various imaging examinations, such as cardiac computed tomography angiogram (CCTA) and transthoracic echocardiogram (TTE), were useful for the diagnosis.
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http://dx.doi.org/10.1532/hsf.3519DOI Listing
February 2021

[Reliability and validity of Healthy Fitness Measurement Scale (V1.0) for evaluating healthy fitness of college students in Guangzhou].

Nan Fang Yi Ke Da Xue Xue Bao 2021 Jan;41(1):47-54

Department of Economic Management, Nanfang Hospital, Guangzhou 510515, China.

Objective: To evaluate the reliability and validity of Healthy Fitness Measurement Scale V1.0 (HFMS V1.0) for assessing healthy fitness status of college students in Guangzhou.

Methods: A total of 584 college students were evaluated with HFMS V1.0. The reliability and validity of HFMS V1.0 scale were assessed for its discrimination degree, Cronbach α coefficient, split-half reliability, test-retest reliability, content validity, structural validity, calibration validity and responsiveness.

Results: The Cronbach α of HFMS V1.0 scale was 0.893, the split-half coefficient was 0.909, and the test-retest coefficient was 0.923. The correlation coefficients of each dimension with its subscales ranged from 0.687 to 0.931. The correlation coefficient between each item and its dimension ranged from 0.558 to 0.863( < 0.05). Exploratory factor analysis showed that the variance interpretation of 8 factors was 55.105%, and the factor structure was basically identical with the theoretical concept of the scale. Confirmatory factor analysis showed excellent goodness-of-fit indices of the model (/DF= 1.952; RMSEA=0.400; GFI=0.906; TLI=0.905; IFI=0.914; and CFI=0.913; < 0.05). The correlation coefficients between the 4 general items and their corresponding scales ranged from 0.585 to 0.670. The proportions of the highest and lowest scores of the scale were very low, suggesting a high responsiveness of the scale.

Conclusions: HFMS V1.0 has high reliability and validity for evaluating healthy fitness status of college students.
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http://dx.doi.org/10.12122/j.issn.1673-4254.2021.01.06DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867479PMC
January 2021

Telomerase expression marks transitional growth-associated skeletal progenitor/stem cells.

Stem Cells 2021 Mar 13;39(3):296-305. Epub 2021 Jan 13.

Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts, USA.

Skeletal progenitor/stem cells (SSCs) play a critical role in postnatal bone growth and maintenance. Telomerase (Tert) activity prevents cellular senescence and is required for maintenance of stem cells in self-renewing tissues. Here we investigated the role of mTert-expressing cells in postnatal mouse long bone and found that mTert expression is enriched at the time of adolescent bone growth. mTert-GFP cells were identified in regions known to house SSCs, including the metaphyseal stroma, growth plate, and the bone marrow. We also show that mTert-expressing cells are a distinct SSC population with enriched colony-forming capacity and contribute to multiple mesenchymal lineages, in vitro. In contrast, in vivo lineage-tracing studies identified mTert cells as osteochondral progenitors and contribute to the bone-forming cell pool during endochondral bone growth with a subset persisting into adulthood. Taken together, our results show that mTert expression is temporally regulated and marks SSCs during a discrete phase of transitional growth between rapid bone growth and maintenance.
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http://dx.doi.org/10.1002/stem.3318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986156PMC
March 2021

Association analysis of Suboptimal health Status: a cross-sectional study in China.

PeerJ 2020 11;8:e10508. Epub 2020 Dec 11.

Department of Sanitation Economy Administration, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China.

Background: Suboptimal health status (SHS) among urban residents is commonplace in China. However, factors influencing SHS have not been thoroughly explored, especially with regard to the effects of internal factors (e.g., personality and health awareness) on SHS.

Methods: A cross-sectional study was conducted with a nationally representative sample of 5460 Chinese urban residents..SHS was measured using the Suboptimal Health Mesurement Scale Version 1.0. Demographic information, and information pertaining to lifestyle behaviors, environmental factors, and internal factors were abtained through a questionnaire. The associations between demographic information, lifestyle behaviors, environmental factors, internal factors and SHS were assessed using logistic regression.

Results: Of the 5460 participants (with a mean age of 41.56 ±  16.14 years), 2640 (48.4 %) were men. Out of 36 variables, 23 were significantly associated with SHS: age (odds ratio [OR]: 1.014), an education level of high school/junior college (OR: 1.443) , marital status (OR: 1.899), area of registered permanent residence (OR: 0.767), monthly household income ( < 0.001) , exposure to second-hand smoke ( = 0.001), alcohol drinking (OR: 1.284), bad eating habits (OR: 1.717), not sleeping before 11 p.m. every day ( = 0.002), spending time online more than five hours a day (OR: 1.526), having a good relationship with parents during one's growth period (OR: 0.602), living with good quality air (OR:0.817), living in not crowded conditions (OR:0.636), having a harmonious neighborhood (OR:0.775), having adequate fitness facilities (OR:0.783), one's health being affected by two-child policy (OR: 1.468) and medical policies (OR: 1.265) , high adverse quotient (OR: 0.488), many (≥3 kinds) interests and hobbies (OR: 0.617), mature and steady personality traits (OR: 0.469) , a high attention to one's health (OR: 0.833), and effective health promotion induced by leading a leisurely lifestyle (OR: 0.466) were significantly associated with SHS.

Conclusions: All these variables were included demographic information, lifestyle behaviors, environmental factors and internal factors. Our study supports the benefits of controlling both internal and external factors in preventing suboptimal health.
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http://dx.doi.org/10.7717/peerj.10508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735074PMC
December 2020

Mediating effect of health consciousness in the relationship of lifestyle and suboptimal health status: a cross-sectional study involving Chinese urban residents.

BMJ Open 2020 10 26;10(10):e039701. Epub 2020 Oct 26.

Department of Sanitation Economy Administration, Nanfang Hospital, Southern Medical University, Guangzhou, China

Objective: Suboptimal health status (SHS), a third state between good health and disease, can easily develop into chronic diseases, and can be influenced by lifestyle and health consciousness. No study has surveyed the intermediation of health consciousness on the relationship between lifestyle and SHS. This study aimed to analyse the association of lifestyle and SHS, and intermediation of health consciousness in Chinese urban residents.

Design: A cross-sectional face-to-face survey using a four-stage stratified sampling method.

Participants: We investigated 5803 Chinese urban residents aged 18 years and over. We measured SHS using the Sub-Health Measurement Scale V1.0. We adopted a structural equation model to analyse relationships among lifestyle, health consciousness and SHS. We applied a bootstrapping method to estimate the mediation effect of health consciousness.

Results: Lifestyle had stronger indirect associations with physical ( -0.185, 95% CI -0.228 to -0.149), mental ( -0.224, 95% CI -0.265 to -0.186) and social SHS ( -0.216, 95% CI -0.257 to -0.179) via health consciousness than direct associations of physical ( -0.144, 95% CI -0.209 to -0.081), mental ( -0.146, 95% CI -0.201 to -0.094) and social SHS ( -0.130, 95% CI -0.181 to -0.077). Health consciousness has a strong direct association with physical ( 0.360, 95% CI 0.295 to 0.427), mental ( 0.452, 95% CI 0.392 to 0.510) and social SHS ( 0.434, 95% CI 0.376 to 0.490). Ratio of mediating effect of health consciousness to direct effect of lifestyle with physical, mental and social SHS was 1.28, 1.53 and 1.66, respectively.

Conclusions: Health consciousness was more important in preventing physical, mental and social SHS than lifestyle. Therefore, it might be useful in changing unhealthy lifestyle and reducing the influence of poor lifestyle on physical, mental and social SHS.
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http://dx.doi.org/10.1136/bmjopen-2020-039701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592276PMC
October 2020

A novel nomogram to predict the overall survival in esthesinoeroblastoma.

BMC Cancer 2020 Oct 14;20(1):993. Epub 2020 Oct 14.

The Otorhinolaryngology Hospital, First Affiliated Hospital of Sun Yat-sen University, No.58 Zhongshan Er Road, Guangzhou, Guangzhou, 510080, P.R. China.

Background: Increasing evidence indicates that the pathology and the modified Kadish system have some influence on the prognosis of esthesioneuroblastoma (ENB). However, an accurate system to combine pathology with a modified Kadish system has not been established.

Methods: This study aimed to set up and evaluate a model to predict overall survival (OS) accurately in ENB, including clinical characteristics, treatment and pathological variables. We screened the information of patients with ENB between January 1, 1976, and December 30, 2016 from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) program as a training cohort. The validation cohort consisted of patients with ENB at Sun Yat-sen University Cancer Center and The First Affiliated Hospital of Sun Yat-sen University in the same period, and 87 patients were included. The Pearson's chi-squared test was used to assess significance of clinicopathological and demographic characteristics. We used the Cox proportional hazards model to examine univariate and multivariate analyses. The model coefficients were used to calculate the Hazard ratios (HR) with 95% confidence intervals (CI). Prognostic factors with a p-value < 0.05 in multivariate analysis were included in the nomogram. The concordance index (c-index) and calibration curve were used to evaluate the predictive power of the nomogram.

Results: The c-index of training cohort and validation cohort are 0.737 (95% CI, 0.709 to 0.765) and 0.791 (95% CI, 0.767 to 0.815) respectively. The calibration curves revealed a good agreement between the nomogram prediction and actual observation regarding the probability of 3-year and 5-year survival. We used a nomogram to calculate the 3-year and 5-year growth probability and stratified patients into three risk groups.

Conclusions: The nomogram provided the risk group information and identified mortality risk and can serve as a reference for designing a reasonable follow-up plan.
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http://dx.doi.org/10.1186/s12885-020-07435-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556920PMC
October 2020

Effect of short-course glucocorticoid application on patients with chronic rhinosinusitis with nasal polyps.

World Allergy Organ J 2020 Jun 11;13(6):100131. Epub 2020 Jun 11.

Department of Otorhinolaryngology, The First Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University. Guangzhou, 510080, PR China.

Background: Local and systemic glucocorticoids are mainstay therapies for chronic rhinosinusitis. With respect to local glucocorticoids, nasal spray is used extensively, but some patients do not benefit from short-course treatment. Recently, some clinicians have focused on the effects of high-dose local glucocorticoids in chronic rhinosinusitis with nasal polyps (CRSwNP), such as treatment using nasal irrigation, transnasal nebulization, and nose-dripping therapy (nasal drop) with high-dose budesonide. However, there are little data comparing the effect of short-course high-dose local glucocorticoids with regular nasal spray and oral steroids in the treatment of preoperative CRSwNP patients. Furthermore, the appropriate use of different types of glucocorticoids in different endotypes of CRSwNP remains unclear.

Methods: This randomized controlled clinical research study was performed at a single academic center. Patients who satisfied the criteria of chronic rhinosinusitis with bilateral nasal polyps were randomly assigned in a 1:1:1 ratio to receive oral methylprednisolone, 24 mg/d and budesonide nasal spray, 256 μg/d, or intranasal budesonide suspension, 1 mg/d and budesonide nasal spray, 256 μg/d, or budesonide nasal spray, 256 μg/d for one week. Symptoms, endoscopic scores, and tissue and blood inflammatory cells were recorded before and after the study. Adverse events were recorded by clinicians.

Results: A total of 127 patients with CRSwNP underwent randomization. The total nasal symptoms scores (TNSS) decreased significantly in all groups compared to those at baseline. The assessment of the reduction in TNSS demonstrated that the change was significantly greater in the nasal drop group than in the nasal spray group (-7.47 vs -4.10,  = 0.032), and it was also greater in the oral steroid group than in the nasal spray group (-7.30 vs -4.10,  = 0.039). A similar trend also appeared in the reduction in Sinonasal-Outcome Test 22 (SNOT-22). After treatment, a significantly reduction in NP score was observed in the nasal drop group (-0.82) and oral steroid group (-0.85) compared with that in the nasal spray group (-0.10), and there was no significant difference between the nasal drop and oral steroid groups ( = 0.98). While calculating the percentage of patients who were sensitive to glucocorticoid treatment, there was 10.26% in the nasal spray group, 47.37% in the nasal drop group, and 52.50% in the oral steroid group that were sensitive to glucocorticoid treatment. The reduction in NP score was more significant in patients with eosinophilic CRSwNP in the nasal drop group and oral steroid group than in the nasal spray group. However, in patients with non-eosinophilic CRSwNP, the change in NP size was similar in the different treatment groups.

Conclusion: Budesonide suspension nasal drop can significantly improve the quality of life and reduce the endoscopic score following short-course treatment, and the treatment effect of nasal drop was better than that of regular nasal spray. Budesonide nasal suspension can be used as a regular treatment for eosinophilic CRSwNP and can be an alternative choice for patients with a high percentage of tissue eosinophil infiltration who cannot use oral glucocorticoids.
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http://dx.doi.org/10.1016/j.waojou.2020.100131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7300158PMC
June 2020

Zearalenone induces NLRP3-dependent pyroptosis via activation of NF-κB modulated by autophagy in INS-1 cells.

Toxicology 2019 12 3;428:152304. Epub 2019 Oct 3.

Department of Nutrition and Food Safety, College of Public Health, Dalian Medical University, No. 9, West Segment of South lvshun Road, Dalian 116044, Liaoning, PR China. Electronic address:

Zearalenone (ZEA), one of the mycotoxins widely found in food and feed, can stimulate an inflammatory reaction. In the present study, we demonstrated that ZEA induced the activation of NLRP3 inflammasome even pyroptotic cell death in rat Insulinoma Cell Line (INS-1). Meanwhile, according to the results of western blot and TEM, the level of autophagy was elevated by ZEA, which protected against the activation of NLRP3 inflammasome and inflammatory response caused by ZEA. Furthermore, we indicated that ZEA-induced NF-κB p65 activation contributed to the activation of the NLRP3 inflammasome, inflammatory response, and pyroptosis in INS-1 cells, which were indicated by western blot and immunofluorescence, and the activation of NF-κB p65 induced by ZEA was autophagy-dependent. This study demonstrates that ZEA induces NLRP3-dependent pyroptosis via activation of NF-κB modulated by autophagy in INS-1 cells.
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http://dx.doi.org/10.1016/j.tox.2019.152304DOI Listing
December 2019

Application of high-resolution CT images information in complicated infection of lung tumors.

J Infect Public Health 2021 Mar 23;14(3):418-422. Epub 2019 Aug 23.

Department of CT, Hengshui People's Hospital, Hengshui, 053000, Hebei, China. Electronic address:

To explore the quality of high-resolution CT images information in the evaluation of pulmonary nodule interface and internal structure of nodules in lung tissue, as well as the value of early diagnosis of lung cancer associated with infection, high-resolution CT images were used as the research object. Through the analysis of the computerized detection and diagnosis (Computer-Aided Diagnosis (CAD)) of lung cancer, the high-resolution CT was further explored in the process of clinical imaging doctors in the diagnosis of lung cancer, and more conditions were created for the application of medical image processing in the early diagnosis of lung cancer. The research results show that CAD can automatically and accurately complete the automatic segmentation of the lung region in the CT image by applying the automatic segmentation algorithm for a series of processing and analysis of the CT image, that is, generating high-resolution CT images. It can enhance the pulmonary nodules in CT images and improve the accuracy of lung nodule detection, which is of great value in the diagnosis of early lung cancer. CAD diagnosis of lung lesions based on high-resolution CT images is studied, which can provide reference for imaging physicians to diagnose early lung cancer. However, in the automatic identification of benign and malignant lesions in the lungs, it is necessary to further improve the analysis function of similar nodules, which will be an important step for humans in the diagnosis and treatment of diseases.
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http://dx.doi.org/10.1016/j.jiph.2019.08.001DOI Listing
March 2021

Multi-Targeting by -Elemene and Its Anticancer Properties: A Good Choice for Oncotherapy and Radiochemotherapy Sensitization.

Nutr Cancer 2020 7;72(4):554-567. Epub 2019 Aug 7.

Department of Traditional Chinese Medicine, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China.

Several studies have focused on chemical agents, tailored from natural edible products, used to prevent and treat various diseases. β-elemene is a well-known compound derived from that possesses a wide spectrum of anticancer properties under preclinical and clinical conditions. Several studies have demonstrated its inhibitory effect both in humans and animals with cancers. Numerous and experimental models have revealed that β-elemene can modulate multiple molecular pathways involved in carcinogenesis. In general, (1) β-elemene itself can inhibit and kill tumor cells through a variety of mechanisms, and (2) can synergistically enhance the effect of radiotherapy and/or chemotherapy, (3) also can regulate autoimmune in the treatment of tumors. In this article, we critically focused on the available scientific evidence discussing the use of β-elemene in cancer prevention, and its molecular targets and mechanisms of action in different types of cancer. In addition, we have discussed its sources, chemistry, bioavailability, and future research directions.
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http://dx.doi.org/10.1080/01635581.2019.1648694DOI Listing
January 2021

Pyrroloquinoline quinine ameliorates doxorubicin-induced autophagy-dependent apoptosis via lysosomal-mitochondrial axis in vascular endothelial cells.

Toxicology 2019 09 18;425:152238. Epub 2019 Jun 18.

Department of Internal Medicine, the Affiliated Zhongshan Hospital of Dalian University, Dalian, 116001, Liaoning, PR China. Electronic address:

The cardiotoxicity of doxorubicin (DOX) limits its clinical use in the treatment of a variety of solid tumors and malignant hematologic disease. However, the mechanism by which it causes cardiotoxicity is not fully understood. Apoptosis has been regarded as one of mechanisms underlying the cardiotoxic effects of DOX. In our study, we found that treatment of human umbilical vein endothelial cells (HUVECs) with DOX induced autophagy and apoptosis in a dose- and time-dependent manner. Treatment with DOX induced autophagy at earlier time (3 h), then lysosomal membrane permeabilization (LMP) altered after treatment for 12 h which followed by the release of cathepsin D (CTSD). Lysosome-associated membrane proteins-1 and -2 (LAMP1 and LAMP2) were decreased in DOX-treated cells. Additionally, DOX induced the collapse of mitochondrial transmembrane potential, reduction of translocase of the outer mitochondrial membrane-20 (TOM-20), and release of cytochrome c. Furthermore, autophagy inhibitor 3-MA relieved DOX-induced apoptosis as assessed by the expression of cleaved caspase-3, cleaved caspase-9 and TUNEL assay. CTSD inhibitor, pepstatin A, upregulated TOM-20 and suppressed the mitochondria release of cytochrome c as well as apoptosis under DOX stress. Pyrroloquinoline quinine (PQQ), a new B vitamin, ameliorated aforementioned phenomenon. In conclusion, our results suggested that DOX-induced apoptosis was autophagy-dependent via lysosomal-mitochondrial axis. PQQ had an ability to protect cell from autophagy-dependent apoptosis induced by DOX via lysosomal-mitochondrial axis to some extent. This study provided new mechanistic insight toward understanding the pathogenesis of DOX-induced cardiotoxicity and the protection effect of PQQ.
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http://dx.doi.org/10.1016/j.tox.2019.152238DOI Listing
September 2019

[Establishment of the norms of Sub-Health Measurement Scale Version 1.0 for Chinese urban residents].

Nan Fang Yi Ke Da Xue Xue Bao 2019 Mar;39(3):271-278

Department of Health Economics Administration, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.

Objective: To establish the norms of Sub-Health Measurement Scale (SHMS V1.0) for Chinese urban residents.

Methods: Using a multistage stratified sampling method, we conducted a large-scale epidemiological investigation among 15 066 urban residents sampled from 6 regions in China, including Tianjin City (north China), Guangdong Province (south China), Anhui Province (central south China), Sichuan Province (southwest China), Lanzhou City (northwest China) and Harbin City (northeast China). The mean, percentile and threshold norms were established based on the characteristics of SHMS V1.0 scores for Chinese urban residents.

Results: The mean and percentile norms of total, physical, mental and social sub-health of Chinese urban residents were established according to gender and different age groups (14-19, 20-29, 30-49, 50-64 and ≥65 years). The threshold norms of SHMS V1.0 divided 5 health states, namely disease, severe sub-health, moderate subhealth, mild sub-health and healthy states according to the ± and ±0.5 of the converted scores.

Conclusions: The norms of Sub-Health Measurement Scale (SHMS V1.0) for Chinese urban residents were established, which provides a reference for rapid screening and diagnosis of sub-health status in Chinese urban residents and facilitates further study of the prevalence and contributing factors of sub-health.
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http://dx.doi.org/10.12122/j.issn.1673-4254.2019.03.03DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6765689PMC
March 2019

[Association analysis between personality and sub-health among urban residents aged over 14 years in 4 Chinese provinces].

Nan Fang Yi Ke Da Xue Xue Bao 2019 Apr;39(4):443-449

Department of Economic Management, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.

Objective: To explore the direct relationship between personality (PN) and sub-health status (SHS) and their indirect association mediated by frustration quotient (FQ) and stress event (SE).

Methods: A multiple-stage stratified sampling method was used to choose the participants, and a total of 4517 eligible urban residents were selected.ANCOVA was used to analyze the independent association between personality and SHS after adjusting the demographic characteristics and lifestyle.A structural equation model was used to analyze the associations among personality, FQ, SE and SHS.Bootstrap method was used to test the direct and indirect association between personality and SHS.

Results: Personality was independently associated with total sub-health (=75.913, < 0.001), physical sub-health (=23.618, < 0.001), mental sub-health (=101.993, < 0.001) and social sub-health (=48.757, < 0.001).The urban residents with the personalities characterized by anger suppression, anxiety and irritability, and impatience and competitiveness had significantly lower health scores than those with a mature and steady personality ( < 0.05).Personality was associated with FQ and SE, and the indirect association between personality and physical sub-health was mainly mediated by FQ and SE (β=-0.110).Personality showed more a direct association (β=-0.172) with mental sub-health and a slightly less indirect association (β=-0.126) with mental sub-health.Personality showed a more indirect association (β=-0.113) with social SHS and slightly less direct association (β=-0.082) with social sub-health.

Conclusions: A mature and steady personality may help to promote the general health level, while the personalities of anger suppression, anxiety and irritability, impatience and competitiveness can be associated with the occurrence of sub-health.Building a mature and steady personality has positive effects on the health in general of an individual.
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http://dx.doi.org/10.12122/j.issn.1673-4254.2019.04.10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6743993PMC
April 2019

Comparative pharmacokinetics of florfenicol in healthy and Pasteurella multocida-infected Gaoyou ducks.

J Vet Pharmacol Ther 2019 May 25;42(3):355-360. Epub 2019 Mar 25.

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

Pasteurella multocida is the causative agent of fowl cholera, and florfenicol (FF) has potent antibacterial activity against P. multocida and is widely used in the poultry industry. In this study, we established a P. multocida infection model in ducks and studied the pharmacokinetics of FF in serum and lung tissues after oral administration of 30 mg/kg bodyweight. The maximum concentrations reached (C were lower in infected ducks (13.88 ± 2.70 μg/ml) vs. healthy control animals (17.86 ± 1.57 μg/ml). In contrast, the mean residence time (MRT: 2.35 ± 0.13 vs. 2.27 ± 0.18 hr) and elimination half-life (T : 1.63 ± 0.08 vs. 1.57 ± 0.12 hr) were similar for healthy and diseased animals, respectively. As a result, the area under the concentration curve for 0-12 hr (AUC ) for FF in healthy ducks was significantly greater than that in infected ducks (49.47 ± 5.31 vs. 34.52 ± 8.29 μg hr/ml). The pharmacokinetic differences of FF in lung tissues between the two groups correlated with the serum pharmacokinetic differences. The C and AUC values of lung tissue in healthy ducks were higher than those in diseased ducks. The concentration of FF in lung tissues was approximately 1.2-fold higher than that in serum both in infected and healthy ducks indicating that FF is effective in treating respiratory tract infections in ducks.
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http://dx.doi.org/10.1111/jvp.12761DOI Listing
May 2019

Taurine protects INS-1 cells from apoptosis induced by Di(2-ethylhexyl) phthalate via reducing oxidative stress and autophagy.

Toxicol Mech Methods 2019 Jul 4;29(6):445-456. Epub 2019 Jun 4.

a Department of Nutrition and Food Safety , College of Public Health, Dalian Medical University , Dalian , Liaoning , PR China.

Di-(2-ethylhexyl) phthalate (DEHP) is an environmental endocrine disruptor widely employed in plastic bags, industrial paints, cosmetics and food packaging, which has been reported to be harmful to human physical health. Many studies have shown that DEHP causes reproductive system toxicity, but its cytotoxicity to islet cells is few to unknown. In our research, it was found that DEHP could induce apoptosis in INS-1 cells via autophagy and oxidative stress. Taurine, a sulfur-containing β-amino acid, could reverse DEHP-induced oxidative stress imbalance. Meanwhile, taurine could reduce DEHP-induced excessive autophagy. The interaction between oxidative stress and autophagy has been investigated in this study. After pretreated with autophagy interventional agents, it was found that autophagy was capable of alleviating oxidative stress and ROS production in DEHP-treated INS-1 cells. And down-regulated ROS production by NAC could also turn over uploaded autophagy. Our research provides a perspective about the mechanism of cytotoxicity of DEHP to INS-1 cells and taurine protective effect.
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http://dx.doi.org/10.1080/15376516.2019.1588931DOI Listing
July 2019

In vivo pharmacokinetic/Pharmacodynamic modeling of Enrofloxacin against Escherichia coli in broiler chickens.

BMC Vet Res 2018 Nov 29;14(1):374. Epub 2018 Nov 29.

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

Background: Systemic Escherichia coli infections cause early mortality of commercial broiler chickens. Although enrofloxacin has long been used in poultry, the in vivo pharmacokinetic/pharmacodynamic (PK/PD) relationship of enrofloxacin against E. coli is unclear. The present study aimed to establish an in vivo PK/PD model of enrofloxacin against E. coli in seven-day-old chicks and to ascertain whether the selection of target organ for PD determination is critical for parameter magnitude calculation in enrofloxacin PK/PD modeling.

Results: The in vivo effectiveness of enrofloxacin against E. coli in different organs varied, with the E ranging from - 4.4 to - 5.8 Log colony forming units (cfu)/mL or cfu/g. Both the surrogate AUC/MIC of enrofloxacin or AUC/MIC of the combination of enrofloxacin and ciprofloxacin correlated well with effectiveness in each organ. The AUC/MIC ratio of the combination of enrofloxacin and ciprofloxacin producing bactericidal and elimination effects were 21.29 and 32.13 in blood; 41.68, and 58.52 in the liver; and 27.65 and 46.22 in the lung, respectively.

Conclusions: The in vivo effectiveness of enrofloxacin against E. coli in different organs was not identical after administration of the same dosage. To describe the magnitude of PK/PD parameter exactly, bacterial loading reduction in different organs as PD endpoints should be evaluated and compared in PK/PD modeling. The selection of a target organ to evaluate PDs is critical for rational dosage recommendation.
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http://dx.doi.org/10.1186/s12917-018-1698-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6267815PMC
November 2018

The ratio of 11β-hydroxysteroid dehydrogenase 1/11β-hydroxysteroid dehydrogenase 2 predicts glucocorticoid response in nasal polyps.

Eur Arch Otorhinolaryngol 2019 Jan 16;276(1):131-137. Epub 2018 Nov 16.

The Otorhinolaryngology Hospital, First Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, No. 58 Zhongshan Er Road, Guangzhou, People's Republic of China.

Background: Glucocorticoids are the first-line medical treatment for chronic rhinosinusitis with nasal polyps (CRSwNP), whose local metabolism is catalyzed by 11β-HSD1 and 11β-HSD2. This study investigates the role of 11β-HSD1 and 11β-HSD2 on the glucocorticoid response of CRSwNP patients and the pathogenic mechanism of these polyps.

Methods: Forty-three adult CRSwNP patients were enrolled in this study. We evaluated the endoscopic scores by a nasal polyp grading system before and after treatment. We estimated the response to glucocorticoids by the total endoscopic scores. The logistic regression models and inflammatory characteristic curves were conducted to explore the prediction of the response to glucocorticoid in CRSwNP. The expression of 11β-HSD1 and 11β-HSD2 on human sinonasal epithelial cells (HSECS) was measured under the stimulation of toll-like receptor agonists and dexamethasone.

Results: The endoscopic scores in the CRSwNP group declined, the expression of 11β-HSD1/11β-HSD2 increased (r = 0.5276, P = 0.0011), and the cutoff value of the ratio of 11β-HSD1/11β-HSD2 was 0.4654 (sensitivity 79.17%, specificity 88.89%). Dexamethasone induced a decrease in the ratio of 11β-HSD1/11β-HSD2 (P = 0.049) by the stimulation of PGN-BS.

Conclusion: We found a strong correlation between the response to glucocorticoids and the ratio of 11β-HSD1/11β-HSD2, which could be used as a marker in predicting the level of tissue response to glucocorticoid therapy in CRSwNP. In addition, PGN-BS could also be a therapeutic target, as it is the negative factor that will decrease the sensitivity of glucocorticoids by reducing the ratio of 11β-HSD1/11β-HSD2.
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http://dx.doi.org/10.1007/s00405-018-5201-3DOI Listing
January 2019

Acrolein induces NLRP3 inflammasome-mediated pyroptosis and suppresses migration via ROS-dependent autophagy in vascular endothelial cells.

Toxicology 2018 12 8;410:26-40. Epub 2018 Sep 8.

Department of Internal Medicine, The Affiliated Zhong Shan Hospital of Dalian University, Dalian, 116001, Liaoning, PR China. Electronic address:

Acrolein is a common environmental pollutant that has been linked to cardiovascular diseases, such as atherosclerosis (AS). Increasing evidence demonstrates that acrolein impairs the cardiovascular system by targeting vascular endothelial cells, but the underlying mechanisms haven't been completely elucidated. In human umbilical vein endothelial cells (HUVECs), we observed that acrolein treatment induced cell reactive oxygen species (ROS) generation, autophagy, pyroptosis and reduced cell migration. In addition, exposure to acrolein resulted in NLRP3 inflammasome activation as evidenced by cleavage of caspase-1 and downstream mature interleukin (IL)-1β and IL-18 secretion. Knockdown of NLRP3 by small interfering RNA remarkably suppressed acrolein-induced pyroptosis and increased cell migration. Moreover, the scavenging ROS relieved the autophagy, NLRP3 inflammasome activation and pyroptosis. Furthermore, the role of autophagy in the acrolein-medicated pyroptosis and cell migration was investigated. In our study, 3-methyladenine (3-MA), an autophagy inhibitor, aggravated NLRP3 inflammasome activation, pyroptosis and decreased cell migration, rapamycin (Rapa), an autophagy inducer, alleviated aforementioned phenomenon under acrolein stress. Besides, we found damaged mitochondrion accentuated NLRP3 inflammasome and pyroptosis in acrolein-treated cells. In conclusion, it is possible that acrolein induced cell pyroptosis and suppressed cell migration via ROS-dependent autophagy. What's more, NLRP3 inflammasome activation plays a key role in this process.
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http://dx.doi.org/10.1016/j.tox.2018.09.002DOI Listing
December 2018

Comparative pharmacokinetics of danofloxacin in healthy and Pasteurella multocida infected ducks.

J Vet Pharmacol Ther 2018 Dec 4;41(6):912-918. Epub 2018 Sep 4.

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

Pasteurella multocida (P. multocida) infection causes substantial economic loss in the duck industry. Danofloxacin, a fluoroquinolone solely used in animals, shows good antibacterial activity against P. multocida. In this study, the in vitro pharmacodynamics of danofloxacin against P. multocida was studied. The serum and lung tissue pharmacokinetics of danofloxacin were studied in healthy and P. multocida infected ducks following oral administration of a single dose of 5 mg/kg body weight (b.w.). The MIC, MBC and MPC of danofloxacin against P. multocida (C ) were 0.25, 1 and 3.2 μg/ml, respectively. The Cmax was 0.34 μg/ml, attained at 2.03 hr in healthy ducks, and was 0.35 μg/ml, attained at 2.87 hr in diseased ducks. Compared to the serum pharmacokinetics of danofloxacin in healthy ducks, the absorption rate and extent were similar in healthy and diseased animals. In contrast, the elimination rate was slower, with an elimination half-life (T ) of 13.17 and 16.18 hr for healthy and infected animals, respectively; the AUCs in the two groups were 5.70 and 7.68 μg hr/ml, respectively, which means the total amount of drug in the circulation was increased in the infected ducks. The maximum concentration in lung tissues between healthy and infected animals was not significantly different (8.96 vs. 8.93 μg/g). However, the T in healthy ducks was longer than that in infected ducks (4 hr vs. 1.75 hr), which means that the distribution rate of danofloxacin was slower in healthy ducks. The concentration of danofloxacin in lung tissues was approximately 24-fold higher than that in the serum. In the serum pharmacokinetic profiles, the ƒAUC /MIC was 18.19 in healthy ducks and was 25.04 in P. multocida infected ducks at the clinical recommended dose, which is far from the PK/PD target (125 hr) of fluoroquinolones. Danofloxacin, at a dose of 5 mg/kg b.w., seems to be insufficient for ducks infected with P. multocida, with an MIC equal to 0.25 μg/ml.
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http://dx.doi.org/10.1111/jvp.12712DOI Listing
December 2018

Acrolein-induced autophagy-dependent apoptosis via activation of the lysosomal-mitochondrial pathway in EAhy926 cells.

Toxicol In Vitro 2018 Oct 12;52:146-153. Epub 2018 Jun 12.

Department of Internal Medicine, The Afliated Zhong Shan Hospital of Dalian University, Dalian, Liaoning 116001, China. Electronic address:

Acrolein, a highly reactive α,β-unsaturated aldehyde, is a toxic component of cigarette smoke. As a lipid peroxidation biomarker, acrolein plays an important role in a wide variety of disease states, such as neurodegenerative, Alzheimer's disease, diabetes and atherosclerosis. Endothelial cell injury is one of the initiating factors of atherosclerosis, but the underlying molecular mechanisms remain unclear. Our study primarily focused on acrolein-induced autophagy-dependent apoptosis and the possible molecular mechanism. The results showed that treatment with acrolein increased the number of intracellular GFP-LC3 II punctuates and the expression of autophagosome biomarker LC3-II, with the low dose (25 μM) or at the early stage of treatment (3 h). Following treatment of EAhy926 cells with acrolein for 6 h, lysosomal permeabilization changed, and cathepsin B (CB) was released. Additionally, acrolein induced the collapse of mitochondrial transmembrane potential, and cytochrome c was released. Furthermore, caspase-3 and caspase-9 activation showed that acrolein induced EAhy926 cell apoptosis. Autophagy inhibitor 3MA and CB inhibitor CA-074 Me (CA) attenuated acrolein-induced apoptosis. Collectively, our results suggested that acrolein-induced apoptosis is autophagy-dependent, occurring via injury to lysosomes and mitochondria. This study provides new mechanistic insight toward understanding the pathogenesis of acrolein-related disorders.
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http://dx.doi.org/10.1016/j.tiv.2018.05.018DOI Listing
October 2018

The role of oxidative stress in DNA damage in pancreatic β cells induced by di-(2-ethylhexyl) phthalate.

Chem Biol Interact 2017 Mar 20;265:8-15. Epub 2017 Jan 20.

Department of Nutrition and Food Safety, College of Public Health, Dalian Medical University, No.9, West Segment of South Lvshun Road, Dalian 116044, Liaoning, PR China; Natural Products Engineering Technology Center, Dalian Medical University, No.9, West Segment of South Lvshun Road, Dalian 116044, Liaoning, PR China. Electronic address:

Di(2-ethyhexyl) phthalate (DEHP) is commonly used as a plasticizer, which loosely binds to plastic materials and easily leaches out of these products and enters into the environment. Exposure to DEHP can impair pancreatic beta cells (INS-1 cells)function, which is associated with Insulin Resistance (IR) and type 2 diabetes. However, the mechanism of how DEHP leads to Insulin Resistance is unknown. Our results showed that the cell viability of INS-1 cells exposed to DEHP (0-1600 μM) were decreased in a concentration-dependent manner. DEHP caused significant increases of DNA migration and oxidative damage in INS-1 cells. Lysosomal membrane permeability was increased and mitochondrial membrane potential was reduced after INS-1 cells treated with DEHP. DEHP was also shown to induce ROS production and cause GSH depletion in INS-1 cells. DEHP brought a significant decrease in super oxide dismutase (SOD) and led to accumulation of malondialdehyde (MDA) in the INS-1 cells. DEHP increased significantly the expression of P53 and ATM gene of INS-1 cell at high dose levels. Simultaneously, Pyrroloquinoline Quinone (PQQ), an antioxidant, and alcohol were used in the study to determine their effects on DEHP-induced INS-1 cells damage. PQQ could protect the INS-1 cells from the damage induced by DEHP to some extent, while alcohol aggravated the toxic effects of DEHP. These results indicate that DEHP-mediated INS-1 cell dysfunction through a lysosomal-mitochondrial pathway, involving oxidative stress and p53 and ATM activation.
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http://dx.doi.org/10.1016/j.cbi.2017.01.015DOI Listing
March 2017

WDPCP regulates the ciliogenesis of human sinonasal epithelial cells in chronic rhinosinusitis.

Cytoskeleton (Hoboken) 2017 Feb;74(2):82-90

The Otorhinolaryngology Hospital, First Affiliated Hospital of Sun Yat-sen, University, SunYat-sen University, Guangzhou, P.R. China.

Damage to the mucociliary clearance system is a typical change in the pathogenesis in chronic rhinosinusitis. However, the mechanisms underlying cilia loss remain unclear. WDPCP is a key protein essential for ciliogenesis, and is also an effector of the planar cell polarity signaling system. In this study, we sought to determine the role of WDPCP in cilia loss in patients with chronic rhinosinusitis. We demonstrated the expression of WDPCP in human sinonasal epithelium from patients with chronic rhinosinusitis and control subjects. We also used air-liquid interface to culture primary human sinonasal epithelial cells in-vitro model and to investigate WDPCP function. We then explored links between rhinosinusitis, WDPCP and inflammation. Accompanied with cilia loss, expression of WDPCP in human sinonasal epithelium from patients with chronic rhinosinusitis was decreased significantly compared with control subjects. In vitro study, we found that WDPCP level increased at first, and then decreased. Inhibiting WDPCP expression could lead to the poor quantity and length of cilia with reduced expression of Septin7. Also, Th1 type inflammatory mediators could decrease the expression of WDPCP. In conclusion, inflammatory cytokines cause reduced WDPCP expression, which contributes to impaired ciliogenesis in human rhinosinusitis.
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http://dx.doi.org/10.1002/cm.21351DOI Listing
February 2017

Activated mutant forms of PIK3CA cooperate with RasV12 or c-Met to induce liver tumour formation in mice via AKT2/mTORC1 cascade.

Liver Int 2016 08 30;36(8):1176-86. Epub 2016 Jan 30.

Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA.

Background & Aims: Activating mutations of PIK3CA occur in various tumour types, including human hepatocellular carcinoma. The mechanisms whereby PIK3CA contributes to hepatocarcinogenesis remain poorly understood.

Methods: PIK3CA mutants H1047R or E545K were hydrodynamically transfected, either alone or in combination with NRasV12 or c-Met genes, in the mouse liver.

Results: Overexpression of H1047R or E545K alone was able to induce AKT/mTOR signalling in the mouse liver, leading to hepatic steatosis. However, none of the mice developed liver tumours over long term. In contrast, H1047R or E545K cooperated with NRasV12 or c-Met to rapidly induce liver tumour formation in mice. At the molecular level, all the tumour nodules displayed activation of AKT/mTOR and Ras/MAPK cascades. Ablation of AKT2 significantly inhibited hepatic steatosis induced by H1047R or E545K and carcinogenesis induced by H1047R/c-Met or E545K/c-Met. Furthermore, tumourigenesis induced by H1047R/c-Met was abolished in conditional Raptor knockout mice.

Conclusions: Both H1047R and E545K are able to activate the AKT/mTOR pathway. An intact AKT2/mTOR complex 1 cascade is required for tumourigenesis induced by H1047R/c-Met or E545K/c-Met in the liver.
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http://dx.doi.org/10.1111/liv.13055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4929046PMC
August 2016

Dormant Intestinal Stem Cells Are Regulated by PTEN and Nutritional Status.

Cell Rep 2015 Dec 10;13(11):2403-2411. Epub 2015 Dec 10.

Division of Endocrinology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, 7 Divinity Avenue, Cambridge, MA 02138, USA. Electronic address:

The cellular and molecular mechanisms underlying adaptive changes to physiological stress within the intestinal epithelium remain poorly understood. Here, we show that PTEN, a negative regulator of the PI3K→AKT→mTORC1-signaling pathway, is an important regulator of dormant intestinal stem cells (d-ISCs). Acute nutrient deprivation leads to transient PTEN phosphorylation within d-ISCs and a corresponding increase in their number. This release of PTEN inhibition renders d-ISCs functionally poised to contribute to the regenerative response during re-feeding via cell-autonomous activation of the PI3K→AKT→mTORC1 pathway. Consistent with its role in mediating cell survival, PTEN is required for d-ISC maintenance at baseline, and intestines lacking PTEN have diminished regenerative capacity after irradiation. Our results highlight a PTEN-dependent mechanism for d-ISC maintenance and further demonstrate the role of d-ISCs in the intestinal response to stress.
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http://dx.doi.org/10.1016/j.celrep.2015.11.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4691543PMC
December 2015

Inactivation of fatty acid synthase impairs hepatocarcinogenesis driven by AKT in mice and humans.

J Hepatol 2016 Feb 22;64(2):333-341. Epub 2015 Oct 22.

Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy. Electronic address:

Background & Aims: Cumulating evidence underlines the crucial role of aberrant lipogenesis in human hepatocellular carcinoma (HCC). Here, we investigated the oncogenic potential of fatty acid synthase (FASN), the master regulator of de novo lipogenesis, in the mouse liver.

Methods: FASN was overexpressed in the mouse liver, either alone or in combination with activated N-Ras, c-Met, or SCD1, via hydrodynamic injection. Activated AKT was overexpressed via hydrodynamic injection in livers of conditional FASN or Rictor knockout mice. FASN was suppressed in human hepatoma cell lines via specific small interfering RNA.

Results: Overexpression of FASN, either alone or in combination with other genes associated with hepatocarcinogenesis, did not induce histological liver alterations. In contrast, genetic ablation of FASN resulted in the complete inhibition of hepatocarcinogenesis in AKT-overexpressing mice. In human HCC cell lines, FASN inactivation led to a decline in cell proliferation and a rise in apoptosis, which were paralleled by a decrease in the levels of phosphorylated/activated AKT, an event controlled by the mammalian target of rapamycin complex 2 (mTORC2). Downregulation of AKT phosphorylation/activation following FASN inactivation was associated with a strong inhibition of rapamycin-insensitive companion of mTOR (Rictor), the major component of mTORC2, at post-transcriptional level. Finally, genetic ablation of Rictor impaired AKT-driven hepatocarcinogenesis in mice.

Conclusions: FASN is not oncogenic per se in the mouse liver, but is necessary for AKT-driven hepatocarcinogenesis. Pharmacological blockade of FASN might be highly useful in the treatment of human HCC characterized by activation of the AKT pathway.
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http://dx.doi.org/10.1016/j.jhep.2015.10.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4718802PMC
February 2016

Olaquindox induces DNA damage via the lysosomal and mitochondrial pathway involving ROS production and p53 activation in HEK293 cells.

Environ Toxicol Pharmacol 2015 Nov 16;40(3):792-9. Epub 2015 Sep 16.

Department of Nutrition and Food Safety, Dalian Medical University, No. 9, West Segment of South Lvshun Road, Dalian 116044, Liaoning, PR China. Electronic address:

Olaquindox (OLA) is a potent antibacterial agent used as a feed additive and growth promoter. In this study, the genotoxic potential of OLA was investigated in the human embryonic kidney cell line 293 (HEK293). Results showed that OLA caused significant increases of DNA migration. Lysosomal membrane permeability and mitochondrial membrane potential were reduced after treatment with OLA. OLA was shown to induce ROS production and GSH depletion. The expression of p53 protein is increased in cells incubated with OLA. The activation of p53 and ATM gene was assessed by exposure to OLA. Furthermore, NAC reduced DNA migration, ROS formation, GSH depletion and the expression of the p53 protein and gene. And desipramine significantly decreased AO fluorescence intensity and the expression of the p53 protein and gene. These results support the assumption that OLA exerted genotoxic effects and induced DNA strand breaks in HEK293 cells, possibly through lysosomal-mitochondrial pathway involving ROS production and p53 activation.
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http://dx.doi.org/10.1016/j.etap.2015.09.008DOI Listing
November 2015

Oxidative DNA damage induced by di-(2-ethylhexyl) phthalate in HEK-293 cell line.

Environ Toxicol Pharmacol 2015 May 1;39(3):1099-106. Epub 2015 Apr 1.

Department of Nutrition and Food Safety, Dalian Medical University, No. 9, West Segment of South lvshun Road, Dalian, 116044 Liaoning, PR China. Electronic address:

Di-(2-ethylhexyl) phthalate (DEHP) is commonly employed as a plasticizer. We have found that exposure of human embryonic kidney cell line 293 (HEK-293) to DEHP resulted in a crucial dose-dependent increase of DNA strand breaks in a comet assay. To elucidate the role of glutathione (GSH) in the DNA damage, the cells were pretreated with buthionine-(S,R)-sulfoximine (BSO) and pretreated with N-acetylcysteine (NAC), a GSH precursor. Here we show that depletion of GSH in HEK-293 cells with BSO dramatically increased the susceptibility of HEK-293 cells to DEHP-induced DNA damage. Furthermore, when the intracellular GSH content was elevated by NAC, the DNA damage induced by DEHP was almost completely abolished. In addition, DEHP had effect on lysosomal or mitochondrial damage at high dose level. These results indicate that DEHP exerts genotoxic effects in HEK-293 cells, probably through DNA damage induced by oxidative stress; GSH is responsible for cellular defense against DEHP-induced DNA damage; lysosome and mitochondria may be the vital targets in DEHP-induced DNA damage.
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http://dx.doi.org/10.1016/j.etap.2015.03.016DOI Listing
May 2015

Co-activation of PIK3CA and Yap promotes development of hepatocellular and cholangiocellular tumors in mouse and human liver.

Oncotarget 2015 Apr;6(12):10102-15

Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, U.S.A.

Activation of the PI3K and Yes-associated protein (Yap) signaling pathways has been independently reported in human hepatocellular carcinoma (HCC). However, the oncogenic interactions between these two cascades in hepatocarcinogenesis remain undetermined. To assess the consequences of the crosstalk between the PI3K and Yap pathways along liver carcinogenesis, we generated a mouse model characterized by combined overexpression of activated mutant forms of PIK3CA (PIK3CAH1047R) and Yap (YapS127A) in the mouse liver using hydrodynamic transfection (PIK3CA/Yap). In addition, suppression of PI3K and Yap pathways was conducted in human HCC and cholangiocarcinoma (CCA) cell lines. We found that concomitant activation of PI3K and Yap pathways triggered rapid liver tumor development in mice. Histologically, tumors were pure HCC, CCA, or mixed HCC/CCA. At the molecular level, PIK3CA/Yap tumors were characterized by activation of the mTORC1/2, ERK/MAPK, and Notch pathways. Simultaneous activation of PI3K and Yap pathways frequently occurred in human liver tumor specimens and their combined suppression was highly detrimental for the growth of HCC and CCA cell lines. In conclusion, our study demonstrates the oncogenic cooperation between PI3K and Yap pathways along liver carcinogenesis. The PIK3CA/Yap mouse represents an important preclinical liver tumor model for the development of novel therapeutics against this malignancy.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4496343PMC
http://dx.doi.org/10.18632/oncotarget.3546DOI Listing
April 2015

SKP2 cooperates with N-Ras or AKT to induce liver tumor development in mice.

Oncotarget 2015 Feb;6(4):2222-34

Institut für Pathologie, Universitätsmedizin Greifswald, Greifswald, Germany.

Mounting evidence indicates that S-Phase Kinase-Associated Protein 2 (SKP2) is overexpressed in human hepatocellular carcinoma (HCC). However, the role of SKP2 in hepatocarcinogenesis remains poorly delineated. To elucidate the function(s) of SKP2 in HCC, we stably overexpressed the SKP2 gene in the mouse liver, either alone or in combination with activated forms of N-Ras (N-RasV12), AKT1 (myr-AKT1), or β-catenin (ΔN90-β-catenin) protooncogenes, via hydrodynamic gene delivery. We found that forced overexpression of SKP2, N-RasV12 or ΔN90-β-catenin alone as well as co-expression of SKP2 and ΔN90-β-catenin did not induce liver tumor development. Overexpression of myr-AKT1 alone led to liver tumor development after long latency. In contrast, co-expression of SKP2 with N-RasV12 or myr-AKT1 resulted in early development of multiple hepatocellular tumors in all SKP2/N-RasV12 and SKP2/myr-AKT1 mice. At the molecular level, preneoplastic and neoplastic liver lesions from SKP2/N-RasV12 and SKP2/myr-AKT1 mice exhibited a strong induction of AKT/mTOR and Ras/MAPK pathways. Noticeably, the tumor suppressor proteins whose levels have been shown to be downregulated by SKP2-dependent degradation in various tumor types, including p27, p57, Dusp1, and Rassf1A were not decreased in liver lesions from SKP2/N-RasV12 and SKP2/myr-AKT1 mice. In human HCC specimens, nuclear translocation of SKP2 was associated with activation of the AKT/mTOR and Ras/MAPK pathways, but not with β-catenin mutation or activation. Altogether, the present data indicate that SKP2 cooperates with N-Ras and AKT proto-oncogenes to promote hepatocarcinogenesis in vivo.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4385847PMC
http://dx.doi.org/10.18632/oncotarget.2945DOI Listing
February 2015

4EBP1/eIF4E and p70S6K/RPS6 axes play critical and distinct roles in hepatocarcinogenesis driven by AKT and N-Ras proto-oncogenes in mice.

Hepatology 2015 Jan 25;61(1):200-13. Epub 2014 Nov 25.

Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA.

Unlabelled: Concomitant expression of activated forms of v-akt murine thymoma viral oncogene homolog (AKT) and Ras in mouse liver (AKT/Ras) leads to rapid tumor development through strong activation of the mammalian target of rapamycin complex 1 (mTORC1) pathway. mTORC1 functions by regulating p70S6K/ribosomal protein S6 (RPS6) and eukaryotic translation initiation factor 4E-binding protein 1/ eukaryotic translation initiation factor 4E (4EBP1/eIF4E) cascades. How these cascades contribute to hepatocarcinogenesis remains unknown. Here, we show that inhibition of the RPS6 pathway by rapamycin effectively suppressed, whereas blockade of the 4EBP1/eIF4E cascade by 4EBP1A4, an unphosphorylatable form of 4EBP1, significantly delayed, AKT/Ras-induced hepatocarcinogenesis. Combined treatment with rapamycin and 4EBP1A4 completely inhibited AKT/Ras hepatocarcinogenesis. This strong antineoplastic effect was successfully recapitulated by ablating regulatory associated protein of mTORC1, the major subunit of mTORC1, in AKT/Ras-overexpressing livers. Furthermore, we demonstrate that overexpression of eIF4E, the proto-oncogene whose activity is specifically inhibited by 4EBP1, resulted in hepatocellular carcinoma (HCC) development in cooperation with activated Ras. Mechanistically, we identified the ectonucleoside triphosphate diphosphohydrolase 5/ adenylate kinase 1/cytidine monophosphate kinase 1 axis and the mitochondrial biogenesis pathway as targets of the 4EBP1/eIF4E cascade in AKT/Ras and Ras/eIF4E livers as well as in human HCC cell lines and tissues.

Conclusions: Complete inhibition of mTORC1 is required to suppress liver cancer development induced by AKT and Ras proto-oncogenes in mice. The mTORC1 effectors, RPS6 and eIF4E, play distinct roles and are both necessary for AKT/Ras hepatocarcinogenesis. These new findings might open the way for innovative therapies against human HCC.
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http://dx.doi.org/10.1002/hep.27396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4280310PMC
January 2015