Publications by authors named "Cuiping Yang"

51 Publications

PLEKHO2 inhibits TNFα-induced cell death by suppressing RIPK1 activation.

Cell Death Dis 2021 Jul 16;12(8):714. Epub 2021 Jul 16.

Department of Biomedical Engineering, the Fifth medical Centre, Chinese PLA General Hospital, Beijing, 100071, China.

Receptor interaction protein kinase 1 (RIPK1) plays a diverse role in tumor necrosis factor α (TNFα) signalings. The ubiquitination of RIPK1 is essential for NF-κB activation, whereas its kinase activity promotes apoptosis and necroptosis. However, the mechanisms underlying have not been fully illuminated. Here we report that PH domain-containing family O member 2 (PLEKHO2) inhibits RIPK1-dependent cell death and is necessary for NF-κB activation in response to TNFα. Cells of PLKEHO2 deficiency are more susceptible to TNF-α induced apoptosis and necroptosis with increased RIPK1 activation, which is consistent with the observation that the susceptibility of PLEKHO2-/- cells is effectively prevented by treatment of RIPK1 kinase inhibitor. Moreover, PLEKHO2 deficient cells exhibit compromised RIPK1 ubiquitination and NF-κB activation in response to TNFα. Ultimately, PLEKHO2-deficient mice display greatly increased hepatotoxicity and lethality after TNFα-induced hepatitis. In summary, our study revealed that PLEKHO2 is a novel inhibitor of apoptosis and necroptosis, which plays a key role in regulating RIPK1 ubiquitination and activation.
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http://dx.doi.org/10.1038/s41419-021-04001-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285381PMC
July 2021

miR-133b targets NCAPH to promote β-catenin degradation and reduce cancer stem cell maintenance in non-small cell lung cancer.

Signal Transduct Target Ther 2021 Jul 7;6(1):252. Epub 2021 Jul 7.

Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China.

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http://dx.doi.org/10.1038/s41392-021-00555-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260594PMC
July 2021

PirB functions as an intrinsic suppressor in hippocampal neural stem cells.

Aging (Albany NY) 2021 06 13;13(12):16062-16071. Epub 2021 Jun 13.

Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan 650223, China.

Neural stem cells play pivotal roles during prenatal development and throughout life. Here, we report that Paired immunoglobulin-like receptor B (PirB) functions as a suppressor during brain neurogenesis in the adult mouse. PirB expression increased with age during development, and its deficiency promoted neural stem cell proliferation and differentiation and . Furthermore, we detected an increase in Type 1 neural stem cells in PirB-deficient mice compared to their wild-type littermates. PirB deficiency promoted stemness marker gene expression of Sox2 and KLF4 by activating Akt1 phosphorylation. These findings suggest that PirB inhibits the self-renewal and differentiation capacities of neural stem cells. Thus, PirB may have the potential to serve as a therapeutic target for treatment of reduced neurogenesis in adults due to aging or other pathological conditions.
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http://dx.doi.org/10.18632/aging.203134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266311PMC
June 2021

A single mutation underlying phenotypic convergence for hypoxia adaptation on the Qinghai-Tibetan Plateau.

Cell Res 2021 Jun 7. Epub 2021 Jun 7.

State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China.

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http://dx.doi.org/10.1038/s41422-021-00517-6DOI Listing
June 2021

Ivacaftor Inhibits Glioblastoma Stem Cell Maintenance and Tumor Progression.

Front Cell Dev Biol 2021 11;9:678209. Epub 2021 May 11.

Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, China.

Glioblastoma (GBM) is the most common and malignant primary brain tumor. Glioblastoma stem cells (GSCs) not only initiate and sustain uncontrolled cell proliferation but also resistant to conventional clinical therapies including temozolomide (TMZ) dependent chemotherapy and radiotherapy, implying that there is an urgent need to identify new therapeutic strategies especially specific targeting GSCs. Here, we provide evidence showing that ivacaftor commonly applied in cystic fibrosis therapy acts as a potent inhibitor for GSCs maintenance. We found that ivacaftor promotes cellular apoptosis and represses patient-derived xenograft (PDX) tumor growth . In addition, we demonstrate that ivacaftor decreases stemness marker gene expressions of GSCs, including CD133, CD44, and Sox2. In summary, our findings reveal that ivacaftor inhibits glioblastoma progression via specifically eliminating GSCs, which opens a new avenue for GBM clinical therapy in the future.
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http://dx.doi.org/10.3389/fcell.2021.678209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8147559PMC
May 2021

Post-Translational Regulations of Foxp3 in Treg Cells and Their Therapeutic Applications.

Front Immunol 2021 12;12:626172. Epub 2021 Apr 12.

Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Science, Shenzhen, China.

Regulatory T (Treg) cells are indispensable for immune homeostasis due to their roles in peripheral tolerance. As the master transcription factor of Treg cells, Forkhead box P3 (Foxp3) strongly regulates Treg function and plasticity. Because of this, considerable research efforts have been directed at elucidating the mechanisms controlling Foxp3 and its co-regulators. Such work is not only advancing our understanding on Treg cell biology, but also uncovering novel targets for clinical manipulation in autoimmune diseases, organ transplantation, and tumor therapies. Recently, many studies have explored the post-translational regulation of Foxp3, which have shown that acetylation, phosphorylation, glycosylation, methylation, and ubiquitination are important for determining Foxp3 function and plasticity. Additionally, some of these targets have been implicated to have great therapeutic values. In this review, we will discuss emerging evidence of post-translational regulations on Foxp3 in Treg cells and their exciting therapeutic applications.
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http://dx.doi.org/10.3389/fimmu.2021.626172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071870PMC
April 2021

The role of m6A modification in the biological functions and diseases.

Signal Transduct Target Ther 2021 Feb 21;6(1):74. Epub 2021 Feb 21.

Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, 650223, Kunming, Yunnan, China.

N-methyladenosine (m6A) is the most prevalent, abundant and conserved internal cotranscriptional modification in eukaryotic RNAs, especially within higher eukaryotic cells. m6A modification is modified by the m6A methyltransferases, or writers, such as METTL3/14/16, RBM15/15B, ZC3H3, VIRMA, CBLL1, WTAP, and KIAA1429, and, removed by the demethylases, or erasers, including FTO and ALKBH5. It is recognized by m6A-binding proteins YTHDF1/2/3, YTHDC1/2 IGF2BP1/2/3 and HNRNPA2B1, also known as "readers". Recent studies have shown that m6A RNA modification plays essential role in both physiological and pathological conditions, especially in the initiation and progression of different types of human cancers. In this review, we discuss how m6A RNA methylation influences both the physiological and pathological progressions of hematopoietic, central nervous and reproductive systems. We will mainly focus on recent progress in identifying the biological functions and the underlying molecular mechanisms of m6A RNA methylation, its regulators and downstream target genes, during cancer progression in above systems. We propose that m6A RNA methylation process offer potential targets for cancer therapy in the future.
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http://dx.doi.org/10.1038/s41392-020-00450-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897327PMC
February 2021

Spatiotemporal drought analysis by the standardized precipitation index (SPI) and standardized precipitation evapotranspiration index (SPEI) in Sichuan Province, China.

Sci Rep 2021 01 14;11(1):1280. Epub 2021 Jan 14.

Institute of Environment Remediation and Human Health, Southwest Forestry University, Kunming, 650224, Yunnan, China.

Drought refers to a meteorological disaster that causes insufficient soil moisture and damage to crop water balance due to long-term lack of precipitation. With the increasing shortage of water resources, drought has become one of the hot issues of global concern. The standardized precipitation index (SPI) and standardized precipitation evapotranspiration index (SPEI) can effectively reflect the changes in drought characteristics of different geomorphologies in Sichuan on time and space scales, to explore the difference in drought characteristics between different physiognomy types in Sichuan Province, We calculated the SPI and SPEI values based on the data of 44 meteorological stations in Sichuan Province from 1961 to 2019 and used Mann-Kendall trend test and multivariable linear regression method (MLR) to quantify the significance of the drought characteristic trends at different time and space scales. The results as follow: (1) The SPEI drought trend in plain and hilly regions was greater than that in plateau and mountain regions on all time scales (- 0.039 year for 1-month in hilly, - 0.035 year for 1-month in plain, - 0.14 year for 1-month in plateau, - 0.026 year for 1-month in mountain) and the magnitude of trend of eastern (- 4.4 to 0.1 year) was lager than western (- 2.1 to 2.7 year), means that the drought trends transfer from northwest to east. (2) The drought intensity in the western region gradually increased (0.54-1.05) and drought events mainly occurred in the southwest plateau and central mountainous regions (24-47 times), means that drought meteorological hotspots were mainly concentrated in the Sichuan basin. (3) The MLR indicated altitude (H) is not the main influencing factor that causes the spatial unevenness of precipitation in Sichuan Province, but altitude (H), temperature (T), longitude (L) and latitude (L) can co-determined the precipitation. The results of this study are instructive and practical for drought assessment, risk management and application decision-making in Sichuan Province, and have guiding significance for agricultural disaster prevention, mitigation and agricultural irrigation in Sichuan Province.
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http://dx.doi.org/10.1038/s41598-020-80527-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809205PMC
January 2021

Research Progress of Herbal Medicines on Drug Metabolizing Enzymes: Consideration Based on Toxicology.

Curr Drug Metab 2020 ;21(12):913-927

New Drug Safety Evaluation Center, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China.

The clinical application of herbal medicines is increasing, but there is still a lack of comprehensive safety data and in-depth research into mechanisms of action. The composition of herbal medicines is complex, with each herb containing a variety of chemical components. Each of these components may affect the activity of metabolizing enzymes, which may lead to herb-drug interactions. It has been reported that the combined use of herbs and drugs can produce some unexpected interactions. Therefore, this study reviews the progress of research on safety issues caused by the effects of herbs on metabolizing enzymes with reference to six categories of drugs, including antithrombotic drugs, non-steroidal anti-inflammatory drugs, anti-diabetic drugs, statins lipid-lowering drugs, immunosuppressants, and antineoplastic drugs. Understanding the effects of herbs on the activity of metabolizing enzymes could help avoid the toxicity and adverse drug reactions resulting from the co-administration of herbs and drugs, and help doctors to reduce the risk of prescription incompatibility.
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http://dx.doi.org/10.2174/1389200221999200819144204DOI Listing
January 2020

Multitarget stool DNA test compared with fecal occult blood test for colorectal cancer screening.

Oncol Lett 2020 Aug 25;20(2):1193-1200. Epub 2020 May 25.

Department of Gastroenterology, Shanghai Jiao Tong University, School of Medicine, Ruijin Hospital North, Shanghai 201800, P.R. China.

Patient screening is important for early diagnosis of colorectal cancer (CRC). The present study aimed to compare the multitarget stool DNA (mt-sDNA) test with the fecal occult blood test (FOBT) for CRC screening. A total of 151 individuals were screened using colonoscopy, mt-sDNA and FOBT for the detection of CRC and adenoma. The results of the mt-sDNA test and FOBT were compared with colonoscopy to examine their sensitivity and specificity. Subsequently, the sensitivity and specificity of the mt-sDNA test were compared with those of FOBT in CRC and large adenoma. Stool samples were collected from patients with CRC (n=50) or large adenoma (n=51), as well as from normal controls (n=50). The mt-sDNA test outperformed FOBT in detecting CRC with a sensitivity of 90.0% (45/50) vs. 42.0% (21/50), advanced adenoma with a sensitivity of 70.6% (36/51) vs. 19.6% (10/51), stage I-III CRC with a sensitivity of 91.9% (34/37) vs. 29.7% (11/37), and stage IV CRC with a sensitivity of 84.6% (11/13) vs. 76.9% (10/13). In addition, the mt-sDNA test exhibited a specificity of 94.0% (47/50) in detecting CRC, which was superior to FOBT with a specificity of 90.0% (45/50). Therefore, the mt-sDNA test may have higher sensitivity and specificity compared with FOBT in diagnosing both CRC and advanced adenoma.
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http://dx.doi.org/10.3892/ol.2020.11674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7377198PMC
August 2020

Experimental study on the movement of heavy metal Zn in paddy soil under different irrigation quota of reclaimed water.

Sci Rep 2020 07 1;10(1):10789. Epub 2020 Jul 1.

Ecology and Environment Department, Southwest Forestry University, Kunming, 650224, China.

To reveal the mechanism of heavy metal Zn migration in the irrigated paddy field reclaimed water, this study investigated irrigation quota of 75, 150, 225 and 300 m/hm for three consecutive years. The results showed that with the same irrigation quota, firstly the content of Zn, its variation and the rate of change in soil increased, and hereafter decreased with the increase of soil depth, and finally become stable of reclaimed water. Study results identified that when the irrigation quota was 75, 150, 225 and 300 m/hm, the average content of Zn in the soil reached the maximum with the value of 9.60, 12.10, 16.75 and 18.50 mg/kg respectively at the depth of 30 cm. The average content of Zn in soil found maximum values of 13.51, 16.01, 19.02 and 20.98 mg/kg, respectively on the 120th day of cultivation. This study also identified that the content of Zn, its variation and the rate of change increased with the increase of irrigation quota at the same soil depth. Additionally, when the soil depth or plant growth time was the same, the content of Zn, its variation and the rate of change increased with the increase of irrigation quota. However, at the soil depth of 30 cm, the content of Zn in the irrigation quota of 75, 150 and 225 m/hm decreased by 48.11%, 34.59% and 9.46%. The fertility time of 120 days also decreased by 35.71%, 23.81% and 9.52% respectively compared to an irrigation quota of 300 m/hm. All the findings are explored by a nonlinear regression under different situations and timing. The mean value of the standard error between the statistical and measured value is found insignificant. However, the correlation coefficient is found greater than 0.9400 and statistically significant. Thus, the findings by nonlinear regression reflected the migration law of soil Zn duly with soil depth and plant growth time in the rice field. This study provided theoretical support for the comprehensive treatment and ecological restoration of heavy metals to the farmland soil in China.
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http://dx.doi.org/10.1038/s41598-020-67777-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7329861PMC
July 2020

Hypoxia and cancer related pathology.

Cancer Lett 2020 08 19;486:1-7. Epub 2020 May 19.

Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, 650223, China; Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, Yunnan, 650223, China. Electronic address:

Hypoxic environments occur normally at high altitude, or in underground burrows and in deep sea habitats. They also occur pathologically in human ischemia and in hypoxic solid tumors. Hypoxia in various cancer types and its related molecular mechanisms are associated with a poor clinical outcome. This review will discuss how hypoxia can influence two aspects of tumorigenesis, namely the direct, cell-intrinsic oncogenic effects, as well as the indirect effects on tumor progression mediated by an altered tumor microenvironment. We will also discuss recent progress in identifying the functional roles of hypoxia-related factors (HIFs), along with their regulators and downstream target genes, in cancer stem cells and therapy. Importantly, we propose, using convergent evolution schemes to identify novel biomarkers for both hypoxia adaptation and hypoxic solid tumors as an important strategy in the future.
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http://dx.doi.org/10.1016/j.canlet.2020.05.002DOI Listing
August 2020

Pharmacokinetics and Metabolism of Naringin and Active Metabolite Naringenin in Rats, Dogs, Humans, and the Differences Between Species.

Front Pharmacol 2020 27;11:364. Epub 2020 Mar 27.

Guangdong Engineering and Technology Research Center for Quality and Efficacy Re-evaluation of Post-Marketed Traditional Chinese Medicine, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.

Background: Pharmacokinetics provides a scientific basis for drug product design, dosage regimen planning, understanding the body's action on the drug, and relating the time course of the drug in the body to its pharmacodynamics and/or toxic effects. Recently, naringin, a natural flavonoid, was approved for clinical trials as a first-class new drug product by the China Food and Drug Administration, owing to its nonclinical efficacy in relieving cough, reducing sputum, and low toxicity. Previous reports focused on the pharmacokinetic studies of naringin or its active metabolite naringenin in rats, which were scattered and insufficient because naringin was coadministered with mixtures such as herbs, fruits, and other traditional medicines. The purpose of this study was to evaluate the pharmacokinetics and metabolism of naringin and naringenin, following oral and intravenous administration of naringin in rats, dogs, and humans, which can be beneficial for new drug development.

Methods: Separate bioanalytical methods were developed and validated to determine the concentrations of naringin and its active metabolite naringenin in biological samples obtained from rats, dogs, and humans. Comprehensive nonclinical and clinical data were used to estimate the pharmacokinetic parameters of naringin and naringenin. Experiments included single-dose studies (oral and intravenous administration), multiple-dose studies, and an assessment of food-effects. Furthermore, the metabolism of naringin and naringenin was studied in rat and human liver and kidney microsomes. All biological samples were analyzed using liquid chromatography-tandem mass spectrometry.

Results: The pharmacokinetic parameters of naringin and naringenin were calculated and the results show an insignificant influence of high-fat diet and insignificant accumulation of the drugs after multiple dosing. Twelve metabolites were detected in the liver and kidney microsomes of rats and humans; naringin metabolism was a complex process simultaneously catalyzed by multiple human enzymes. All evaluated species demonstrated differences in the pharmacokinetics and metabolism of naringin and naringenin.

Conclusion: The results can be used to design a dosage regimen, deepen understanding of mechanisms, and accelerate new drug development.

Clinical Trial Registration: http://www.chinadrugtrials.org.cn/eap/main, identifiers CTR20130704 and CTR20190127.
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http://dx.doi.org/10.3389/fphar.2020.00364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118210PMC
March 2020

PAQR4 promotes chemoresistance in non-small cell lung cancer through inhibiting Nrf2 protein degradation.

Theranostics 2020 19;10(8):3767-3778. Epub 2020 Feb 19.

Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan 650223, China.

Lung cancer is the leading cause of cancer related deaths worldwide. We have previously identified many differentially expressed genes (DEGs) from large scale pan-cancer dataset using the Cross-Value Association Analysis (CVAA) method. Here we focus on Progestin and AdipoQ Receptor 4 (PAQR4), a member of the progestin and adipoQ receptor (PAQR) family localized in the Golgi apparatus, to determine their clinical role and mechanism in the development of non-small cell lung cancer (NSCLC). The protein expression profile of PAQR4 was examined by IHC using tissue microarrays, and the effects of PAQR4 on cell proliferation, colony formation and xenograft tumor formation were tested in NSCLC cells. Real-time RT-PCR, co-immunoprecipitation (co-IP) and GST-pulldown assays were used to explore the mechanism of action of PAQR4. We provided evidence showing that PAQR4 is increased in NSCLC cancer cell lines (A549, H1299, H1650, H1975, H358, GLC-82 and SPC-A1), and identified many mutations in PAQR4 in non-small cell lung cancer (NSCLC) tissues. We demonstrated that PAQR4 high expression correlates with a worse clinical outcome, and that its knockdown suppresses cell proliferation by inducing apoptosis. Importantly, overexpressed PAQR4 physically interacts with Nrf2 in NSCLC cells, blocking the interaction between Nrf2 and Keap1. Our results suggest that PAQR4 depletion enhances the sensitivity of cancerous cell to chemotherapy both and xenograft tumor formation , by promoting Nrf2 protein degradation through a Keap1-mediated ubiquitination process.
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http://dx.doi.org/10.7150/thno.43142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069097PMC
May 2021

Study on antibiotic susceptibility of Salmonella typhimurium L forms to the third and forth generation cephalosporins.

Sci Rep 2020 02 20;10(1):3042. Epub 2020 Feb 20.

Department of Microbiology, Bengbu Medical College, Bengbu, Anhui, 233030, P.R. China.

Salmonella typhimurium is a pathogenic gram-negative bacterium, which is found primarily in the intestinal lumen. It often causes diarrhea in infants and young children and leads to food poisoning. Drug resistance of Salmonella typhimurium presented serious complications in clinical patients. In this study, we investigated the antibiotic susceptibility of Salmonella typhimurium standard strain L forms to the third and forth generation cephalosporins, in order to control and eliminate Salmonella typhimurium L forms in infection treatment. Salmonella typhimurium L forms were induced by β-lactam antibiotic cefazolin in the culture medium of bacterial L forms. The antibiotic susceptibility of Salmonella typhimurium L forms was analyzed by K-B drug susceptibility testing. The change trend of drug susceptibility and resistance of Salmonella typhimurium L forms was obtained in accordance with USA clinical and laboratory standards institute (CLSI) evaluation data and statistical analysis. Drug resistance of Salmonella typhimurium L forms showed little increasing trend compared with their parent bacteria. The L form inhibition zone was smaller than in the parent bacteria. However, the drug susceptibility of L forms of Salmonella typhimurium to the third and forth generation cephalosporins remained sensitive.The antibiotic susceptibility of Salmonella typhimurium L forms to the third and forth generation cephalosporins remains sensitive, and the combined use of multi-antibiotics is a convenient and effective method to reduce Salmonella typhimurium L forms occurrence.
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http://dx.doi.org/10.1038/s41598-020-59456-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033113PMC
February 2020

Roles for IFT172 and Primary Cilia in Cell Migration, Cell Division, and Neocortex Development.

Front Cell Dev Biol 2019 26;7:287. Epub 2019 Nov 26.

State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, China.

The cilium of a cell translates varied extracellular cues into intracellular signals that control embryonic development and organ function. The dynamic maintenance of ciliary structure and function requires balanced bidirectional cargo transport involving intraflagellar transport (IFT) complexes. IFT172 is a member of the IFT complex B, and IFT172 mutation is associated with pathologies including short rib thoracic dysplasia, retinitis pigmentosa and Bardet-Biedl syndrome, but how it underpins these conditions is not clear. We used the WIM cell line, derived from embryonic fibroblasts of mice (carrying homozygous Leu1564Pro mutation in Ift172), to probe roles of Ift172 and primary cilia in cell behavior. WIM cells had ablated cilia and deficiencies in directed migration (electrotaxis), cell proliferation and intracellular signaling. Additionally, WIM cells displayed altered cell cycle progression, with increased numbers of chromatids, highlighting dysfunctional centrosome status. Exposure to a physiological electric field promoted a higher percentage of primary cilia in wild-type cells. Interestingly, hybridization revealed an extensive and dynamic expression profile of Ift172 in both developing and adult mouse cortex. manipulation of Ift172 expression in germinal regions of embryonic mouse brains perturbed neural progenitor proliferation and radial migration of post-mitotic neurons, revealing a regulatory role of Ift172 in cerebral morphogenesis. Our data suggest that Ift172 regulates a range of fundamental biological processes, highlighting the pivotal roles of the primary cilium in cell physiology and brain development.
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http://dx.doi.org/10.3389/fcell.2019.00287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6890611PMC
November 2019

YTHDF1 links hypoxia adaptation and non-small cell lung cancer progression.

Nat Commun 2019 10 25;10(1):4892. Epub 2019 Oct 25.

Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, 650223, China.

Hypoxia occurs naturally at high-altitudes and pathologically in hypoxic solid tumors. Here, we report that genes involved in various human cancers evolved rapidly in Tibetans and six Tibetan domestic mammals compared to reciprocal lowlanders. Furthermore, mA modified mRNA binding protein YTHDF1, one of evolutionary positively selected genes for high-altitude adaptation is amplified in various cancers, including non-small cell lung cancer (NSCLC). We show that YTHDF1 deficiency inhibits NSCLC cell proliferation and xenograft tumor formation through regulating the translational efficiency of CDK2, CDK4, and cyclin D1, and that YTHDF1 depletion restrains de novo lung adenocarcinomas (ADC) progression. However, we observe that YTHDF1 high expression correlates with better clinical outcome, with its depletion rendering cancerous cells resistant to cisplatin (DDP) treatment. Mechanistic studies identified the Keap1-Nrf2-AKR1C1 axis as the downstream mediator of YTHDF1. Together, these findings highlight the critical role of YTHDF1 in both hypoxia adaptation and pathogenesis of NSCLC.
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http://dx.doi.org/10.1038/s41467-019-12801-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814821PMC
October 2019

miR-200c overexpression inhibits the invasion and tumorigenicity of epithelial ovarian cancer cells by suppressing lncRNA HOTAIR in mice.

J Cell Biochem 2020 02 18;121(2):1514-1523. Epub 2019 Sep 18.

Department of Geriatrics, Ruijin Hospital North, Shanghai Jiaotong University School of Medicine, Shanghai, China.

Epithelial ovarian cancer (EOC) is a common ovarian cancer in gynecological cancers today. It has been found that microRNAs and long-chain noncoding RNA (lncRNA) regulate the gene transcriptional expression in cells. However, it is not well understood that the upstream and downstream regulatory molecules of lncRNA HOX antisense intergenic RNA (HOTAIR). The effects of miR-200c overexpression on the invasion and nude mouse tumorigenicity, as well as lncRNA HOTAIR and snail expression of EOC SKOV3 cells, should be further explored. The expression of miR-200c and lncRNA HOTAIR was detected by reverse transcription PCR (RT-PCR) in EOC SKOV3 cells. The whole miR-200c gene fragment was cloned into a lentiviral plasmid vector. The miR-200c expression in transducted SKOV3 cells with reconstructed miR-200c lentivirus was significantly higher than the negative control (P < .01). The lentivirus-miR-200c-SKOV3 cells show that the invasion ability was significantly decreased compared with the negative control (P < .01). The nude mouse tumorigenicity was significantly decreased compared with that of the control group (P < .01). The snail protein expression in lentivirus-miR-200c-SKOV3 xenograft tumor was significantly decreased compared with the negative control lentivirus-SKOV3 group (P < .05). The miR-200c overexpression significantly decreased the expressions of lncRNA HOTAIR and snail, but increased E-cadherin expression in the lentivirus-miR-200c transducted SKOV3 cells of xenograft tumor, compared with the negative control (P < .05). The miR-200c overexpression in SKOV3 cells with transducted lentivirus-miR-200c can inhibit lncRNA HOTAIR expression, decrease snail, increase E-cadherin and significantly reduce the invasion and tumorigenicity of EOC SKOV3 cells. These results suggest that the miR-200c and lncRNA HOTAIR could be effective therapeutic targets for human epithelial ovarian cancer treatment.
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http://dx.doi.org/10.1002/jcb.29387DOI Listing
February 2020

A review of medical image detection for cancers in digestive system based on artificial intelligence.

Expert Rev Med Devices 2019 Oct 30;16(10):877-889. Epub 2019 Sep 30.

Institute of Biomedical Manufacturing and Life Quality Engineering, State Key Laboratory of Mechanical System and Vibration, School of Mechanical Engineering, Shanghai Jiao Tong University , Shanghai , China.

: At present, cancer imaging examination relies mainly on manual reading of doctors, which requests a high standard of doctors' professional skills, clinical experience, and concentration. However, the increasing amount of medical imaging data has brought more and more challenges to radiologists. The detection of digestive system cancer (DSC) based on artificial intelligence (AI) can provide a solution for automatic analysis of medical images and assist doctors to achieve high-precision intelligent diagnosis of cancers. : The main goal of this paper is to introduce the main research methods of the AI based detection of DSC, and provide relevant reference for researchers. Meantime, it summarizes the main problems existing in these methods, and provides better guidance for future research. : The automatic classification, recognition, and segmentation of DSC can be better realized through the methods of machine learning and deep learning, which minimize the internal information of images that are difficult for humans to discover. In the diagnosis of DSC, the use of AI to assist imaging surgeons can achieve cancer detection rapidly and effectively and save doctors' diagnosis time. These can lay the foundation for better clinical diagnosis, treatment planning and accurate quantitative evaluation of DSC.
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http://dx.doi.org/10.1080/17434440.2019.1669447DOI Listing
October 2019

Role of Nrf2 in the antioxidation and oxidative stress induced developmental toxicity of honokiol in zebrafish.

Toxicol Appl Pharmacol 2019 06 3;373:48-61. Epub 2019 May 3.

New Drug Safety Evaluation Center, Institute of Materia Medica, Chinese Academy of Medical Sciences, Beijing 100050, China; Beijing Union-Genious Pharmaceutical Technology Ltd., Beijing 100176, China. Electronic address:

Honokiol, the main bioactive component of Magnolia officinalis, has a variety of pharmacological actions. However, its toxicity has rarely been reported. According to previous studies performed in our laboratory, honokiol microemulsion has embryo developmental toxicity. For further exploration, Zebrafish embryos were exposed to different doses of honokiol microemulsion to record the rates of mortality, malformation, and hatching. We found that high doses of honokiol microemulsion (0.6 and 0.9 μg/ml) increased mortality, inhibited hatching, caused malformation and reduced swimming activities. The low-dose group (0.15 and 0.30 μg/ml) had decreased production of reactive oxygen species (ROS), but the high-dose group had inhibited superoxide dismutase (SOD) enzyme activity and increased ROS content. The mRNA expression of sod1, sod2, catalase(cat), and heme oxygenase 1 (ho1) was up-regulated at low doses but down-regulated at high doses. The nuclear factor E2-related factor 2 (Nrf2) mRNA expression increased at low doses but decreased at high doses. After knocking down Nrf2 in zebrafish embryos, the rates of mortality and malformation were markedly increased and the hatching rate was significantly decreased. These results suggest that honokiol has antioxidative effects at low doses but causes embryo-developmental toxicity at high doses, and the Nrf2 gene may play a pivotal role in regulating these processes.
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http://dx.doi.org/10.1016/j.taap.2019.04.016DOI Listing
June 2019

A rapid and efficient analytical method for the quantification of a novel anticholinergic compound, R-phencynonate, by stable isotope-dilution LC-MS/MS and its application to bioavailability and dose proportionality studies.

Biomed Chromatogr 2017 May 5;31(5). Epub 2017 Feb 5.

State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, People's Republic of China.

A rapid, specific and high-throughput stable isotope-dilution LC-MS/MS method was developed and validated with high sensitivity for the quantification of R-phencynonate (a eutomer of phencynonate racemate) in rat and dog plasma. Plasma samples were deproteinized using acetonitrile and then separated on a C column with an isocratic mobile phase containing acetonitrile-water-formic acid mixture (60:40:0.1, v/v/v) at a flow rate of 0.2 mL/min. Each sample had a total run time of 3 min. Quantification was performed using triple quadrupole mass spectrometry in selected reaction monitoring mode with positive electrospray ionization. The method was shown to be highly linear (r  > 0.99) and to have a wide dynamic range (0.1-100 ng/mL) with favourable accuracy and precision. No matrix effects were observed. The detailed pharmacokinetic profiles of R-phencynonate at therapeutic doses in rats and dogs were characterized by rapid oral absorption, quick clearance, high volume of distribution and poor absolute bioavailability. R-Phencynonate lacked dose proportionality over the oral dose range, based on the power model. However, the area under concentration-time curve and the maximum plasma concentration increased linearly in a dose-dependent manner in both animal models. The absolute bioavailability of R-phencynonate was 16.6 ± 2.75 and 4.78 ± 1.26% in dogs and rats, respectively.
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http://dx.doi.org/10.1002/bmc.3879DOI Listing
May 2017

Polymeric micelles with α-glutamyl-terminated PEG shells show low non-specific protein adsorption and a prolonged in vivo circulation time.

Mater Sci Eng C Mater Biol Appl 2016 Feb 28;59:766-772. Epub 2015 Oct 28.

State Key Laboratory of Toxicology and Medical Countermeasures, and Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China. Electronic address:

Although PEG remains the gold standard for stealth functionalization in drug delivery field up to date, complete inhibition of protein corona formation on PEG-coated nanoparticles remains a challenge. To improve the stealth property of PEG, herein an α-glutamyl group was conjugated to the end of PEG and polymeric micelles with α-glutamyl-terminated PEG shells were prepared. After incubation with bovine serum albumin or in fetal calf serum, the size of the micelles changed slightly, while the size of the micelles of similar diblock copolymer but without α-glutamyl group increased markedly. These results indicated that the micelles with α-glutamyl-terminated PEG shells showed low non-specific protein adsorption. In vivo blood clearance kinetics assay showed that the micelles with α-glutamyl-terminated PEG shells exhibited a longer in vivo blood circulation time compared with similar micelles but without α-glutamyl groups. The better stealth property of the micelles with α-glutamyl-terminated PEG shells was presumably attributed to the zwitterionic property of the α-glutamyl groups.
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http://dx.doi.org/10.1016/j.msec.2015.10.084DOI Listing
February 2016

Target therapy of multiple myeloma by PTX-NPs and ABCG2 antibody in a mouse xenograft model.

Oncotarget 2015 Sep;6(29):27714-24

School of Biological Science & Medical Engineering & Collaborative Innovation Center of Suzhou NanoScience and Technology, Southeast University, Nanjing 210096, China.

Multiple myeloma (MM) remains to be an incurable disease. The purpose of this study was to evaluate the effect of ABCG2 monoclonal antibody (McAb) combined with paclitaxel (PTX) conjugated with Fe3O4 nanoparticles (NPs) on MM progressed from cancer stem cells (CSCs) in non-obese-diabetic/severe-combined-immunodeficiency (NOD/SCID) mouse model. Mice were injected with MM CSCs as marked by CD138-CD34- phenotypes through tail veins. The developed MM mice were examined by micro-computer tomography scanning, ultrasonography and enzyme-linked immunosorbent analysis. These mice were then intravenously treated with different combinations of NPs, PTX, McAb, PTX-NPs and melphalan/prednisone once a week for four weeks. The injected mice developed characteristic MM-associated syndromes, including lytic bone lesions, renal damages and proteinuria. All the treated mice showed decrease in bone lesions, renal damages and anemia but increase in apoptosis compared with the mice treated with NPs only. In particular, the treatment with ABCG2 McAb plus PTX-NPs induced the strongest therapeutic response and had an efficacy even better than that of melphalan/prednisone, a conventional regimen for MM patients. These data suggest that PTX-NPs with ABCG2 McAb can be developed into potential treatment regimens for patients with relapsed/refractory MM.
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http://dx.doi.org/10.18632/oncotarget.4663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4695020PMC
September 2015

Liquid chromatography-tandem mass spectrometry determination and pharmacokinetic analysis of amentoflavone and its conjugated metabolites in rats.

J Agric Food Chem 2015 Feb 16;63(7):1957-66. Epub 2015 Feb 16.

Beijing Institute of Pharmacology and Toxicology , 27 Taiping Road, Haidian District, Beijing, 100850 P. R. China.

Amentoflavone (AMF) is a biflavone found in many herbal dietary supplements. To investigate the pharmacokinetic profile of AMF in rats, a sensitive, simple, and accurate liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and used to monitor AMF and its conjugated metabolites in plasma. AMF was administered to rats by oral gavage (po), or by intravenous (iv) or intraperitoneal (ip) injection. Plasma samples (with apiolin as an internal standard) were liquid/liquid extracted after hydrolysis with β-glucuronidase/sulfatase in vitro. Following chromatographic separation on a C18 column with a methanol:water:formic acid (70:30:0.1, v/v/v) mobile phase, AMF and internal standard were determined by electrospray ionization in negative ion mode and their precursor-product ion pairs (m/z 537.1 → 374.9 and m/z 269.2 → 224.9, respectively) were used for measurement. This bioanalytical method was fully validated and showed good linearity (r(2) > 0.99), wide dynamic range (0.93-930 nmol/L), and favorable accuracy and precision. After iv or ip AMF (10 mg/kg) injection, 73.2% ± 6.29% and 70.2% ± 5.18% of the total AMF detected in plasma was present as conjugated metabolites. Furthermore, AMF and AMF conjugates showed similar time courses with no significant differences in the time to reach the maximum plasma concentration (tmax) and terminal half-life (t1/2) (p > 0.05). Following po AMF administration (300 mg/kg), 90.7% ± 8.3% of the total AMF was circulating as conjugated metabolites. When compared with iv administration (with dose correction), the bioavailability of po AMF was very low (0.04% ± 0.01% for free AMF; 0.16% ± 0.04% for conjugated AMF). Collectively, these data provided a preliminary pharmacokinetic profile for AMF that should inform further evaluations of its biological efficacy and preclinical development.
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http://dx.doi.org/10.1021/jf5019615DOI Listing
February 2015

Gamma-Fe2O3 nanoparticles increase therapeutic efficacy of combination with paclitaxel and anti-ABCG2 monoclonal antibody on multiple myeloma cancer stem cells in mouse model.

J Biomed Nanotechnol 2014 Feb;10(2):336-44

Cancer stem cells (CSCs) are thought to be responsible for the relapse of multiple myeloma (MM). The objective of this study was to target therapy of MM cancer stem cells using [email protected] magnetic nanoparticle combination with paclitaxel and anti-ABCG2 monoclonal antibody, and to evaluate the combined therapeutic efficacy. CSCs were isolated from human MM cell line RPMI 8226 based on negative expression of CD138 and CD34. In vivo and in vitro studies demonstrated that the isolated CD138-CD34- cells displayed certain stem cell characteristics, including significant increase in expression of ABCG2 transporter, proliferation, mobility, drug resistance, clonogenic potential in soft agar media and tumorigenecity in mice. Treatment with nanoparticles, paclitaxel and anti-ABCG2 antibody remarkably inhibited the growth of CD138-CD34- cells in vitro and their derived tumors in xenografts. The inhibition was also correlated with elevated expression of caspase-9, caspase-8 and caspase-3, and down-regulation of NF-KB. Our data indicate that the nanoparticle combination with paclitaxel and anti-ABCG2 monoclonal antibody offers an effective approach to treatment of MM CSCs through an apoptotic pathway.
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http://dx.doi.org/10.1166/jbn.2014.1730DOI Listing
February 2014

Observation of ovarian cancer stem cell behavior and investigation of potential mechanisms of drug resistance in three-dimensional cell culture.

J Biosci Bioeng 2014 Aug 27;118(2):214-22. Epub 2014 Mar 27.

Department of Pathogenic Biology and Immunology, Medical School, Southeast University, Dingjiaqiao 87, Nanjing 210009, China. Electronic address:

Cancer cells behave differently in a three-dimensional (3D) cell culture compared with in the conventional two-dimensional (2D) one. Accumulated evidences indicate that the characteristics of cancer stem cells (CSCs) are different from common cancer cells due to their ability to produce tumors and resist chemoradiation. The objective of this work was to observe CSC behavior and investigate the potential mechanisms of CSC drug resistance in 3D versus 2D in vitro environment. We first demonstrated that the CD44(+)CD117(+)cells isolated from the human epithelial ovarian cancer HO8910 cell line have the properties of CSCs that revealed faster growth, larger tumorsphere and stronger survival potential in the hypoxic environment in 3D cell culture as well as more powerful tumorigenicity in a xenograft mice than the HO8910 cells. The CD44(+)CD117(+)CSCs also exhibited high chemoresistance to anticancer drugs when the cells were incubated with 5-fluorouracil, cisplatin and carboplatin, respectively in 3D versus 2D environment. This might be associated with the high expression of ABCG2, ABCB1 and the high expression of MMP-2 and MMP-9 in CD44(+)CD117(+)CSCs. Overall, these results suggest the advantages of using 3D culture model to accurately display CSC behavior in vitro. 3D model may improve the efficacy of screening anticancer drugs for treatment of ovarian CSCs.
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http://dx.doi.org/10.1016/j.jbiosc.2014.01.008DOI Listing
August 2014

Characterization of preclinical in vitro and in vivo ADME properties and prediction of human PK using a physiologically based pharmacokinetic model for YQA-14, a new dopamine D3 receptor antagonist candidate for treatment of drug addiction.

Biopharm Drug Dispos 2014 Jul 13;35(5):296-307. Epub 2014 Apr 13.

The Key Laboratory of Drug Metabolism and Pharmacokinetics, Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing, 100850, PR China; Department of Pharmacy, The First Affiliated Hospital of PLA, 51 Fucheng Road, Beijing, 10048, PR China.

YQA-14 is a novel and selective dopamine D3 receptor antagonist, with potential for the treatment of drug addiction. However, earlier compounds in its structural class tend to have poor oral bioavailability. The objectives of this study were to characterize the preclinical absorption, distribution, metabolism and excretion (ADME) properties and pharmacokinetics (PK) of YQA-14, then to simulate the clinical PK of YQA-14 using a physiologically based pharmacokinetics (PBPK) model to assess the likelihood of developing YQA-14 as a clinical candidate. For human PK prediction, PBPK models were first built in preclinical species, rats and dogs, for validation purposes. The model was then modified by input of human in vitro ADME data obtained from in vitro studies. The study data showed that YQA-14 is a basic lipophilic compound, with rapid absorption (Tmax ~ 1 h) in both rats and dogs. Liver microsomal clearances and in vivo clearances were moderate in rats and dogs consistent with the moderate bioavailability observed in both species. The PBPK models built for rats and dogs simulated the observed PK data well in both species. The PBPK model refined with human data predicted that YQA-14 would have a clearance of 8.0 ml/min/kg, a volume distribution of 1.7 l/kg and a bioavailability of 16.9%. These acceptable PK properties make YQA-14 an improved candidate for further research and development as a potential dopamine D3R antagonism for the treatment of drug addiction in the clinic.
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http://dx.doi.org/10.1002/bdd.1897DOI Listing
July 2014

Effect of down-regulated transcriptional repressor ZEB1 on the epithelial-mesenchymal transition of ovarian cancer cells.

Int J Gynecol Cancer 2013 Oct;23(8):1357-66

*Department of Pathogenic Biology and Immunology of Medical College, Southeast University, Nanjing, China; †Department of Microbiology, Bengbu Medical School, Bengbu, PR China; and ‡Department of Gynecology and Obstetrics, Zhongda Hospital, Medical School, Southeast University, Nanjing, PR China.

Background: Progress has been made against early events of malignant transformation and drug resistance associated with epithelial ovarian cancer; uncontrolled metastases, however, still accounts for most patient deaths. The molecular mechanism that regulates the process of epithelial ovarian cancer metastases is not yet clearly understood. The purpose of this study was to investigate the effect of down-regulating the transcriptional repressor zinc-finger E-box-binding homeobox 1 (ZEB1) on an epithelial-mesenchymal transition (EMT) of human ovarian cancer SKOV3 cell line in vitro and in vivo.

Methods: The human ovarian cancer cells SKOV3 and HO8910 were transfected with an expression vector-based small hairpin RNA (shRNA) targeting ZEB1 (shZEB1), and the stably transfected cells were selected. Colony-forming, wound-healing, and cellular migration assays were respectively used. The tumorigenicity of shZEB1-SKOV3 was also evaluated in mice.

Results: The shZEB1-SKOV3 and shZEB1-HO8910 cells showed a lower level of ZEB1 expression and weaker cell migration than the control cells. Moreover, down-regulating ZEB1 expression with shRNA in the cells enhanced the expression of miR-200c that acted as a tumor suppressor to inhibit the epithelial-mesenchymal transition of shZEB1-SKOV3 cells and to block shZEB1-SKOV3 cell metastasis in vivo. The shRNA-mediated down-regulation ZEB1 in SKOV3 cells significantly decreased the tumor growth in the xenograft mice.

Conclusion: The shZEB1-mediated down-regulation of the ZEB1 expression in the SKOV3 cells may be considered for future clinical trials.
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http://dx.doi.org/10.1097/IGC.0b013e3182a5e760DOI Listing
October 2013

P-glycoprotein is responsible for the poor intestinal absorption and low toxicity of oral aconitine: in vitro, in situ, in vivo and in silico studies.

Toxicol Appl Pharmacol 2013 Dec 9;273(3):561-8. Epub 2013 Oct 9.

Key Laboratory of Drug Metabolism and Pharmacokinetics, Beijing Institute of Pharmacology and Toxicology, Beijing, China. Electronic address:

Aconitine (AC) is a highly toxic alkaloid from bioactive plants of the genus Aconitum, some of which have been widely used as medicinal herbs for thousands of years. In this study, we systematically evaluated the potential role of P-glycoprotein (P-gp) in the mechanisms underlying the low and variable bioavailability of oral AC. First, the bidirectional transport of AC across Caco-2 and MDCKII-MDR1 cells was investigated. The efflux of AC across monolayers of these two cell lines was greater than its influx. Additionally, the P-gp inhibitors, verapamil and cyclosporin A, significantly decreased the efflux of AC. An in situ intestinal perfusion study in rats showed that verapamil co-perfusion caused a significant increase in the intestinal permeability of AC, from 0.22×10(-5) to 2.85×10(-5) cm/s. Then, the pharmacokinetic profile of orally administered AC with or without pre-treatment with verapamil was determined in rats. With pre-treatment of verapamil, the maximum plasma concentration (Cmax) of AC increased sharply, from 39.43 to 1490.7 ng/ml. Accordingly, a 6.7-fold increase in the area under the plasma concentration-time curve (AUC0-12h) of AC was observed when co-administered with verapamil. In silico docking analyses suggested that AC and verapamil possess similar P-gp recognition mechanisms. This work demonstrated that P-gp is involved in limiting the intestinal absorption of AC and attenuating its toxicity to humans. Our data indicate that potential P-gp-mediated drug-drug interactions should be considered carefully in the clinical application of aconite and formulations containing AC.
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http://dx.doi.org/10.1016/j.taap.2013.09.030DOI Listing
December 2013

Morpholino-decorated long circulating polymeric micelles with the function of surface charge transition triggered by pH changes.

Chem Commun (Camb) 2013 Aug;49(66):7286-8

Key Laboratory of Functional Polymer Materials (Ministry of Education), Institute of Polymer Chemistry, Nankai University, Tianjin 300071, China.

Micelles with surface morpholino groups were stealthy at blood and normal tissue pH (7.4) due to the unprotonated hydrophilic morpholino groups on the surfaces. At tumor pH (<7), the micelle surfaces were positively charged because of the protonation of the morpholino groups, which promoted the cellular uptake of the micelles.
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http://dx.doi.org/10.1039/c3cc43334jDOI Listing
August 2013
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