Publications by authors named "Zhu Man"

74 Publications

TAD1822-7 induces ROS-mediated apoptosis of HER2 positive breast cancer by decreasing E-cadherin in an EphB4 dependent manner.

Life Sci 2021 Sep 11;285:119954. Epub 2021 Sep 11.

School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta West street, #54, Xi'an, Shaanxi Province 710061, PR China. Electronic address:

HER2-positive breast cancer (HER2-BC) shows the over-expression of tyrosine kinase receptor EphB4 associated with poor disease prognosis. E-cadherin is found as a survival factor in multiple models of breast cancer by suppressing reactive oxygen-mediated apoptosis. This study confirmed that both HER2 and EphB4 are positively correlated with E-cadherin in HER2-BC. Inhibition of HER2 or EphB4 is discovered to induce ROS-dependent apoptosis by decreasing E-cadherin expression in SKBR3 and MDA-MB-453 cells. TAD1822-7 (TAD), a novel biphenyl urea taspine derivative, exhibits good growth inhibition, apoptosis induction and ROS accumulation effects on SKBR3 and MDA-MB-453 cells. Mechanistic investigation revealed that TAD blockades both EphB4 positive signal transduction and activation of HER2 signal transduction, thereby suppressing E-cadherin/TGF-β/p-Smad2/3 signaling axis to elicit ROS-dependent endogenous mitochondrial apoptosis. Together, these findings not only provide a new approach for HER2-BC therapy but also increase our understanding of the regulating effect of E-cadherin by HER2 and EphB4 in ROS-mediated apoptosis.
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http://dx.doi.org/10.1016/j.lfs.2021.119954DOI Listing
September 2021

Diterpenoids from the genus Euphorbia: Structure and biological activity (2013-2019).

Phytochemistry 2021 Oct 3;190:112846. Epub 2021 Jul 3.

Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China. Electronic address:

Euphorbiaceae is one of the largest families of higher plants, including 7500 species, and many of them are used as medicines in China. From 2013 to 2019, a total of 455 previously undescribed diterpenoids were isolated from 53 species of Euphorbia, and some skeleton types were first discovered from the genus Euphorbia. Most of the diterpenoids isolated from Euphorbia spp. have been tested for their biological activity, and some of them were first reported for Euphorbia diterpenoids in recent years, such as neuroprotection, antimalarial activity and inhibition of osteoclast formation. In this review, we summarize all the isolated diterpenoids from the genus Euphorbia according to their skeleton types, classify all these diterpenoids into 26 normal classes and 37 novel skeleton types, and summarize their biological activity.
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http://dx.doi.org/10.1016/j.phytochem.2021.112846DOI Listing
October 2021

The facile formation of hierarchical mesoporous silica nanocarriers for tumor-selective multimodal theranostics.

Biomater Sci 2021 Jul;9(15):5237-5246

Department of Chemical Engineering, Shaanxi Key Laboratory of Energy Chemical Process Intensification, Institute of Polymer Science in Chemical Engineering, School of Chemical Engineering and Technology, Xi'an Jiaotong University, Xi'an, 710049, P. R. China.

The combination of therapeutic and diagnostic functions in a single platform has aroused great interest due to the more optimal synergistic effects that can be obtained as compared to any single theranostic approach alone. However, current nanotheranostics are normally formed via complicated construction steps involving the pre-synthesis of each component and further conjugation via chemical bonds, which may cause low integration efficiency and limit production and applications. Herein, a tumor-targeting and tumor-responsive all-in-one nanoplatform based on mesoporous silica nanocarriers (MSNs) was fabricated via a facile approach utilizing efficient and nondestructive physical interactions for long-wavelength fluorescence imaging-guided synergistic chemo-catalytic-photothermal tumor therapy. The MSNs were endowed with these multimodal theranostics via a simple hydrothermal method after coordinating with Fe2+ and glutathione (GSH) to introduce ferroferric oxide and carbon dots in situ. The former acts as a photothermal agent and catalytic agent to generate local heat under 808 nm irradiation and also when toxic hydroxyl radicals (˙OH) are in contact with abundant hydrogen peroxide in cancer cells, while the latter participates in fluorescence imaging. After loading with paclitaxel (PTX), polyester and folic-acid-conjugated cyclodextrin were employed to serve as an esterase-sensitive gatekeeper controlling PTX release from the MSN pores and as a tumor-targeting agent for accurate therapy, respectively. As expected, the nanoplatform was efficiently taken up by tumor cells over healthy cells, and then, synergetic chemo-catalytic-photothermal therapy was performed, resulting in 5-fold greater apoptosis of tumor cells as compared to healthy cells under 808 nm irradiation. Moreover, in vivo data from tumor-bearing mouse models showed that tumors were significantly inhibited, and the survival rates of these mice increased to greater than 80% after 5 weeks of treatment with our nanoplatform. These therapeutic processes could be directly tracked via fluorescence imaging enabled by carbon dots and, therefore, our nanoplatform provides a promising theranostics approach for tumor treatment.
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http://dx.doi.org/10.1039/d1bm00564bDOI Listing
July 2021

Pyruvate dehydrogenase deficiency disease detected by the enzyme activity of peripheral leukocytes.

Mol Genet Genomic Med 2021 Aug 22;9(8):e1728. Epub 2021 Jun 22.

ChinovoLaboratory, Beijing, P. R. China.

Background: Pyruvate dehydrogenase complex (PDHC) deficiency is a common neurodegenerative disease associated with abnormal mitochondrial energy metabolism. The diagnosis of PDHC is difficult because of the lack of a rapid, accurate, and cost-effective clinical diagnostic method.

Methods: A 4-year-old boy was preliminarily diagnosed with putative Leigh syndrome based on the clinical presentation. PDHC activity in peripheral blood leukocytes and a corresponding gene analysis were subsequently undertaken. Sodium pyruvate 1- C was used for the analysis of PDHC activity in peripheral leukocytes. The genes encoding PDHC were then scanned for mutations.

Results: The results showed that the corresponding PDHC activity was dramatically decreased to 10.5 nmol/h/mg protein as compared with that of healthy controls (124.6 ± 7.1 nmol/h/mg). The ratio of PDHC to citrate synthase was 2.1% (control: 425.3 ± 27.1). The mutation analysis led to the identification of a missense mutation, NM_000284.4:g214C>T, in exon 3 of PDHC.

Conclusion: The peripheral blood leukocyte PDHC activity assay may provide a practical enzymatic diagnostic method for PDHC-related mitochondrial diseases.
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http://dx.doi.org/10.1002/mgg3.1728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8404224PMC
August 2021

Hybridization Chain Reaction-Amplified Electrochemical DNA-Based Sensors Enable Calibration-Free Measurements of Nucleic Acids Directly in Whole Blood.

Anal Chem 2021 06 1;93(23):8354-8361. Epub 2021 Jun 1.

State Key Laboratory of Biogeology Environmental Geology, Engineering Research Center of Nano-Geomaterials of Ministry of Education, Engineering Research Center of Nano-Geomaterials of Ministry of Education, Faculty of Materials Science and Chemistry, China University of Geosciences, Wuhan 430074, China.

Hybridization chain reaction (HCR) amplification strategy has been extensively explored for the application of electrochemical DNA-based sensors. Despite the enhancement in its sensitivity using the HCR, such sensor platform exhibited significant sensor-to-sensor variations in current due to variations in probe counts and lengths. To circumvent this, we are developing here a calibration-free "O-N" approach to generate a ratiometric, unitless value that is independent of these variations. Specifically, this approach employs two types of redox reporters, denoted as "One reporter" and "N reporters", with the former attached on the capture DNA and the latter on H1 and H2 strands. By optimizing the attachment sites of these reporters onto DNA strands, we demonstrate a significantly enhanced sensitivity of such sensor platform by four orders of magnitude, achieving accurate, calibration-free measurement of nucleic acids including ctDNA directly in undiluted whole blood without the requirement to calibrate each individual sensor.
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http://dx.doi.org/10.1021/acs.analchem.1c01436DOI Listing
June 2021

ND‑09 inhibits chronic myeloid leukemia K562 cell growth by regulating BCR‑ABL signaling.

Oncol Rep 2021 Jul 26;46(1). Epub 2021 May 26.

School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.

Chronic myeloid leukemia (CML) accounts for approximately 15% of new adult leukemia cases. The fusion gene is an important biological basis and target for CML. In the present study, a novel compound, ND‑09, was developed and its inhibitory effect and mechanism of action on CML growth were evaluated using RT‑PCR and western blot analysis. The results showed that ND‑09 demonstrated a high level of inhibitory action toward CML cells overexpressing BCR‑ABL and induced K562 cell apoptosis through the mitochondrial pathway. Notably, combined ND‑09 and siRNA treatment could better inhibit cell proliferation and induce apoptosis in K562 cells. Furthermore, this growth effect of siRNA could be fully rescued by transfection with . ND‑09 exhibited a good fit within BCR‑ABL and occupied its ATP‑binding pocket, thus altering BCR‑ABL kinase activity. Therefore, ND‑09 downregulated the phosphorylation of BCR‑ABL and ABL, ultimately inhibiting the downstream signaling pathways in K562 cells. These findings suggest that ND‑09 induces growth arrest in CML cells by targeting BCR‑ABL.
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http://dx.doi.org/10.3892/or.2021.8087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144938PMC
July 2021

WWOX activation by toosendanin suppresses hepatocellular carcinoma metastasis through JAK2/Stat3 and Wnt/β-catenin signaling.

Cancer Lett 2021 Aug 18;513:50-62. Epub 2021 May 18.

School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, PR China; State Key Laboratory of Shaanxi for Natural Medicines Research and Engineering, Xi'an, 710061, PR China. Electronic address:

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide. Loss of WW-domain containing oxidoreductase (WWOX) has been proven to be associated with malignant metastasis in patients with HCC. In this study, by using a non-biased CRISPR knockout genetic screen targeting 19,050 human genes, we found that toosendanin (TSN) is a novel druggable WWOX candidate agonist for metastatic HCC patients. We also found that TSN exhibited significant anti-proliferative and anti-metastatic effects on HCC cells in a WWOX-dependent manner. Overexpression and knockdown of WWOX in vitro and in vivo confirmed that the suppression of HCC by TSN involved WWOX. TSN regulated Stat3, DVL2, and GSK3β by transforming their interactions with WWOX as demonstrated by a Co-IP assay. TSN accelerated the degradation of β-catenin by promoting the function of APC, AXIN1, CK1, and GSK3β complex. Nuclear translocation of p-Stat3 Y705 and β-catenin was impeded by the TSN-induced blockade of JAK2/Stat3 and Wnt/β-catenin signaling, accompanied by the inhibition of MMPs and C-MYC.
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http://dx.doi.org/10.1016/j.canlet.2021.05.010DOI Listing
August 2021

Homer2 and Homer3 Act as Novel Biomarkers in Diagnosis of hepatitis B virus-induced Hepatocellular Carcinoma.

J Cancer 2021 19;12(12):3439-3447. Epub 2021 Apr 19.

Department & Program of Clinical Laboratory Medicine, Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related mortality worldwide. Early detection of HCC can significantly improve patients' outcomes. An increasing number of studies have validated that Homer is dysregulated in cancers and may serve as diagnostic markers. In the present study, we investigated the expression profile and diagnostic significance of Homer2 and Homer3 in hepatitis B virus-induced HCC (HBV-HCC). Quantitative real-time PCR (QRT-PCR), western blot analysis and immunohistochemistry analysis. Homer2 and Homer3 were downregulated in HCC. The expression of Homer2 was associated with tumor differentiation grade (= 0.012) and total protein (TP) level (= 0.032). Homer3 was related to tumor size (= 0.010), tumor nodes (= 0.026) and γ-glutamyl transferase (GGT) level (= 0.001). The receiver operating characteristic curve analyses indicated that the combination of Homer2, Homer3 and AFP possessed a high accuracy (AUC=0.900) to diagnose HCC cases from healthy controls. : Our data indicated that Homer2 and Homer3 were downregulated in HCC and might be potential diagnostic marker for HCC.
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http://dx.doi.org/10.7150/jca.52118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120171PMC
April 2021

Carnitine palmitoyl transferase 1A is a novel diagnostic and predictive biomarker for breast cancer.

BMC Cancer 2021 Apr 15;21(1):409. Epub 2021 Apr 15.

Department of Medical Laboratory, the Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430014, Hubei, China.

Background: Carnitine palmitoyl transferase 1A (CPT1A), the key regulator of fatty acid oxidation, contributes to tumor metastasis and therapeutic resistance. We aimed to identify its clinical significance as a biomarker for the diagnosis and prediction of breast cancer.

Methods: Western blot, ELISA and in silico analysis were used to confirm CPT1A levels in breast cancer cell lines, cell culture medium and breast cancer tissues. Four hundred thirty breast cancer patients, 200 patients with benign breast disease, and 400 healthy controls were enrolled and randomly divided into a training set and a test set with a 7:3 ratio. Training set was used to build diagnostic models and 10-fold cross validation was used to demonstrate the performance of the models. Then test set was aimed to validate the effectiveness of the diagnostic models. ELISA was conducted to detect individual serum CPT1A levels. Receiver operating characteristic (ROC) curves were generated, and binary logistic regression analyses were performed to evaluate the effectiveness of CPT1A as a biomarker in breast cancer diagnosis. CPT1A levels between post-operative and pre-operative samples were also compared.

Results: CPT1A was overexpressed in breast cancer tissues, cell lines and cell culture medium. Serum CPT1A levels were higher in breast cancer patients than in controls and were significantly associated with metastasis, TNM stage, histological grading and molecular subtype. CPT1A levels were decreased in post-operative samples compared with paired pre-operative samples. Moreover, CPT1A exhibited a higher efficacy in differentiating breast cancer patients from healthy controls (training set: area under the curve, AUC, 0.892, 95% CI, 0.872-0.920; test set, AUC, 0.904, 95% CI, 0.869-0.939) than did CA15-3, CEA, or CA125.

Conclusion: CPT1A is overexpressed in breast cancer and can be secreted out of breast cancer cell. Serum CPT1A is positively associated with breast cancer progression and could serve as an indicator for disease monitoring. Serum CPT1A displayed a remarkably high diagnostic efficiency for breast cancer and could be a novel biomarker for the diagnosis of breast cancer.
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http://dx.doi.org/10.1186/s12885-021-08134-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048260PMC
April 2021

Roles of the MYST Family in the Pathogenesis of Alzheimer's Disease via Histone or Non-histone Acetylation.

Aging Dis 2021 Feb 1;12(1):132-142. Epub 2021 Feb 1.

1State Key Lab for Conservation and Utilization of Bio-Resources, Yunnan University, Kunming, Yunnan, China.

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases and a major cause of death among elderly individuals. The etiology of AD involves a combination of genetic, environmental, and lifestyle factors. A number of epigenetic alterations in AD have recently been reported; for example, studies have found an increase in histone acetylation in patients with AD and the protective function of histone deacetylase inhibitors. The histone acetylases in the MYST family are involved in a number of key nuclear processes, such as gene-specific transcriptional regulation, DNA replication, and DNA damage response. Therefore, it is not surprising that they contribute to epigenetic regulation as an intermediary between genetic and environmental factors. MYST proteins also exert acetylation activity on non-histone proteins that are closely associated with the pathogenesis of AD. In this review, we summarized the current understanding of the roles of MYST acetyltransferases in physiological functions and pathological processes related to AD. Additionally, using published RNA-seq, ChIP-seq, and ChIP-chip data, we identified enriched pathways to further evaluate the correlation between MYST and AD. The recent research described in this review supports the importance of epigenetic modifications and the MYST family in AD, providing a basis for future functional studies.
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http://dx.doi.org/10.14336/AD.2020.0329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801277PMC
February 2021

Multiple olfactory pathways contribute to the lure process of Caenorhabditis elegans by pathogenic bacteria.

Sci China Life Sci 2021 Aug 1;64(8):1346-1354. Epub 2020 Dec 1.

State Key Lab for Conservation and Utilization of Bio-Resources, and College of Life Science, Yunnan University, Kunming, 650091, China.

Chemosensation is indispensable for the survival of Caenorhabditis elegans to discriminate food and pathogenic bacteria in their living environment. Food-like odors emitted by the pathogen Bacillus nematocida B16 for trapping its hosts and an olfactory signaling pathway responsible to sense the attractant 2-heptanone were identified in our previous study. Here, we further explore how the worms recognize the attractive molecules indole and 2-ethyl hexanol, which have different chemical properties and modest nematode-luring ability. We show that the chemotaxis toward indole and 2-ethyl hexanol requires the G protein-coupled receptors encoded by str-193 on AWC and str-7 on AWA. In a further genetic screen for downstream effectors in olfactory signaling cascades, the Gα subunit GSA-1, guanylyl cyclase ODR-1 and DAF-11 and the cGMP-gated channel TAX-2/TAX-4 were found to be necessary for indole sensation, whereas the TRPV channels OSM-9/OCR-2 and the PLC pathway activated by GPA-6 are responsible for the detection of 2-ethyl hexanol. Altogether, our current work further clarifies the distinct olfactory signaling pathways through which C. elegans senses different chemicals and is lured by B. nematocida B16, improving our comprehensive understanding of the mechanisms by which bacterial pathogens effectively infect their hosts.
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http://dx.doi.org/10.1007/s11427-020-1842-7DOI Listing
August 2021

Effect of augmented renal clearance on the therapeutic drug monitoring of vancomycin in patients after neurosurgery.

J Int Med Res 2020 Oct;48(10):300060520949076

Pharmacy Department, Medical Supplies Center of Chinese PLA General Hospital, Beijing, China.

Objective: To study the effect of augmented renal clearance (ARC) on vancomycin therapeutic drug monitoring in patients undergoing neurosurgery.

Methods: A retrospective observational analysis was conducted in a neurosurgery department from January 2019 to June 2019. Patients undergoing vancomycin therapeutic drug monitoring were assigned to the normal renal function or ARC group. The baseline characteristics, vancomycin therapeutic drug monitoring data, and prognosis were compared and analyzed.

Results: In total, 104 patients were enrolled, including 78 and 26 patients in the normal renal function and ARC groups, respectively. There were significant differences in age, weight, creatinine clearance, the vancomycin treatment duration, the total dose, the trough concentration, and the trough concentration achievement rate between the two groups. Prognosis did not differ between the two groups. The trough concentration achievement rate in the ARC group was only 19.23%.

Conclusion: For young, obese, or otherwise healthy patients undergoing neurosurgery, attention should be paid to the possibility of ARC and the need for individualized dose adjustment based on the results of therapeutic drug monitoring.
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http://dx.doi.org/10.1177/0300060520949076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604945PMC
October 2020

High-concentration homocysteine inhibits mitochondrial respiration function and production of reactive oxygen species in neuron cells.

J Stroke Cerebrovasc Dis 2020 Oct 28;29(10):105109. Epub 2020 Jul 28.

Central Laboratory, Affiliated Hospital of Qinghai University, Tongren Road 29, Xining, Qinghai Province, China, 810000. Electronic address:

Objective: Homocysteine plays critical roles in cellular redox homeostasis, and hyperhomocysteinemia has been associated with multiple diseases, including neurological disorders involving reactive oxygen species-inducing and pro-inflammatory effects of homocysteine that are related to mitochondria. This study investigated the role of homocysteine in regulating mitochondria of neuron cell lines.

Methods: Neuron cells were pre-treated with homocysteine, and then flow cytometry was used to detect reactive oxygen species production and mitochondrial membrane potential, while Seahorse XFp Mito stress assay was used to comprehensively analyze mitochondrial function.

Results: The experimental results showed that high-concentration homocysteine diminished carbonyl cyanide-4 (trifluoromethoxy) phenylhydrazone-stimulated oxygen consumption rate and mitochondrial spare respiration capacity in a time- and concentration-dependent manner, and homocysteine also reduced reactive oxygen species in cultured neuron cell lines while no changes in mitochondrial membrane potential were observed.

Conclusion: These results indicate that homocysteine diminished mitochondrial respiration function in neuron cell lines mediated by its reactive oxygen species-reducing effects, which may underlie the association between hyperhomocysteinemia and human diseases.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2020.105109DOI Listing
October 2020

miR-4454 up-regulated by HPV16 E6/E7 promotes invasion and migration by targeting ABHD2/NUDT21 in cervical cancer.

Biosci Rep 2020 09;40(9)

Department of Medical Laboratory, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430014, China.

The abnormal expression of HPV16 E6/E7 activates oncogenes and/or inactivates tumor suppressor genes, resulting in the selective growth and malignant transformation of cancer cells. miR-4454 was selected by sequencing due to its abnormal high expression in HPV16 E6/E7 positive CaSki cell compared with HPV16 E6/E7 negative C33A cell. Overexpression of miR-4454 enhances cervical cancer cell invasion and migration. ABHD2 and NUDT21 are identified as a target gene of miR-4454.The effects of ABHD2 and NUDT21 on migration and invasion of CaSki and C33A cells were determined. The dual luciferase and RT-qPCR assays confirmed that miR-4454 might regulate its targets ABHD2 and NUDT21 to promote the proliferation, invasion and migration, whereas, inhibit the apoptosis in CaSki and C33A cells.
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http://dx.doi.org/10.1042/BSR20200796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468098PMC
September 2020

Homoharringtonine suppresses tumor proliferation and migration by regulating EphB4-mediated β-catenin loss in hepatocellular carcinoma.

Cell Death Dis 2020 08 14;11(8):632. Epub 2020 Aug 14.

School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta Weststreet, #54, 710061, Xi'an, Shaanxi, P.R. China.

Overexpressed EphB4 conduce to tumor development and is regarded as a potential anticancer target. Homoharringtonine (HHT) has been approved for hematologic malignancies treatment, but its effect on hepatocellular carcinoma (HCC) has not been studied. This study elucidated HHT could restrain the proliferation and migration of HCC via an EphB4/β-catenin-dependent manner. We found that the antiproliferative activity of HHT in HCC cells and tumor xenograft was closely related to EphB4 expression. In HepG2, Hep3B and SMMC-7721 cells, EphB4 overexpression or EphrinB2 Fc stimulation augmented HHT-induced inhibitory effect on cell growth and migration ability, and such effect was abrogated when EphB4 was knocked down. The similar growth inhibitory effect of HHT was observed in SMMC-7721 and EphB4/SMMC-7721 cells xenograft in vivo. Preliminary mechanistic investigation indicated that HHT directly bound to EphB4 and suppressed its expression. Data obtained from HCC patients revealed increased β-catenin expression and a positive correlation between EphB4 expression and β-catenin levels. HHT-induced EphB4 suppression promoted the phosphorylation and loss of β-catenin, which triggered regulation of β-catenin downstream signaling related to migration, resulting in the reversion of EMT in TGF-β-induced HepG2 cells. Collectively, this study provided a groundwork for HHT as an effective antitumor agent for HCC in an EphB4/β-catenin-dependent manner.
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http://dx.doi.org/10.1038/s41419-020-02902-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429962PMC
August 2020

Employing an Intercalated Redox Reporter in Electrochemical Aptamer-Based Biosensors to Enable Calibration-Free Molecular Measurements in Undiluted Serum.

Anal Chem 2020 09 27;92(18):12437-12441. Epub 2020 Aug 27.

Engineering Research Center of Nano-Geomaterials of Ministry of Education, Faculty of Materials Science and Chemistry, China University of Geosciences, Wuhan 430074, China.

Electrochemical aptamer-based (E-AB) biosensors suffer from sensor-to-sensor signal variations due to the variation of the total number and the heterogeneity of probes immobilized on the electrode surface, with the former attracting more attention. As such, a calibration process to correct for such variations is required for this type of sensor, causing inconvenience and inaccessibility in harsh sensing environments such as blood samples, which has dramatically limited the widespread clinical use of biosensors. In response, here, we have adopted E-AB sensors to achieve calibration-free measurements of small biological/drug molecules. Specifically, we employ one probe-attached redox reporter and a second intercalated redox reporter to generate two signals, achieving good sensor-to-sensor reproducibility and thus obviating the need for calibration. We first demonstrated the capability of E-AB sensors for the accurate measurement of kanamycin, tobramycin, and adenosine triphosphate (ATP) in phosphate-buffered saline (PBS) buffer, achieving concentration ranges of approximately 4.7 × 10-, 2.0 × 10-, and 12.7-fold, respectively. Then, we applied this calibration-free approach to the measurement of these three target molecules directly in undiluted serum, achieving a concentration precision of a few micromolars.
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http://dx.doi.org/10.1021/acs.analchem.0c02205DOI Listing
September 2020

protein2vec: Predicting Protein-Protein Interactions Based on LSTM.

IEEE/ACM Trans Comput Biol Bioinform 2020 Jun 22;PP. Epub 2020 Jun 22.

The semantic similarity of gene ontology (GO) terms is widely used to predict protein-protein interactions (PPIs). The traditional semantic similarity measures are based mainly on manually crafted features, which may ignore some important hidden information of the gene ontology. Moreover, those methods usually obtain the similarity between proteins from similarity between GO terms by some simple statistical rules, such as MAX and BMA (best-match average), oversimplifying the possible complex relationship between the proteins and the GO terms annotated with them. To overcome the two deficiencies, we propose a new method named protein2vec, which characterizes a protein with a vector based on the GO terms annotated to it and combines the information of both the GO and known PPIs. We firstly try to apply the network embedding algorithm on the GO network to generate feature vectors for each GO term. Then, Long Short-Time Memory (LSTM) encodes the feature vectors of the GO terms annotated with a protein into another vector (called protein vector). Finally, two protein vectors are forwarded into a feedforward neural network to predict the interaction between the two corresponding proteins. The experimental results show that protein2vec outperforms almost all commonly used traditional semantic similarity methods.
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http://dx.doi.org/10.1109/TCBB.2020.3003941DOI Listing
June 2020

Intraventricular administration of antibiotics by ommaya reservoir for patients with multidrug-resistant central nervous system infection.

Br J Neurosurg 2021 Apr 13;35(2):170-173. Epub 2020 Jul 13.

Center of Clinical Pharmacy, Chinese PLA General Hospital, Beijing, China.

Aim: To investigate whether the Ommaya reservoir can be used to treat multiple drug-resistant Acinetobacter baumannii (MDR-AB) infections in the central nervous system (CNS).

Methods: Retrospectively analyzed the clinical records and data of 15 MDR-AB CNS infection patients who were treated in our neuro-ICU. Four patients with MDR-AB CNS infection were involved in this study.

Results: We report the successful treatment of MDR-AB CNS infection by Ommaya reservoirs and intraventricular antibiotic (IVA) administration. Ommaya reservoirs allow serial CSF sampling and IVA injection. Furthermore, debridement can be performed during the operation to insert the Ommaya.

Conclusion: Ommaya reservoirs can be used as an effective treatment approach of MDR-AB or other multidrug-resistant Gram-negative bacteria CNS infections.
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http://dx.doi.org/10.1080/02688697.2020.1777255DOI Listing
April 2021

Sanguinarine suppresses migration and metastasis in colorectal carcinoma associated with the inversion of EMT through the Wnt/β-catenin signaling.

Clin Transl Med 2020 Jan 14;10(1):1-12. Epub 2020 Apr 14.

School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, P.R. China.

Background: Unresectable lung or liver organ metastases of colorectal carcinoma (CRC) remain a major obstacle in clinical therapeutics. Epithelial to mesenchymal transition (EMT), a major cause of highly frequent metastasis in tumor, can be promoted by the Wnt/β-catenin pathway that is aberrantly activated in approximately 90% of CRC. This research aimed to elucidate the antimetastatic potential of sanguinarine (SG) in CRC and the underlying molecular mechanism.

Methods: The in vitro anticancer effect of SG was determined via cell viability experiment and colony formation assay. Xenograft model of nude mice was used to confirm the antitumor effect of SG in vivo. The antimetastatic potential of SG was investigated by the metastasis model of nude mice, hematoxylin and eosin (H&E) staining, migration assay, and wound-healing analysis. Immunoblotting analysis, immunofluorescence staining, and immunohistochemistry assay were conducted to elucidate the molecular mechanism.

Results: In this study, we reported that SG has a selective inhibitory effect on LoVo cells with metastatic characteristics. Furthermore, our results showed attenuation in the migration and metastatic ability of SG-treated LoVo cells and also decreased metastatic nodules of liver and lung in mice metastasis model. This was also confirmed at the molecular level via H&E staining. Further study revealed that SG had negative impacts on the Wnt/β-catenin pathway and EMT markers in LoVo cells both in vitro and in vivo.

Conclusions: Taken together, the antimetastatic potential of SG attributed to the suppression of the Wnt/β-catenin signaling, which further prevented EMT progression. SG may be of value in a potential therapy for the management of metastasis CRC.
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http://dx.doi.org/10.1002/ctm2.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239267PMC
January 2020

Cantharidin treatment inhibits hepatocellular carcinoma development by regulating the JAK2/STAT3 and PI3K/Akt pathways in an EphB4-dependent manner.

Pharmacol Res 2020 08 12;158:104868. Epub 2020 May 12.

School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta Weststreet, #54, Xi'an, Shaanxi Province 710061, PR China. Electronic address:

Hepatocellular carcinoma (HCC) is a lethal malignancy with limited treatment options. The tyrosine kinase receptor EphB4 promotes oncogenesis and tumor development and progression. Its inhibition is regarded as an effective strategy for the treatment of solid tumors. In the present study, we identified cantharidin as a novel EphB4 inhibitor for HCC treatment and evaluated the underlying molecular pharmacological mechanisms of action. We observed increased expression levels of EphB4 in HCC patients and a positive correlation between EphB4 and p-JAK2 levels in HCC patient samples. Knockdown of EphB4 using small interfering RNA decreased the expression levels of p-JAK2 and p-STAT3 in HCC cells, suggesting JAK2/STAT3 being a novel downstream signaling target of EphB4. Cell viability experiments revealed that the anti-cancer effect of cantharidin was positively correlated with EphB4 expression levels in HCC cell lines. We confirmed the potent antiproliferative activity of cantharidin on HepG2 cells with high expression of EphB4 and tumor xenograft. Molecular docking assay, immunoblotting assay and quantitative reverse transcription PCR assay indicated that cantharidin bound to EphB4, and thereby resulted in EphB4 suppression at mRNA and protein levels. Hep3B and SMMC-7721 cells were with low expression of EphB4. In EphB4/HepG2, EphB4/HepG2, and EphB4/Hep3B cells, EphB4 knockdown alleviated the cantharidin-induced decrease in cell viability and colony formation ability and increase in apoptosis in HepG2 cells, while its overexpression exacerbated these effects in Hep3B cells and increased the apoptosis of HepG2 cells. In nude mouse models, cantharidin suppressed tumor growth more effectively in EphB4/SMMC-7721 xenografts than in wild-type SMMC-7721 xenografts. Underlying mechanistic study showed that by targeting EphB4, cantharidin blocked a novel target, the downstream JAK2/STAT3 pathway, and the previously known target, the PI3K/Akt signaling, resulting in intrinsic apoptosis. These results indicated that cantharidin may be a potential candidate for HCC treatment by regulating the EphB4 signaling pathway.
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http://dx.doi.org/10.1016/j.phrs.2020.104868DOI Listing
August 2020

The association between homocysteine and ischemic stroke subtypes in Chinese: A meta-analysis.

Medicine (Baltimore) 2020 Mar;99(12):e19467

Qinghai University Affiliated Hospital, Xining, Qinghai Province.

Background: The findings on the association between elevated plasma homocysteine levels and the risk of the trial of org 10172 in acute stroke treatment (TOAST) of ischemic stroke have been inconsistent in Chinese. So far, there is no meta-analysis about the association between Hcy and the TOAST subtypes of ischemic stroke in Chinese. This study; therefore, aimed to evaluate whether elevated homocysteine levels are associated with the TOAST subtypes of ischemic stroke using a meta-analysis.

Materials And Methods: A systematic search of electronic databases were conducted for studies reporting homocysteine levels in ischemic stroke and the TOAST of ischemic stroke to April 18, 2018. The data were extracted after the application of inclusion and exclusion criteria. All the data were analyzed using Stata software version 9.0 (Stata Corp LP, College Station, TX). The standardized mean difference (SMD) and 95% confidence interval (CI) were used to compare continuous variables.

Results: Thirteen studies comprising 3114 participants (2243 patients and 871controls) met the eligibility criteria and were included in the meta-analysis. The meta-analysis revealed that the ischemic stroke group had significantly higher levels of homocysteine than controls (SMD = 1.15, 95% CI = 0.85-1.45, P < .05). The subgroup analyses suggested that the groups of patients with large-artery atherosclerosis, small-vessel occlusion, cardioembolism, stroke of other determined etiology and stroke of undetermined etiology had significantly higher levels of homocysteine compared to those in the control group (large-artery atherosclerosis: SMD = 2.12, 95% CI = 1.40-2.84, P < .05; small-vessel occlusion: SMD = 1.10, 95% CI = 0.72-1.48, P < .05; CE: SMD = 1.17, 95% CI = 0.64-1.71, P < .05; stroke of other determined etiology: SMD = 0.88, 95% CI = 0.53-1.24, P < .05; stroke of undetermined etiology: SMD = 1.50, 95% CI = 0.66-2.33, P < .05, respectively).

Conclusion: This meta-analysis found that ischemic stroke patients and the TOAST of ischemic stroke patients in Chinese had significantly higher homocysteine levels than the controls, suggesting that serum homocysteine levels may be a risk factor for ischemic stroke and the TOAST subtypes of ischemic stroke in Chinese.
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http://dx.doi.org/10.1097/MD.0000000000019467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220264PMC
March 2020

Development and Validation of a Novel Recurrence Risk Stratification for Initial Non-Muscle Invasive Bladder Cancer in the Han Chinese Population.

J Cancer 2020 14;11(7):1668-1678. Epub 2020 Jan 14.

Department of Clinical Laboratory, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P. R. China.

: Some classification models for determining the risk of recurrence after transurethral resection of bladder tumor (TURBT) in patients with non-muscle invasive bladder cancer (NMIBC) had some shortcomings in clinical applications. This study aimed to investigate whether the European Organization for Research and Treatment of Cancer (EORTC) risk stratification was useful to predict the recurrence of NMIBC in the Han Chinese population. In addition, we developed and validated a novel risk stratification method for recurrence prediction of NMIBC. : Excluding cases who do not meet the inclusion criteria, 606 patients with NMIBC from the First Affiliated Hospital of Zhengzhou University were included in the testing and validation groups. The recurrence-free survival (RFS) curve according to the EORTC risk classifications was calculated by the Kaplan-Meier and the log-rank test methods. Receiver operating characteristic (ROC) curve analysis was used to estimate the diagnosis value for recurrence. We built a logistic regression model for recurrence in NMIBC patients combining the independent recurrence prognostic factors. One external validation group including 166 patients with NMIBC from the Zhongnan Hospital of Wuhan University was also used to assess the logistic regression model. : There was no significant difference in RFS rates between the groups grouped according to EORTC. We constructed a novel risk model to predict recurrence by classifying patients into two groups using ten independent prognostic factors [bladder cancer-specific nuclear matrix protein 4 (BLCA-4), bladder tumour antigen (BTA), nuclear matrix protein 22 (NMP22), carcinoembryonic antigen (CEA), body mass index, smoking, family history of bladder cancer, occupational exposure to aromatic amine chemicals, number of tumours, bladder instillation of chemotherapeutic agents] to predict tumour recurrence based on logistic regression analyses (testing group). According to the novel recurrence risk classification, there was a significant difference in 5-year RFS rates between the low-risk group and the high-risk group (Validation group and the external validation group). : Our novel classification model can be a useful tool to predict recurrence risk in the Han Chinese population with NMIBC.
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http://dx.doi.org/10.7150/jca.38649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052852PMC
January 2020

Forward genetic screening of a novel gene hmgs-1 Involved in Alzheimer Disease Pathogenesis in a transgenic Caenorhabditis elegans model.

Biochem Biophys Res Commun 2020 Feb 17. Epub 2020 Feb 17.

State Key Lab for Conservation and Utilization of Bio-Resources, College of Life Science, Yunnan University, Kunming, 650091, China. Electronic address:

Alzheimer disease (AD), which poses a serious challenge in aging societies, still lacks effective treatments to reverse its progression, and thus, has been a major focus of research for decades. There are several risk factors associated with the etiology of AD. To further identify potential new factors involved in AD pathogenesis, a forward genetic screening method using transgenic Caenorhabditis elegans CL4176 exposed to different temperatures was employed to screen mutant worms resistant to β-amyloid toxicity. After transcriptome sequencing, and analysis of single nucleotide polymorphism variations by RNA-Seq and DNA-Seq, it is suggested that a novel gene hmgs-1 is involved in AD pathogenesis. We verified its involvement again by the phenotype of gene knockdown mutant and the rescue effect of complementing hmgs-1. Our study provides a workable screening method for new gene mutations and a potential target of hmgs-1 in the AD pathogenesis.
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http://dx.doi.org/10.1016/j.bbrc.2020.02.076DOI Listing
February 2020

Outcome and factors of patients with nosocomial meningitis by multi-drug-resistant Gram-negative bacteria in a tertiary hospital in China: a retrospective study.

Br J Neurosurg 2020 Jun 7;34(3):324-328. Epub 2020 Feb 7.

Center for Clinical Laboratory Medicine, Chinese PLA General Hospital, Beijing, China.

Few data are available on the risk factors involved in nosocomial meningitis from multi-drug-resistant Gram-negative bacteria (MDR-GNB). Our aim was to identify the risk factors of prognosis for MDR-GNB nosocomial meningitis. Retrospective study of patients undergoing neurosurgery and with positive cerebrospinal fluid culture results post operation between January 2012 and January 2017 in a tertiary hospital in China. In total, 3533 patients were screened. Forty patients with meningitis and completed data were included and divided into two groups, 29 who survived in the successful group (SG) and 11 who died in the failed group (FG). Statistically significant different factors involved in treating successful and failed were pathogen types, highest body temperature in the first 24h of symptoms, CSF glucose content and meropenem susceptibility (for ). The most common pathogen in the failed ones is with meropenem MIC ≥ 16mg/L. Treatment of MDR-GNB nosocomial meningitis is more likely to fail in patients with severe condition when symptoms occur and infected by . Researches with larger population are needed to find more factors to improve patient outcome.
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http://dx.doi.org/10.1080/02688697.2019.1710819DOI Listing
June 2020

Development of a Computer-Assisted Adverse Drug Events Alarm and Assessment System for Hospital Inpatients in China.

Ther Innov Regul Sci 2020 01 6;54(1):32-41. Epub 2020 Jan 6.

Department of Pharmacy, The General Hospital of the People's Liberation Army, 28 Fu Xing Road, Beijing, 100853, China.

Background: Computerized detection is a promising method for monitoring adverse drug events (ADEs); however, this method is currently in its infancy and is a new area of exploration in China. This study aimed to develop a computerized ADE alarm and assessment system to help pharmacists effectively detect, assess, and analyze possible ADEs in patients in China.

Methods: Based on the clinical characteristics of these adverse drug events, we designed combined multiparameters as ADE alert rules to be assembled into detection configurations. We also developed system function modules by extracting data from the People's Liberation Army (PLA) general hospital information system (electronic medical records). Positive predictive values were calculated for the alert.

Results: Five function modules were created in this platform: automatic screening, assisted evaluation, risk characteristic analysis, report generation into SRS (spontaneous reporting system), and a dictionary database. Four ADE alert configurations were set in our ADE alarm and assessment system: drug-related thrombocytopenia, anemia, liver injury, and kidney injury. The positive predictive values of the 4 monitored ADEs were approximately 44.4% to 95.8%.

Conclusions: An automatic ADE screening system was established for hospitalized patients in Chinese medical institutions. Compared with previous studies, combined drug-event alerts and a system-assisted assessment interface performed better than alerts based only on laboratory values. Furthermore, this platform's assisted-layered evaluation and risk factor analysis functions could save considerable time for professionals and improve early prevention of potentially serious ADEs. To date, this system has been applied in 10 large-scale medical institutions.
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http://dx.doi.org/10.1007/s43441-019-00027-zDOI Listing
January 2020

TPD7 inhibits the growth of cutaneous T cell lymphoma H9 cell through regulating IL-2R signalling pathway.

J Cell Mol Med 2020 01 19;24(1):984-995. Epub 2019 Nov 19.

School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, China.

IL-2R pathway is a key regulator in the development of immune cells and has emerged as a promising drug target in cancer treatment, but there is a scarcity of related inhibitors. TPD7 is a novel biphenyl urea taspine derivate, which has been shown anti-cancer effect. Here, we demonstrated the anti-cancer activity of TPD7 in cutaneous T cell lymphoma and investigated the underlying mechanism of TPD7 through IL-2R signalling. The inhibitory effect of TPD7 on cell viability exhibited a strong correlation with the expression level of IL-2R, and cutaneous T cell lymphoma H9 and HUT78 cells were most sensitive to TPD7. TPD7 was nicely bound to IL-2R and down-regulated the mRNA and protein levels of IL-2R. Furthermore, TPD7 suppressed the downstream cascades of IL-2R including JAK/STAT, PI3K/AKT/mTOR and PLCγ/Raf/MAPK signalling, resulting in Bcl-2 mitochondrial apoptosis pathway and cell cycle proteins CDK/Cyclins regulation. And, these were verified by flow cytometry analysis that TPD7 facilitated cell apoptosis in H9 cells via mitochondrial pathway and impeded cell cycle progression at G2/M phase. TPD7 is a novel anti-cancer agent and may be a potential candidate for cutaneous T cell lymphoma treatment by regulating IL-2R signalling pathway.
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http://dx.doi.org/10.1111/jcmm.14810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6933353PMC
January 2020

Homoharringtonine suppresses LoVo cell growth by inhibiting EphB4 and the PI3K/AKT and MAPK/EKR1/2 signaling pathways.

Food Chem Toxicol 2020 Feb 11;136:110960. Epub 2019 Nov 11.

School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta Weststreet, #54, Xi'an, Shaanxi Province, 710061, PR China. Electronic address:

Colorectal cancer (CRC) remains one of the most common gastrointestinal tumors, characterized by a poor survival rate. Effects of single use of homoharringtonine (HHT), approved for the treatment of acute myelocytic leukemia (AML) and chronic myeloid leukemia (CML), on CRC, are unknown. According to the TCGA database, EphB4 is aberrantly overexpressed in CRC patients. Therefore, the purpose of this study was to investigate the inhibitory effect of HHT on CRC and its underlying mechanism. HHT significantly suppressed LoVo cell growth in vitro and in vivo, and induced apoptosis and cell cycle arrest at the S phase. Mechanistic investigation using western blotting revealed that HHT suppressed EphB4, and this suppression was augmented by both HHT and NVP-BHG712 co-administration and EphB4 overexpression, indicating that HHT targets EphB4 to suppress LoVo cell growth. HHT inhibited EphB4 downstream pathways such as PI3K/AKT and MAPK/EKR1/2, resulting in the regulation of cell cycle-related molecules (cyclinA2 and CDC2), and the molecules in the Bcl-2 mitochondrial apoptosis pathway including Bcl-2, Mcl-1, Bax, Bad, caspase-3, caspase-7, and caspase-9. HHT may therefore be a promising EphB4 inhibitor with great potential for CRC treatment.
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http://dx.doi.org/10.1016/j.fct.2019.110960DOI Listing
February 2020

Annexin-1 Mimetic Peptide Ac2-26 Suppresses Inflammatory Mediators in LPS-Induced Astrocytes and Ameliorates Pain Hypersensitivity in a Rat Model of Inflammatory Pain.

Cell Mol Neurobiol 2020 May 13;40(4):569-585. Epub 2019 Nov 13.

Department of Medical Laboratory, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, 26 Shengli St., Jiangan District, Wuhan, 430014, China.

Ac2-26, a mimetic peptide of Annexin-A1, plays a vital role in the anti-inflammatory response mediated by astrocytes. In this study, we aimed to explore the underlying mechanisms of Ac2-26-mediated anti-inflammatory effect. Specifically, we investigated the inhibitory effects of Ac2-26 on lipopolysaccharide (LPS)-induced astrocyte migration and on pro-inflammatory cytokines and chemokines expressions, as well as one glutathione (GSH) reductase mRNA and total intracellular GSH levels in LPS-induced astrocytes. Additionally, we investigated whether mitogen-activated protein kinases (MAPK) and nuclear factor kappa-B (NF-κB) signaling pathway were involved in this process. Finally, we evaluated the analgesic effect of Ac2-26 in complete Freund's adjuvant (CFA)-induced inflammatory pain model. Our results demonstrated that Ac2-26 inhibited LPS-induced astrocytes migration, reduced the production of pro-inflammatory mediators [tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1 (MIP-1α)] and upregulated GSH reductase mRNA and GSH levels in LPS-induced astrocytes in vitro. This process was mediated through the p38, JNK-MAPK signaling pathway, but not dependent on the NF-κB pathway. Furthermore, the p38 and JNK inhibitors mimicked the effects of Ac2-26, whereas a p38 and JNK activator anisomycin partially reversed its function. Finally, Ac2-26 treatment reduced CFA-induced activation of astrocytes and production of inflammatory mediators in the spinal cord. These results suggest that Ac2-26 attenuates pain by inhibiting astrocyte activation and the production of inflammatory mediators; thus, this work presents Ac2-26 as a potential drug to treat neuropathic pain.
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http://dx.doi.org/10.1007/s10571-019-00755-8DOI Listing
May 2020

High frequency, calibration-free molecular measurements in the living body.

Chem Sci 2019 Nov 6;10(47):10843-10848. Epub 2019 Nov 6.

Department of Chemistry and Biochemistry, University of California Santa Barbara Santa Barbara California 93106 USA

Abolition of the need for end-users to perform sensor calibration proved key to the widespread use of home-glucose monitors. Motivated by this observation here we have adapted electrochemical aptamer-based (E-AB) sensors, a sensing technology that is far more general than the glucose monitor, to the problem of performing calibration-free measurements of molecules other than glucose. Specifically, we first demonstrate the ability of E-AB sensors to achieve the accurate and precise measurement of cocaine, ATP and kanamycin in undiluted whole blood, achieving clinically relevant accuracy (better than ±20%) in this sample matrix without the need to calibrate individual sensors. We then demonstrate similar, calibration-free accuracy (±30%) for ATP and kanamycin measurements with sensors placed in the jugular veins of live rats over multi-hour measurements runs that achieve time resolution of seconds and concentration precision of a few micromolar.
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http://dx.doi.org/10.1039/c9sc04434eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8132996PMC
November 2019

Differential Expression and Diagnostic Significance of Pre-Albumin, Fibrinogen Combined with D-Dimer in AFP-Negative Hepatocellular Carcinoma.

Pathol Oncol Res 2020 Jul 2;26(3):1669-1676. Epub 2019 Oct 2.

Department of Clinical Laboratory, Key Laboratory of Laboratory Medicine of Henan, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China.

Hepatocellular carcinoma (HCC) is one of the most malignant cancers with high morbidity and mortality. Nowadays, AFP-negative hepatocellular carcinoma (AFP-NHCC) has been found in many HCC patients and AFP analysis can't be used to screen HCC in these cases. In this study, we have examined the expression patterns of pre-albumin (PA), fibrinogen, D-Dimer and their clinical significance in AFP-NHCC. We recruited 214 AFP-NHCC patients and 210 controls in the study. PA, fibrinogen and D-Dimer levels were detected by turbidimetry, clauss and immunoturbidimetry methods, respectively. Serum PA levels were significantly lower in AFP-NHCC (84.5 ± 24.7 mg/L) than that in the controls (240.6 ± 59.4 mg/L, P < 0.05). For plasma fibrinogen levels, there was no difference between the controls (2.9 ± 0.7 g/L) and AFP-NHCC (2.5 ± 0.7 g/L). Compared with AFP-NHCC (0.8 ± 0.2 mg/L), plasma D-Dimer levels were significantly lower in controls (0.1 ± 0.0 mg/L, P < 0.05). The levels of PA, fibrinogen and D-Dimer were significantly correlated with differentiation (P < 0.01), and the PA and D-Dimer values were correlated with TNM stage (P < 0.05). Moreover, PA levels were correlated with tumor size (P = 0.034). Receiver operating characteristic curve (ROC) analyses elaborated that combination of PA, fibrinogen and D-Dimer possessed a higher sensitivity (93.4%) for differentiating AFP-NHCC from the controls, but the diagnostic specificity was reduced due to the combination of fibrinogen. After adjusting for all significant outcome predictors of the univariate logistic regression analysis, low levels of PA and high levels of D-Dimer were remained independent unfavorable outcome predictors (P < 0.05). Our data suggested that the expression levels of PA, fibrinogen and D-Dimer played critical roles in AFP-NHCC tumorigenesis. Moreover, PA and D-Dimer might be considered as potential diagnostic indicators in AFP-NHCC.
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http://dx.doi.org/10.1007/s12253-019-00752-8DOI Listing
July 2020
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