Publications by authors named "Xuehong Chen"

48 Publications

ITGA8 positive cells in the conventional outflow tissue exhibit Schlemm's canal endothelial cell properties.

Life Sci 2021 May 4;278:119564. Epub 2021 May 4.

School of Basic Medicine, Qingdao University, Qingdao 266021, China. Electronic address:

Aims: Elevated intraocular pressure is primarily induced by the increased resistance of conventional outflow of aqueous humor. Dysfunction of the juxtacanalicular region of trabecular meshwork (TM) and Schlemm's canal (SC) endothelium, as the main conventional outflow tissue, have been implicated as the major reasons for the increased resistance. Integrins are widespread in these tissues, especially alpha8 integrin (ITGA8). We aim to investigate the properties of cells expressing ITGA8 in the conventional outflow tissue.

Main Methods: Fluorescence in situ hybridization (FISH) and immunofluorescence (IF) were performed to detect the mRNA and protein levels of ITGA8 in human conventional outflow tissue. ITGA8-positive cells were isolated from the cultured human TM cells through a magnetic bead-based approach. Flow Cytometry was used to determine the purification efficiency. The expressions of TM and SC biomarkers and dexamethasone-induced myocilin secretion capacity of ITGA8-positive cells was assessed by Real-time PCR, IF and Western blot. A gel contraction assay was performed to evaluate contractility of ITGA8-positive cells after endothelin 1 treatment.

Key Findings: ITGA8 was found with robust expression near the inner wall of SC endothelium. After purification, the proportion of ITGA8-positive cells were increased by about 10%. ITGA8-positive cells were identified with the properties as SC endothelial cells, such as more robust expressions of SC biomarkers, less dexamethasone-inducible myocilin expression, and stronger contractility.

Significance: This study demonstrated that cells expressing ITGA8 in SC region possess more properties as SC endothelial cells. Our data implicate a crucial role of ITGA8 in aqueous humor (AH) outflow resistance regulation.
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http://dx.doi.org/10.1016/j.lfs.2021.119564DOI Listing
May 2021

Targeting macrophages using nanoparticles: a potential therapeutic strategy for atherosclerosis.

J Mater Chem B 2021 Apr 30;9(15):3284-3294. Epub 2021 Mar 30.

School of Basic Medicine, Qingdao University, Ningxia Road 308, Qingdao, P. R. China.

Atherosclerosis is one of the leading causes of vascular diseases, with high morbidity and mortality worldwide. Macrophages play a critical role in the development and local inflammatory responses of atherosclerosis, contributing to plaque rupture and thrombosis. Considering their central roles, macrophages have gained considerable attention as a therapeutic target to attenuate atherosclerotic progression and stabilize existing plaques. Nanoparticle-based delivery systems further provide possibilities to selectively and effectively deliver therapeutic agents into intraplaque macrophages. Although challenges are numerous and clinical application is still distant, the design and development of macrophage-targeting nanoparticles will generate new knowledge and experiences to improve therapeutic outcomes and minimize toxicity. Hence, the review aims to discuss various strategies for macrophage modulation and the development and evaluation of macrophage targeting nanomedicines for anti-atherosclerosis.
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http://dx.doi.org/10.1039/d0tb02956dDOI Listing
April 2021

Stimuli-responsive nanoparticles based on poly acrylic derivatives for tumor therapy.

Int J Pharm 2021 May 31;601:120506. Epub 2021 Mar 31.

School of Basic Medicine, Qingdao University, Ningxia Road 308, Qingdao, PR China. Electronic address:

Serve side effects caused by discriminate damage of chemotherapeutic drugs to normal cell and cancer cells remain a main obstacle in clinic. Hence, continuous efforts have been made to find ways to effectively enhance drug delivery and reduce side effects. Recent decades have witnessed impressive progresses in fighting against cancer, with improved understanding of tumor microenvironment and rapid development in nanoscale drug delivery system (DDS). Nanocarriers based on biocompatible materials provide possibilities to improve antitumor efficiency and minimize off-target effects. Among all kinds of biocompatible materials applied in DDS, polymeric acrylic derivatives such as poly(acrylamide), poly(acrylic acid), poly(N-isopropylacrylamide) present inherent biocompatibility and stimuli-responsivity, and relatively easy to be functionalized. Furthermore, nanocarrier based on polymeric acrylic derivatives have demonstrated high drug encapsulation, improved uptake efficiency, prolonged circulation time and satisfactory therapeutic outcome in tumor. In this review, we aim to discuss recent progress in design and development of stimulus-responsive poly acrylic polymer based nanocarriers for tumor targeting drug delivery.
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http://dx.doi.org/10.1016/j.ijpharm.2021.120506DOI Listing
May 2021

Cloning and Characterization of a New Chitosanase From a Deep-Sea Bacterium sp. QD07.

Front Microbiol 2021 24;12:619731. Epub 2021 Feb 24.

Department of Pharmacology, School of Basic Medicine, Qingdao University, Qingdao, China.

Chitosanase is a significant chitosan-degrading enzyme involved in industrial applications, which forms chitooligosaccharides (COS) as reaction products that are known to have various biological activities. In this study, the gene was cloned from a deep-sea bacterium sp. QD07, as well as over-expressed in , which is a new chitosanase encoding gene. The recombinant strain was cultured in a 5 L fermenter, which yielded 324 U/mL chitosanases. After purification, CsnS is a cold-adapted enzyme with the highest activity at 60°C, showing 37.5% of the maximal activity at 0°C and 42.6% of the maximal activity at 10°C. It exhibited optimum activity at pH 5.8 and was stable at a pH range of 3.4-8.8. Additionally, CsnS exhibited an endo-type cleavage pattern and hydrolyzed chitosan polymers to yield disaccharides and trisaccharides as the primary reaction products. These results make CsnS a potential candidate for the industrial manufacture of COS.
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http://dx.doi.org/10.3389/fmicb.2021.619731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943732PMC
February 2021

Endoplasmic reticulum stress, cell death and tumor: Association between endoplasmic reticulum stress and the apoptosis pathway in tumors (Review).

Oncol Rep 2021 Mar 12;45(3):801-808. Epub 2021 Jan 12.

School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China.

External and internal stimuli are often involved in the pathogenesis of tumors, and the deterioration of endoplasmic reticulum (ER) function within cells is also an important etiological factor of tumorigenesis resulting in the impairment of the endoplasmic reticulum, which is termed ER stress. The ER is an organelle that serves a crucial role in the process of protein synthesis and maturation, and also acts as a reservoir of calcium to maintain intracellular Ca2+ homeostasis. ER stress has been revealed to serve a critical role in tumorigenesis. In the present review, the association between ER stress‑related pathways and tumor cell apoptosis is examined. Primarily, the role of ER stress in tumor cell apoptosis is discussed, and it is stipulated that ER stress, induced by drugs both directly and indirectly, promotes tumor cell apoptosis.
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http://dx.doi.org/10.3892/or.2021.7933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859917PMC
March 2021

Dual-targeting tumor cells and tumor associated macrophages with lipid coated calcium zoledronate for enhanced lung cancer chemoimmunotherapy.

Int J Pharm 2021 Feb 15;594:120174. Epub 2020 Dec 15.

School of Basic Medicine, Qingdao University, Ningxia Road 308, Qingdao, PR China. Electronic address:

Lung cancer is the leading cause of cancer death among both men and women, and non-small cell lung cancer (NSCLC) accounts for almost 80% of such death. Tumor associated macrophage (TAMs) are abundant components in NSCLC. TAMs play critical roles in angiogenesis, immune escape and chemoresistance. Here we developed a dual-targeting drug delivery system (CaZOL@BMNPs) of zoledronate, which could bind to both tumor cells with overexpressed biotin receptors and macrophage mannose receptor (MMR) positive TAMs. The biotin- and mannose-modified lipid coated calcium zoledronate nanoparticles were preferentially internalized in both tumor cells and TAMs, and thereby inhibited their survivals. Our studies demonstrated that CaZOl@BMNPs treatment obviously reduced angiogenesis, reprogrammed immunosuppressive tumor microenvironment and eventually restrained tumor progression with negligible systemic toxicity. Collectively, CaZOL@BMNPs could be a promising approach by dual-targeting tumor cells and TAMs for NSCLS chemoimmunotherapy.
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http://dx.doi.org/10.1016/j.ijpharm.2020.120174DOI Listing
February 2021

Ischemia Reperfusion Injury: Opportunities for Nanoparticles.

ACS Biomater Sci Eng 2020 12 24;6(12):6528-6539. Epub 2020 Nov 24.

School of Basic Medicine, Qingdao University, Ningxia Road 308, Qingdao 110016, P.R. China.

Ischemia reperfusion (IR)-induced oxidative stress, accompanied by inflammatory responses, contributes to morbidity and mortality in numerous diseases such as acute coronary syndrome, stroke, organ transplantation, and limb injury. Ischemia results in profound hypoxia and tissue dysfunction, whereas subsequent reperfusion further aggravates ischemic tissue damage through inducing cell death and activating inflammatory responses. In this review, we highlight recent studies of therapeutic strategies against IR injury. Furthermore, nanotechnology offers significant improvements in this area. Hence, we also review recent advances in nanomedicines for IR therapy, suggesting them as potent and promising strategies to improve drug delivery to IR-injured tissues and achieve protective effects.
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http://dx.doi.org/10.1021/acsbiomaterials.0c01197DOI Listing
December 2020

Cloning and Characterization of a New β-Galactosidase from sp. QD01 and Its Potential in Synthesis of Galacto-Oligosaccharides.

Mar Drugs 2020 Jun 14;18(6). Epub 2020 Jun 14.

School of Basic Medicine, Qingdao University, Qingdao 266071, China.

As prebiotics, galacto-oligosaccharides (GOSs) can improve the intestinal flora and have important applications in medicine. β-galactosidases could promote the synthesis of GOSs in lactose and catalyze the hydrolysis of lactose. In this study, a new β-galactosidase gene (), which belongs to the glycoside hydrolase family 2, was cloned from marine bacterium sp. QD01 and expressed in . The molecular weight of Gal2A was 117.07 kDa. The optimal pH and temperature of Gal2A were 8.0 and 40 °C, respectively. At the same time, Gal2A showed wide pH stability in the pH range of 6.0-9.5, which is suitable for lactose hydrolysis in milk. Most metal ions promoted the activity of Gal2A, especially Mn and Mg. Importantly, Gal2A exhibited high transglycosylation activity, which can catalyze the formation of GOS from milk and lactose. These characteristics indicated that Gal2A may be ideal for producing GOSs and lactose-reducing dairy products.
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http://dx.doi.org/10.3390/md18060312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7344425PMC
June 2020

Erratum: Hispidulin prevents hypoxia-induced epithelial-mesenchymal transition in human colon carcinoma cells.

Am J Cancer Res 2020 1;10(4):1271-1273. Epub 2020 Apr 1.

Medical College, Qingdao University Qingdao 266071, Shandong, China.

[This corrects the article on p. 1047 in vol. 5, PMID: 26045985.].
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191100PMC
April 2020

Dihydrotanshinone I Attenuates Plaque Vulnerability in Apolipoprotein E-Deficient Mice: Role of Receptor-Interacting Protein 3.

Antioxid Redox Signal 2021 02 4;34(5):351-363. Epub 2020 Jun 4.

Key Lab for Pharmacology of Ministry of Education, Department of Pharmacology, Zunyi Medical College, Zunyi, China.

Vulnerable plaque disruption in advanced atherosclerosis leads to acute thrombus and subsequent myocardial infarction and severely threatens human health. Necroptosis of macrophage involved in the necrotic core is one key factor for plaque vulnerability. Dihydrotanshinone I (DHT) is a natural diterpenoid isolated from Danshen demonstrating effective anti-inflammatory property. It is accepted that inflammation plays a crucial role in the process of atherogenesis. However, whether DHT prevents atherosclerosis is poorly understood. Here, we investigated the effect of DHT on vulnerable plaque in an apolipoprotein E-deficient (ApoE) mice model of atherosclerosis and the underlying protective mechanisms. In the experiment, first LPS/ZVAD (LPS, lipopolysaccharide; ZVAD, ZVAD-FMK, a cell-permeable pan-caspase inhibitor) stimulated necroptosis of macrophage in a receptor-interacting protein 3 (RIP3)-dependent pathway, which was regulated by Toll-like receptor 4 (TLR4) dimerization. Further study illustrated that activated RIP3 evoked endoplasmic reticulum stress as well as reactive oxygen species generation. Both DHT and RIP3 silence reversed the above phenomena. In the experiment, aorta and serum samples were collected to determine features of plaque stability, including plaque size, necrotic core area, as well as collagen content in fibrous cap and the expression of related protein molecules. Both DHT and RIP3 inhibitor GSK872 significantly enhanced plaque stability in ApoE mice by reducing oxidative stress, shrinking necrotic core area, increasing collagen content, and decreasing RIP3 expression. Our study showed that DHT may stabilize vulnerable plaque by suppressing RIP3-mediated necroptosis of macrophage, which indicates its potential application as a lead compound for cardiovascular treatments, especially for advanced atherosclerosis. 34, 351-363.
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http://dx.doi.org/10.1089/ars.2019.7796DOI Listing
February 2021

Folic Acid-Modified Nanoerythrocyte for Codelivery of Paclitaxel and Tariquidar to Overcome Breast Cancer Multidrug Resistance.

Mol Pharm 2020 04 23;17(4):1114-1126. Epub 2020 Mar 23.

School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China.

The efflux of anticancer agents mediated by P-glycoprotein (P-gp) is one of the main causes of multidrug resistance (MDR) and eventually leads to chemotherapy failure. To overcome this problem, the delivery of anticancer agents in combination with a P-gp inhibitor using nanocarrier systems is considered an effective strategy. On the basis of the physiological compatibility and excellent drug loading ability of erythrocytes, we hypothesized that nanoerythrocytes could be used for the codelivery of an anticancer agent and a P-gp inhibitor to overcome MDR in breast cancer. Herein, a folic acid-modified nanoerythrocyte system (PTX/TQR NPs@NanoRBC-PEG/FA) was prepared to simultaneously transport paclitaxel and tariquidar, and the in vitro and in vivo characteristics of this delivery system were evaluated through several experiments. The results indicated that the average diameter and surface potential of this nanocarrier system were 159.8 ± 1.4 nm and -10.98 mV, respectively. Within 120 h, sustained release of paclitaxel was observed in both pH 6.5 media and pH 7.4 media. Tariquidar release from this nanocarrier suppressed the P-gp function of MCF-7/Taxol cells and significantly increased the intracellular paclitaxel level ( < 0.01 versus the PTX group). The results of the MTT assay indicated that the simultaneous transportation of paclitaxel and tariquidar could significantly inhibit the growth of MCF-7 cells or MCF-7/Taxol cells. After 48 h of incubation with PTX/TQR NPs@NanoRBC-PEG/FA, the viability of MCF-7 cells and MCF-7/Taxol cells decreased to 7.37% and 30.2%, respectively, and the IC values were 2.49 μM and 6.30 μM. Pharmacokinetic results illustrated that, compared with free paclitaxel, all test paclitaxel nanoformulations prolonged the drug release time and showed similar plasma concentration-time profiles. The peak concentration (), area under the curve (AUC), and half-life () of PTX/TQR NPs@NanoRBC-PEG/FA were 3.33 mg/L, 6.02 mg/L·h, and 5.84 h, respectively. Moreover, this active targeting nanocarrier dramatically increased the paclitaxel level in tumor tissues. Furthermore, compared with those of the other paclitaxel formulations, the cellular reactive oxygen species (ROS) and malondialdehyde (MDA) levels of the PTX/TQR NPs@NanoRBC-PEG/FA group increased by 1.38-fold ( < 0.01) and 1.36-fold ( < 0.01), respectively, and the activities of superoxide dismutase (SOD) and catalase (CAT) decreased to 67.8% ( < 0.01) and 65.4% ( < 0.001), respectively. More importantly, in vivo antitumor efficacy results proved that the PTX/TQR NPs@NanoRBC-PEG/FA group exerted an outstanding tumor inhibition effect with no marked body weight loss and fewer adverse effects. In conclusion, by utilizing the inherent and advantageous properties of erythrocytes and surface modification strategies, this biomimetic targeted drug delivery system provides a promising platform for the codelivery of an anticancer agent and a P-gp inhibitor to treat MDR in breast cancer.
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http://dx.doi.org/10.1021/acs.molpharmaceut.9b01148DOI Listing
April 2020

Enhancing the Thermo-Stability and Anti-Bacterium Activity of Lysozyme by Immobilization on Chitosan Nanoparticles.

Int J Mol Sci 2020 Feb 27;21(5). Epub 2020 Feb 27.

Department of Pharmacology, School of Basic Medicine, Qingdao University, Qingdao 266071, China.

The recent emergence of antibiotic-resistant bacteria requires the development of new antibiotics or new agents capable of enhancing antibiotic activity. Lysozyme degrades bacterial cell wall without involving antibiotic resistance and has become a new antibacterial strategy. However, direct use of native, active proteins in clinical settings is not practical as it is fragile under various conditions. In this study, lysozyme was integrated into chitosan nanoparticles (CS-NPs) by the ionic gelation technique to obtain lysozyme immobilized chitosan nanoparticles (Lys-CS-NPs) and then characterized by dynamic light scattering (DLS) and transmission electron microscopy (TEM), which showed a small particle size (243.1 ± 2.1 nm) and positive zeta potential (22.8 ± 0.2 mV). The immobilization significantly enhanced the thermal stability and reusability of lysozyme. In addition, compared with free lysozyme, Lys-CS-NPs exhibited superb antibacterial properties according to the results of killing kinetics in vitro and measurement of the minimum inhibitory concentration (MIC) of CS-NPs and Lys-CS-NPs against Pseudomonas aeruginosa (P. aeruginosa), Klebsiella pneumoniae (K. pneumoniae), Escherichia coli (E. coli), and Staphylococcus aureus (S. aureus). These results suggest that the integration of lysozyme into CS-NPs will create opportunities for the further potential applications of lysozyme as an anti-bacterium agent.
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http://dx.doi.org/10.3390/ijms21051635DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7084273PMC
February 2020

Julichrome Monomers from Marine Gastropod Mollusk-Associated Streptomyces and Stereochemical Revision of Julichromes Q and Q.

Chem Biodivers 2020 Apr 12;17(4):e2000057. Epub 2020 Mar 12.

CAS Key Laboratory of Tropical Marine Bio-resources and Ecology, Guangdong Key Laboratory of Marine Materia Medica, South China Sea Institute of Oceanology, Chinese Academy of Sciences, 164 West Xingang Road, Guangzhou, 510301, P. R. China.

Two julichrome monomers, julichromes Q (1) and Q (2), along with five known julichromes (Q , Q , Q , Q , Q , 3-7) and four known anthraquinones (chrysophanol, 4-acetylchrysophanol, islandicin, huanglongmycin A, 8-11), were isolated from the marine gastropod mollusk Batillaria zonalis-associated Streptomyces sampsonii SCSIO 054. This is the first report of julichromes isolated from a marine source. Extensive dissection of 1D and 2D NMR datasets combined with X-ray crystallography enabled rigorous elucidation of the previously reported configurations of julichrome Q (4) and related julichrome Q (5); both of the configuration at C(9) needs to be revised. In addition, julichrome Q (2) was found to display antibacterial activity against Micrococcus luteus and Bacillus subtilis with MICs of 2.0 and 8.0 μg mL ; four compounds (1, 3, 6, 7) also showed inhibitory activities against an array of methicillin-resistant Staphylococcus aureus, S. aureus and S. simulans AKA1 with MIC values ranging from 8 to 64 μg mL .
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http://dx.doi.org/10.1002/cbdv.202000057DOI Listing
April 2020

Preventive effects of a natural anti-inflammatory agent Salvianolic acid A on acute kidney injury in mice.

Food Chem Toxicol 2020 Jan 23;135:110901. Epub 2019 Oct 23.

School of Basic Medicine, Qingdao University, Qingdao, 266071, China. Electronic address:

Acute kidney injury (AKI) is an abrupt loss of kidney function with high mortality. Inflammatory is considered driving the progression of AKI. Salvianolic acid A (SA), one of the major ingredients of Salvia miltiorrhiza Bunge, displays plenty of biological effects. Herein, the effect of SA on lipopolysaccharide (LPS)-induced AKI in mice and further related mechanism in inflammatory cells were explored. In vivo experiments demonstrated that SA significantly ameliorated LPS-challenged AKI by preventing glomerulus atrophy and decreasing plasma creatinine and blood urea nitrogen (BUN) levels. Meanwhile, SA significantly decreased the release of serum inflammatory cytokines and blocked macrophage infiltration in damaged renal tissue. In in vitro studies, SA significantly decreased TNF-α and IL-6 release levels and altered the expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in LPS-stimulated macrophages, which were consistent with the results from in vivo experiments. Furthermore, SA that bound to Toll-Like Receptor 4 (TLR4) was able to reduce endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) generation in response to LPS stimulation. All silence of TLR4 gene, ROS scavenger and Ca chelator decreased inflammatory cytokines releases. Taken together, SA could be used as a potential therapeutic agent for preventing AKI by suppressing inflammatory responses.
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http://dx.doi.org/10.1016/j.fct.2019.110901DOI Listing
January 2020

Small Molecular Gemcitabine Prodrugs for Cancer Therapy.

Curr Med Chem 2020 ;27(33):5562-5582

Department of Medicinal Chemistry, School of Pharmacy, Qingdao University, Shandong Province, Qingdao, China.

Gemcitabine as a pyrimidine nucleoside analog anticancer drug has high efficacy for a broad spectrum of solid tumors. Gemcitabine is activated within tumor cells by sequential phosphorylation carried out by deoxycytidine kinase to mono-, di-, and triphosphate nucleotides with the last one as the active form. But the instability, drug resistance and toxicity severely limited its utilization in clinics. In the field of medicinal chemistry, prodrugs have proven to be a very effective means for elevating drug stability and decrease undesirable side effects including the nucleoside anticancer drug such as gemcitabine. Many works have been accomplished in design and synthesis of gemcitabine prodrugs, majority of which were summarized in this review.
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http://dx.doi.org/10.2174/0929867326666190816230650DOI Listing
December 2020

Anti-tumor activity evaluation of novel tubulin and HDAC dual-targeting inhibitors.

Bioorg Med Chem Lett 2019 09 24;29(18):2638-2645. Epub 2019 Jul 24.

Department of Medicinal Chemistry, School of Pharmacy, Qingdao University, Qingdao, Shandong, China. Electronic address:

Histone deacetylases (HDACs) have proven to be promising targets for the development of anti-cancer drugs. In this study, we reported a series of novel chalcone based tubulin and HDAC dual-targeting inhibitors. Three compounds inhibited the activities of HDAC and tubulin polymerization simultaneously and displayed anti-proliferative activities toward eleven human tumor cell lines. Compound 8a remarkably induced growth inhibition, apoptosis and G2/M phase arrest of A549 tumor cells. Finally, the inhibitory activities of 8a against HDAC6 and tubulin were rationalized by molecular docking studies.
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http://dx.doi.org/10.1016/j.bmcl.2019.07.045DOI Listing
September 2019

Characterization of an Alkaline Alginate Lyase with pH-Stable and Thermo-Tolerance Property.

Mar Drugs 2019 May 24;17(5). Epub 2019 May 24.

Department of Pharmacology, College of Basic Medicine, Qingdao University, Qingdao 266071, China.

Alginate oligosaccharides (AOS) show versatile bioactivities. Although various alginate lyases have been characterized, enzymes with special characteristics are still rare. In this study, a polysaccharide lyase family 7 (PL7) alginate lyase-encoding gene, , was cloned from the marine bacterium sp. SY01 and expressed in The purified alginate lyase Aly08, with a molecular weight of 35 kDa, showed a specific activity of 841 U/mg at its optimal pH (pH 8.35) and temperature (45 °C). Aly08 showed good pH-stability, as it remained more than 80% of its initial activity in a wide pH range (4.0-10.0). Aly08 was also a thermo-tolerant enzyme that recovered 70.8% of its initial activity following heat shock treatment for 5 min. This study also demonstrated that Aly08 is a polyG-preferred enzyme. Furthermore, Aly08 degraded alginates into disaccharides and trisaccharides in an endo-manner. Its thermo-tolerance and pH-stable properties make Aly08 a good candidate for further applications.
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http://dx.doi.org/10.3390/md17050308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562718PMC
May 2019

Design and Synthesis of a Chitodisaccharide-Based Affinity Resin for Chitosanases Purification.

Mar Drugs 2019 Jan 21;17(1). Epub 2019 Jan 21.

Department of Pharmacology, College of basic Medicine, Qingdao University, Qingdao 266071, China.

Chitooligosaccharides (CHOS) have gained increasing attention because of their important biological activities. Enhancing the efficiency of CHOS production essentially requires screening of novel chitosanase with unique characteristics. Therefore, a rapid and efficient one-step affinity purification procedure plays important roles in screening native chitosanases. In this study, we report the design and synthesis of affinity resin for efficient purification of native chitosanases without any tags, using chitodisaccharides (CHDS) as an affinity ligand, to couple with Sepharose 6B via a spacer, cyanuric chloride. Based on the CHDS-modified affinity resin, a one-step affinity purification method was developed and optimized, and then applied to purify three typical glycoside hydrolase (GH) families: 46, 75, and 80 chitosanase. The three purified chitosanases were homogeneous with purities of greater than 95% and bioactivity recovery of more than 40%. Moreover, we also developed a rapid and efficient affinity purification procedure, in which tag-free chitosanase could be directly purified from supernatant of bacterial culture. The purified chitosanases samples using such a procedure had apparent homogeneity, with more than 90% purity and 10⁻50% yield. The novel purification methods established in this work can be applied to purify native chitosanases in various scales, such as laboratory and industrial scales.
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http://dx.doi.org/10.3390/md17010068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6356299PMC
January 2019

Purification and Characterization of A New Cold-Adapted and Thermo-Tolerant Chitosanase from Marine Bacterium sp. SY39.

Molecules 2019 Jan 6;24(1). Epub 2019 Jan 6.

Department of Pharmacology, College of Basic Medicine, Qingdao University, Qingdao 266071, China.

Chitosanases play an important role in chitosan degradation, forming enzymatic degradation products with several biological activities. Although many chitosanases have been discovered and studied, the enzymes with special characteristics are still rather rare. In this study, a new chitosanase, CsnM, with an apparent molecular weight of 28 kDa was purified from the marine bacterium sp. SY39. CsnM is a cold-adapted enzyme, which shows highest activity at 40 °C and exhibits 30.6% and 49.4% of its maximal activity at 10 and 15 °C, respectively. CsnM is also a thermo-tolerant enzyme that recovers 95.2%, 89.1% and 88.1% of its initial activity after boiling for 5, 10 and 20 min, respectively. Additionally, CsnM is an endo-type chitosanase that yields chitodisaccharide as the main product (69.9% of the total product). It's cold-adaptation, thermo-tolerance and high chitodisaccharide yield make CsnM a superior candidate for biotechnological application to produce chitooligosaccharides.
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http://dx.doi.org/10.3390/molecules24010183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6337222PMC
January 2019

Hyperspectral Image Classification with Capsule Network Using Limited Training Samples.

Sensors (Basel) 2018 Sep 18;18(9). Epub 2018 Sep 18.

State Key Laboratory of Geohazard Prevention and Geoenvironment Protection, Chengdu University of Technology, Chengdu 610059, China.

Deep learning techniques have boosted the performance of hyperspectral image (HSI) classification. In particular, convolutional neural networks (CNNs) have shown superior performance to that of the conventional machine learning algorithms. Recently, a novel type of neural networks called capsule networks (CapsNets) was presented to improve the most advanced CNNs. In this paper, we present a modified two-layer CapsNet with limited training samples for HSI classification, which is inspired by the comparability and simplicity of the shallower deep learning models. The presented CapsNet is trained using two real HSI datasets, i.e., the PaviaU (PU) and SalinasA datasets, representing complex and simple datasets, respectively, and which are used to investigate the robustness or representation of every model or classifier. In addition, a comparable paradigm of network architecture design has been proposed for the comparison of CNN and CapsNet. Experiments demonstrate that CapsNet shows better accuracy and convergence behavior for the complex data than the state-of-the-art CNN. For CapsNet using the PU dataset, the Kappa coefficient, overall accuracy, and average accuracy are 0.9456, 95.90%, and 96.27%, respectively, compared to the corresponding values yielded by CNN of 0.9345, 95.11%, and 95.63%. Moreover, we observed that CapsNet has much higher confidence for the predicted probabilities. Subsequently, this finding was analyzed and discussed with probability maps and uncertainty analysis. In terms of the existing literature, CapsNet provides promising results and explicit merits in comparison with CNN and two baseline classifiers, i.e., random forests (RFs) and support vector machines (SVMs).
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http://dx.doi.org/10.3390/s18093153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6165568PMC
September 2018

Mismatch in elevational shifts between satellite observed vegetation greenness and temperature isolines during 2000-2016 on the Tibetan Plateau.

Glob Chang Biol 2018 11 26;24(11):5411-5425. Epub 2018 Sep 26.

Department of Ecology, College of Urban and Environmental Sciences, Peking University, Beijing, China.

Climate warming on the Tibetan Plateau tends to induce an uphill shift of temperature isolines. Observations and process-based models have both shown that climate warming has resulted in an increase in vegetation greenness on the Tibetan Plateau in recent decades. However, it is unclear whether the uphill shift of temperature isolines has caused greenness isolines to shift upward and whether the two shifts match each other. Our analysis of satellite observed vegetation greenness during the growing season (May-Sep) and gridded climate data for 2000-2016 documented a substantial mismatch between the elevational shifts of greenness and temperature isolines. This mismatch is probably associated with a lagging response of greenness to temperature change and with the elevational gradient of greenness. The lagging response of greenness may be associated with water limitation, resources availability, and acclimation. This lag may weaken carbon sequestration by Tibetan ecosystems, given that greenness is closely related to primary carbon uptake and ecosystem respiration increases exponentially with temperature. We also found that differences in terrain slope angle accounted for large spatial variations in the elevational gradient of greenness and thus the velocity of elevational shifts of greenness isolines and the sensitivity of elevational shifts of greenness isolines to temperature, highlighting the role of terrain effects on the elevational shifts of greenness isolines. The mismatches and the terrain effect found in this study suggest that there is potentially large micro-topographical difference in response and acclimation/adaptation of greenness to temperature changes in plants. More widespread in situ measurements and fine-resolution remote sensing observations and fine-gridded climate data are required to attribute the mismatch to specific environmental drivers and ecological processes such as vertical changes in community structure, plant physiology, and distribution of species.
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http://dx.doi.org/10.1111/gcb.14432DOI Listing
November 2018

Hispidulin suppresses cell growth and metastasis by targeting PIM1 through JAK2/STAT3 signaling in colorectal cancer.

Cancer Sci 2018 May 17;109(5):1369-1381. Epub 2018 Apr 17.

Department of Pharmacology, School of Pharmacy, Qingdao University, Qingdao, China.

Colorectal cancer (CRC) accounts for over 600 000 deaths annually worldwide. The current study aims to evaluate the value of proto-oncogene PIM1 as a therapeutic target in CRC and investigate the anticancer activity of hispidulin, a naturally occurring phenolic flavonoid compound, against CRC. Immunohistochemistry analysis showed that PIM1 was upregulated in CRC tissue. The role of PIM1 as an oncogene was evidenced by the fact that PIM1 knockdown inhibits cell growth, induces apoptosis, and suppresses invasion. Our results showed that hispidulin exerts antitumor activity in CRC through inhibiting the expression of PIM1. Moreover, our findings revealed that hispidulin downregulated the expression of PIM1 by inhibiting JAK2/STAT3 signaling by generating reactive oxygen species. Furthermore, our in vivo studies showed that hispidulin can significantly inhibit tumor growth and metastasis in CRC. Collectively, our results provide an experimental basis for trialing hispidulin in CRC treatment. PIM1 can be considered a potential therapeutic target in CRC.
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http://dx.doi.org/10.1111/cas.13575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5980372PMC
May 2018

Cloning, Expression, and Biochemical Characterization of Two New Oligoalginate Lyases with Synergistic Degradation Capability.

Mar Biotechnol (NY) 2018 Feb 24;20(1):75-86. Epub 2018 Jan 24.

Department of Pharmacology, College of basic Medicine, Qingdao University, Qingdao, 266071, China.

Alginate, the most abundant carbohydrate presents in brown macroalgae, has recently gained increasing attention as an alternative biomass for the production of biofuel. Oligoalginate lyases catalyze the degradation of alginate oligomers into monomers, a prerequisite for bioethanol production. In this study, two new oligoalginate lyase genes, oalC6 and oalC17, were cloned from Cellulophaga sp. SY116, and expressed them in Escherichia coli. The deduced oligoalginate lyases, OalC6 and OalC17, belonged to the polysaccharide lyase (PL) family 6 and 17, respectively. Both showed less than 50% amino acid identity with all of the characterized oligoalginate lyases. Moreover, OalC6 and OalC17 could degrade both alginate polymers and oligomers into monomers in an exolytic mode. Substrate specificity studies demonstrated that OalC6 preferred α-L-guluronate (polyG) blocks, while OalC17 preferred poly β-D-mannuronate (polyM) blocks. The combination of OalC6 and OalC17 showed synergistic degradation ability toward both alginate polymers and oligomers. Finally, an efficient process for the production of alginate monomers was established by combining the new-isolated exotype alginate lyases (i.e., OalC6 and OalC17) and the endotype alginate lyase AlySY08. Overall, our work provides new insights for the development of novel biotechnologies for biofuel production from seaweed.
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http://dx.doi.org/10.1007/s10126-017-9788-yDOI Listing
February 2018

Long-term trends and spatial patterns of satellite-retrieved PM concentrations in South and Southeast Asia from 1999 to 2014.

Sci Total Environ 2018 Feb 29;615:177-186. Epub 2017 Sep 29.

State Key Laboratory of Earth Surface Processes and Resource Ecology, Beijing Normal University, Beijing 100875, China.

Fine particulate matter, or PM, is a serious air pollutant and has significant effects on human health, including premature death. Based on a long-term series of satellite-retrieved PM concentrations, this study analyzed the spatial and temporal characteristics of PM in South and Southeast Asia (SSEA) from 1999 to 2014 using standard deviation ellipse and trend analyses. A health risk assessment of human exposure to PM between 1999 and 2014 was then undertaken. The results show that PM concentrations increased in most areas of SSEA from 1999 to 2014 and exceeded the World Health Organization average annual limit of primary PM standards. Bangladesh, Pakistan and India experienced average PM values higher than the total average for SSEA. From 1999 to 2014, the entirety of SSEA exhibited an increased rate of 0.02μg/m/year on average. Bangladesh and Myanmar witnessed greater incremental rates of PM than India. Correspondingly, the center of the average regional PM concentration gradually shifted to the southeast during the study period. The proportion of areas with PM concentrations exceeding 35μg/m increased consistently, and the areas with PM concentrations below 15μg/m decreased continuously. The proportion of the population exposed to high PM (above 35μg/m) increased annually. The extent of high-health-risk areas in SSEA expanded in size and extent between 1999 and 2014, particularly in North India, Bangladesh and East Pakistan. Therefore, all of SSEA should receive special attention, and strict controls on PM concentrations in SSEA countries are urgently required.
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http://dx.doi.org/10.1016/j.scitotenv.2017.09.241DOI Listing
February 2018

The anti-proliferative effects of oleanolic acid on A7r5 cells-Role of UCP2 and downstream FGF-2/p53/TSP-1.

Cell Biol Int 2017 Dec 31;41(12):1296-1306. Epub 2017 Aug 31.

Qingdao University Medical College, 308 Ningxia Road, Qingdao 266071, Shandong, China.

Vascular smooth muscle cell (VSMC) proliferation is a major contributor to atherosclerosis. This study investigated the inhibitory effects of oleanolic acid (OA) against oxidized low-density lipoprotein (ox-LDL)-induced VSMC proliferation in A7r5 cells and explored underlying molecular mechanism. The cell proliferation was quantified with cell counting kit-8 (CCK-8), in which ox-LDL significantly increased A7r5 cells proliferation, while OA pretreatment effectively alleviated such changes without inducing overt cytotoxicity, as indicated by lactate dehydrogenase (LDH) assay. Quantitative real-time RT-PCR (qRT-PCR) and Western blotting revealed increased UCP2 and FGF-2 expression levels as well as decreased p53 and TSP-1 expression levels in A7r5 cells following ox-LDL exposure, while OA pretreatment reversed such changes. Furthermore, inhibiting UCP2 with genipin remarkably reversed the changes in the expression levels of FGF-2, p53, and TSP-1 induced by ox-LDL exposure; silencing FGF-2 with siRNA did not significantly change the expression levels of UCP2 but effectively reversed the changes in the expression levels of p53 and TSP-1, and activation of p53 with PRIMA-1 only significantly affected the changes in the expression levels of TSP-1, but not in UCP2 or FGF-2, suggesting a UCP-2/FGF-2/p53/TSP-1 signaling in A7r5 cells response to ox-LDL exposure. Additionally, co-treatment of OA and genipin exhibited similar effects to the expression levels of UCP2, FGF-2, p53, and TSP-1 as OA or genipin solo treatment in ox-LDL-exposed A7r5 cells, suggesting the involvement of UCP-2/FGF-2/p53/TSP-1 in the mechanism of OA. In conclusion, OA inhibits ox-LDL-induced VSMC proliferation in A7r5 cells, the mechanism involves the changes in UCP-2/FGF-2/p53/TSP-1.
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http://dx.doi.org/10.1002/cbin.10838DOI Listing
December 2017

The role of autophagy in pro-inflammatory responses of microglia activation via mitochondrial reactive oxygen species in vitro.

J Neurochem 2017 07 18;142(2):215-230. Epub 2017 May 18.

Department of Clinical Laboratory, the Affiliated Hospital of Medical College Qingdao University, Qingdao, China.

Microglia over-activation contributes to neurodegenerative processes by neurotoxin factors and pro-inflammatory molecules of pro-inflammatory processes. Mitochondrial reactive oxygen species (ROS) and autophagy pathway might be involved in microglial activation, but the underlying mechanism is unclear. Here, we regulated autophagy pathway of microglia in vitro by autophagy inhibition (3-methyladenine treatment, siRNA-Beclin 1 or siRNA-ATG5 transfection) or induction (rapamycin treatment) in murine microglial BV-2 cells or cultured primary mouse microglial cells. And we found that autophagy inhibition could sensitize mitochondrial profile and microglial activation of cultured microglial cells, demonstrated by significant production of mitochondrial ROS, loss of mitochondrial membrane potential, secretion of pro-inflammatory cytokines including interleukin 1β (IL-1β), interleukin 6 (IL-6), interleukin 12 (IL-12) and tumor necrosis factor α and marked activation of mitogen-activated proteinkinases (MAPKs) and nuclear factor κB (NF-κB). These effects could be blocked by specific inhibitors of MAPK and NF-κB or mitochondrial antioxidants, Mito-TEMPO. Meanwhile, induction of autophagy with rapamycin treatment could significantly suppress microglial inflammatory responses, mitochondrial ROS production, activation of MAPKs and NF-κB. Taken together, our in vitro results from primary cultured microglia and BV-2 cell lines indicated that autophagy inhibition might participate in brain macrophage or microglia over-activation and mitochondrial ROS generation might be involved in the regulatory microglial pro-inflammatory responses.
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http://dx.doi.org/10.1111/jnc.14042DOI Listing
July 2017

l-carnitine protects human hepatocytes from oxidative stress-induced toxicity through Akt-mediated activation of Nrf2 signaling pathway.

Can J Physiol Pharmacol 2016 May 18;94(5):517-25. Epub 2016 Feb 18.

c Department of Pharmacology, Medical College, Qingdao University, 308 Ningxia Road, Qingdao 266071, China.

In our previous study, l-carnitine was shown to have cytoprotective effect against hydrogen peroxide (H2O2)-induced injury in human normal HL7702 hepatocytes. The aim of this study was to investigate whether the protective effect of l-carnitine was associated with the nuclear factor erythroid 2 (NFE2)-related factor 2 (Nrf2) pathway. Our results showed that pretreatment with l-carnitine augmented Nrf2 nuclear translocation, DNA binding activity and heme oxygenase-1 (HO-1) expression in H2O2-treated HL7702 cells, although l-carnitine treatment alone had no effect on them. Analysis using Nrf2 siRNA demonstrated that Nrf2 activation was involved in l-carnitine-induced HO-1 expression. In addition, l-carnitine-mediated protection against H2O2 toxicity was abrogated by Nrf2 siRNA, indicating the important role of Nrf2 in l-carnitine-induced cytoprotection. Further experiments revealed that l-carnitine pretreatment enhanced the phosphorylation of Akt in H2O2-treated cells. Blocking Akt pathway with inhibitor partly abrogated the protective effect of l-carnitine. Moreover, our finding demonstrated that the induction of Nrf2 translocation and HO-1 expression by l-carnitine directly correlated with the Akt pathway because Akt inhibitor showed inhibitory effects on the Nrf2 translocation and HO-1 expression. Altogether, these results demonstrate that l-carnitine protects HL7702 cells against H2O2-induced cell damage through Akt-mediated activation of Nrf2 signaling pathway.
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http://dx.doi.org/10.1139/cjpp-2015-0305DOI Listing
May 2016

Cytoprotective Effects of Oleanolic Acid in Human Umbilical Vascular Endothelial Cells is Mediated Via UCP2/ROS/Cytochrome C/AIF Pathway.

J Cardiovasc Pharmacol 2016 Apr;67(4):344-50

*Department of Pharmacology, School of Pharmacy, Qingdao University, Qingdao, China; and†Department of Pharmacy, The Affiliated Hospital of Medical College, Qingdao University, Qingdao, China.

The aim of this study is to assess the potential protective effect of oleanolic acid (OA) against ox-LDL induced damage in human umbilical vascular endothelial cells (HUVECs) and investigate potential mechanism of action including antioxidative effects and inhibition of mitochondria apoptosis pathway. Cell counting kit 8 was used to evaluate the viability of HUVECs. 2', 7'-DCFH-DA staining and flow cytometry was used to assess the levels of intracellular reactive oxygen species in HUVECs. The protein expression levels of uncoupling protein 2, cytochrome C, and apoptosis induction factors were measured by western blotting. The results indicated that OA treatment alleviated ox-LDL induced cytotoxicity in HUVECs and ameliorated the reactive oxygen species levels. Western blotting results demonstrated that OA treatment increased the expression level of uncoupling protein 2 and decreased the release of cytochrome C and apoptosis induction factors from mitochondria to cytoplasm, suggesting inhibition of mitochondria apoptosis pathway. In conclusion, OA could protect HUVECs from ox-LDL-induced cytotoxicity; its antioxidant property and inhibition of mitochondria apoptosis are likely crucial contributors.
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http://dx.doi.org/10.1097/FJC.0000000000000360DOI Listing
April 2016

[A clinical study on the treatment of mucocele by bleomyin A5 combined with phosphorus-32 colloid].

Zhonghua Kou Qiang Yi Xue Za Zhi 2015 Oct;50(10):624-6

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Objective: To evaluate the effect of bleomyin A5 combined with phosphorus-32 colloid in the treatment of mucocele.

Methods: A total of 214 patients divided into three groups, bleomyin A5 (50 cases), phosphorus-32 colloid (50 cases) and bleomyin A5 combined with phosphorus-32 colloid (114 cases).

Results: The efficacy of bleomyin A5 group, phosphorus-32 colloid group, and bleomyin A5 combined with phosphorus-32 colloid group was 84% (42/50), 82% (41/50) and 98% (112/114), respectively. There were significant difference in efficacy among the three groups (P < 0.05). The phosphorus-32 colloid group and the bleomyin A5 group had no significant difference in efficacy (P > 0.05).

Conclusions: The independent use of bleomyin A5 and phosphorus-32 colloid is effective, but the combined use of the two methods is more effective.
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October 2015