Publications by authors named "Ji-Hua Liu"

57 Publications

Hybrid Cell Membrane-Functionalized Biomimetic Nanoparticles for Targeted Therapy of Osteosarcoma.

Int J Nanomedicine 2022 22;17:837-854. Epub 2022 Feb 22.

Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, People's Republic of China.

Purpose: In order to prepare a biomimetic nano-carrier which has inflammatory chemotaxis, homologous targeting and reduce immune clearance, for targeted chemotherapy of osteosarcoma, we fabricated the paclitaxel-loaded poly(lactic-co-glycolic) acid (PLGA) nanoparticles coated with 143B-RAW hybrid membrane ([email protected][143B-RAW] NPs) and evaluate its anti-cancer efficacy in vitro and vivo.

Methods: [email protected][143B-RAW] NPs were prepared by the ultrasonic method and were characterized by size, zeta potential, polymer dispersion index (PDI), Coomassie bright blue staining, transmission electron microscopy (TEM) and high performance liquid chromatography (HPLC). Cellular uptake, cell viability assay, flow cytometry and chemotactic effect of [email protected][143B-RAW] NPs were evaluated in vitro. Biodistribution, anti-cancer therapeutic efficacy and safety of [email protected][143B-RAW] NPs were evaluated in 143B osteosarcoma xenograft mice.

Results: The hybrid membrane successfully coated onto the surface of PLGA nanoparticles. [email protected][143B-RAW] NPs had a drug loading capacity of 4.24 ± 0.02% and showed targeting ability to osteosarcoma. [email protected][143B-RAW] NPs showed high cellular uptake and improved anti-cancer efficacy against 143B cells. More importantly, [email protected][143B-RAW] NPs treatment suppressed tumor growth in tumor-bearing mice with minimal damage to normal tissues.

Conclusion: [email protected][143B-RAW] NPs could be used for targeted drug delivery and osteosarcoma therapy.
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http://dx.doi.org/10.2147/IJN.S346685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8881933PMC
March 2022

The dopamine D1-D2DR complex in the rat spinal cord promotes neuropathic pain by increasing neuronal excitability after chronic constriction injury.

Exp Mol Med 2021 02 9;53(2):235-249. Epub 2021 Feb 9.

Jiangsu Key Laboratory of TCM Evaluation and Translational Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, 211198, China.

Dopamine D1 receptor (D1DR) and D2 receptor (D2DR) are closely associated with pain modulation, but their exact effects on neuropathic pain and the underlying mechanisms remain to be identified. Our research revealed that intrathecal administration of D1DR and D2DR antagonists inhibited D1-D2DR complex formation and ameliorated mechanical and thermal hypersensitivity in chronic constriction injury (CCI) rats. The D1-D2DR complex was formed in the rat spinal cord, and the antinociceptive effects of D1DR and D2DR antagonists could be reversed by D1DR, D2DR, and D1-D2DR agonists. Gαq, PLC, and IP3 inhibitors also alleviated CCI-induced neuropathic pain. D1DR, D2DR, and D1-D2DR complex agonists all increased the intracellular calcium concentration in primary cultured spinal neurons, and this increase could be reversed by D1DR, D2DR antagonists and Gαq, IP3, PLC inhibitors. D1DR and D2DR antagonists significantly reduced the expression of p-PKC γ, p-CaMKII, p-CREB, and p-MAPKs. Levo-corydalmine (l-CDL), a monomeric compound in Corydalis yanhusuo W.T. Wang, was found to obviously suppress the formation of the spinal D1-D2DR complex to alleviate neuropathic pain in CCI rats and to decrease the intracellular calcium concentration in spinal neurons. l-CDL-induced inhibition of p-PKC γ, p-MAPKs, p-CREB, and p-CaMKII was also reversed by D1DR, D2DR, and D1-D2DR complex agonists. In conclusion, these results indicate that D1DR and D2DR form a complex and in turn couple with the Gαq protein to increase neuronal excitability via PKC γ, CaMKII, MAPK, and CREB signaling in the spinal cords of CCI rats; thus, they may serve as potential drug targets for neuropathic pain therapy.
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http://dx.doi.org/10.1038/s12276-021-00563-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080784PMC
February 2021

Blockade of spinal dopamine D1/D2 receptor suppresses activation of NMDA receptor through Gαq and Src kinase to attenuate chronic bone cancer pain.

J Adv Res 2021 Feb 13;28:139-148. Epub 2020 Aug 13.

Jiangsu Key Laboratory of TCM Evaluation and Translational Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 211198, China.

Introduction: Spinal N-methyl-D-aspartate receptor (NMDAR) is vital in chronic pain, while NMDAR antagonists have severe side effects. NMDAR has been reported to be controlled by G protein coupled receptors (GPCRs), which might present new therapeutic targets to attenuate chronic pain. Dopamine receptors which belong to GPCRs have been reported could modulate the NMDA-mediated currents, while their exact effects on NMDAR in chronic bone cancer pain have not been elucidated.

Objectives: This study was aim to explore the effects and mechanisms of dopamine D1 receptor (D1DR) and D2 receptor (D2DR) on NMDAR in chronic bone cancer pain.

Methods: A model for bone cancer pain was established using intra-tibia bone cavity tumor cell implantation (TCI) of Walker 256 in rats. The nociception was assessed by Von Frey assay. A range of techniques including the fluorescent imaging plate reader, western blotting, and immunofluorescence were used to detect cell signaling pathways. Primary cultures of spinal neurons were used for in vitro evaluation.

Results: Both D1DR and D2DR antagonists decreased NMDA-induced upregulation of Ca oscillations in primary culture spinal neurons. Additionally, D1DR/D2DR antagonists inhibited spinal Calcitonin Gene-Related Peptide (CGRP) and c-Fos expression and alleviated bone cancer pain induced by TCI which could both be reversed by NMDA. And D1DR/D2DR antagonists decreased p-NR1, p-NR2B, and Gαq protein, p-Src expression. Both Gαq protein and Src inhibitors attenuated TCI-induced bone cancer pain, which also be reversed by NMDA. The Gαq protein inhibitor decreased p-Src expression. In addition, D1DR/D2DR antagonists, Src, and Gαq inhibitors inhibited spinal mitogen-activated protein kinase (MAPK) expression in TCI rats, which could be reversed by NMDA.

Conclusions: Spinal D1DR/D2DR inhibition eliminated NMDAR-mediated spinal neuron activation through Src kinase in a Gαq-protein-dependent manner to attenuate TCI-induced bone cancer pain, which might present a new therapeutic strategy for bone cancer pain.
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http://dx.doi.org/10.1016/j.jare.2020.08.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7753228PMC
February 2021

The Value of Enhanced MR Radiomics in Estimating the IDH1 Genotype in High-Grade Gliomas.

Biomed Res Int 2020 24;2020:4630218. Epub 2020 Oct 24.

Radiology Department, The Affiliated Hospital of Qingdao University, Qingdao 266000, China.

Background: The prognosis of IDH1-mutant glioma is significantly better than that of wild-type glioma, and the preoperative identification of IDH mutations in glioma is essential for the formulation of surgical procedures and prognostic assessment.

Purpose: To explore the value of a radiomic model based on preoperative-enhanced MR images in the assessment of the IDH1 genotype in high-grade glioma.

Materials And Methods: A retrospective analysis was performed on 182 patients with high-grade glioma confirmed by surgical pathology between December 2012 and January 2019 in our hospital with complete preoperative brain-enhanced MR images, including 79 patients with an IDH1 mutation (45 patients with WHO grade III and 34 patients with WHO grade IV) and 103 patients with wild-type IDH1 (33 patients with WHO grade III and 70 patients with WHO grade IV). Patients were divided into a primary dataset and a validation dataset at a ratio of 7 : 3 using a stratified random sampling; radiomic features were extracted using A.K. (Analysis Kit, GE Healthcare) software and were initially reduced using the Kruskal-Wallis and Spearman analyses. Lasso was finally conducted to obtain the optimized subset of the feature to build the radiomic model, and the model was then tested with cross-validation. ROC (receiver operating characteristic curve) analysis was performed to evaluate the performance of the model.

Results: The radiomic model showed good discrimination in both the primary dataset (AUC = 0.87, 95% CI: 0.754 to 0.855, ACC = 0.798, sensitivity = 85.5%, specificity = 75.4%, positive predictive value = 0.734, and negative predictive value = 0.867) and the validation dataset (AUC = 0.86, 95% CI: 0.690 to 0.913, ACC = 0.789, sensitivity = 91.3%, specificity = 69.0%, positive predictive value = 0.700, and negative predictive value = 0.909).

Conclusion: The radiomic model, based on the preoperative-enhanced MR, can effectively predict the IDH1 genotype in high-grade glioma.
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http://dx.doi.org/10.1155/2020/4630218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604586PMC
May 2021

Regulation of the K-JNK gap junction signaling pathway by immunomodulator astragaloside IV attenuates neuropathic pain.

Reg Anesth Pain Med 2020 12 22;45(12):955-963. Epub 2020 Sep 22.

Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu, China

Background And Objectives: Gap junctions play a pivotal role in contributing to the formation of astroglial networks and in chronic pain. However, the mechanisms underlying the dysfunction of astroglial gap junctions in chronic pain have not been fully elucidated.

Methods: Chronic constriction injury (CCI) of the sciatic nerve was used to establish rat neuropathic pain model. C6 cells were used to perform experiments in vitro. Von Frey hairs and Hargreave's method were used to determine the withdrawal threshold of rats. Protein expression was detected by immunofluorescence and western blotting.

Results: Astragaloside IV (AST IV) significantly attenuated neuropathic pain and suppressed the excitation of spinal astrocytes in rats with CCI. The antinociceptive effect of AST IV was reversed by the gap junction decoupler carbenoxolone (CBX). AST IV inhibited the high expression of phosphorylated connexin 43 (p-Cx43) and p-c-Jun N-terminal kinase (p-JNK) in spinal cord of rats with CCI. JNK inhibitor alleviated neuropathic pain, which was reversed by CBX. JNK inhibitor decreased the high expression of p-Cx43 in both rats with CCI and tumor necrosis factor-alpha (TNF-α)-treated C6 cells. Additionally, the analgesic effect of AST IV was reversed by the adenosine triphosphate-sensitive potassium (K) channel blocker, glibenclamide (Glib). Glib abolished the inhibitory effects of AST IV on p-JNK and p-Cx43 both in vivo and in vitro. K channel opener (KCO) mimicked the inhibitory effects of AST IV on p-JNK and p-Cx43 in TNF-α-treated C6 cells.

Conclusion: Our results indicate that the sciatic nerve CCI induces the dysfunction of gap junctions in the spinal cord by activating K/JNK signaling to contribute to neuropathic pain. AST IV attenuates neuropathic pain via regulating the K-JNK gap junction axis.
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http://dx.doi.org/10.1136/rapm-2020-101411DOI Listing
December 2020

A rapid strategy for screening high-efficiency PCSK9 inhibitors from Ginkgo biloba leaves by ligand fishing, HPLC-Q-TOF-MS and interdisciplinary assay.

J Food Drug Anal 2020 Jun 15;28(2):273-282. Epub 2020 Jun 15.

Jiangsu Key Laboratory of TCM Evaluation and Translational Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 211198, PR China.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an attractive target for new cholesterol-lowering drug development. Here, we developed a method integrating ligand fishing, HPLC-Q-TOF-MS and interdisciplinary assay, aiming to explore potential PCSK9 inhibitors from mixtures rapidly and accurately. PCSK9 was expressed and purified firstly, and then the recombined PCSK9 was coated on the surface of magnetic beads (MBs). The PCSK9-immobilized MBs (PCSK9-MBs) were used for ligand fishing combined with HPLC and Q-TOF-MS/MS. Ginkgo biloba leaves (GBL), an herbal medicine widely used in Asia and Europe with good efficacy in treatment of hypercholesterolemia, were chosen as an illustration for ligand fishing. Two PCSK9 ligands were discovered from GBL and identified as kaempferol-3-O-rutinoside (1) and kaempferol 3-O-26″-(6‴-p-coumaroyl) glucosylrhamnoside (KCGR) (2). In order to verify fishing results and pick out more powerful PCSK9 inhibitors, molecular docking assay was further performed and KCGR was optimized to be an excellent PCSK9 inhibitor by the confirmation of affinity and activity bioassay. These results suggested that the developed approach could be applied to screen and analysis potential bioactive constituents from mixtures, which may improve the efficiency of drug discovery. Moreover, KCGR separated from GBL was expected to be a potential candidate of PCSK9 inhibitors.
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http://dx.doi.org/10.38212/2224-6614.1061DOI Listing
June 2020

Rapid and sensitive detection of NGAL for the prediction of acute kidney injury via a polydopamine nanosphere/aptamer nanocomplex coupled with DNase I-assisted recycling amplification.

Analyst 2020 May;145(10):3620-3625

State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Research Center for Traceability and Standardization of TCMs, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, P.R. China.

Early detection of acute kidney injury (AKI) is important, as early intervention and treatment can prevent further kidney injury and improve kidney health. Neutrophil gelatinase-associated lipocalin (NGAL) has emerged as the earliest and promising non-invasive biomarker of AKI in urine, and has been used as a new predictive biomarker of AKI in the bench-to-bedside journey. In this work, a nanocomplex composed of a polydopamine nanosphere (PDANS) and a fluorophore-labelled aptamer has been constructed for the detection of NGAL using a DNase I-assisted recycling amplification strategy. After the addition of NGAL, the fluorescence intensity increases linearly over the NGAL concentration range from 12.5 to 400 pg mL-1. The limit of detection of this strategy is found to be 6.25 pg mL-1, which is almost 5 times lower than that of the method that does not involve DNase I. The process can be completed within 1 h, indicating a fast fluorescence response. Furthermore, the method using the nanocomplex coupled with DNase I has been successfully utilized for the detection of NGAL in the urine from cisplatin-induced AKI and five-sixths nephrectomized mice, demonstrating its promising ability for the early prediction of AKI. This method also demonstrates the protective effect of the Huangkui capsule on AKI, and provides an effective way to screen potentially protective drugs for renal disease.
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http://dx.doi.org/10.1039/d0an00474jDOI Listing
May 2020

Suppression of peripheral NGF attenuates neuropathic pain induced by chronic constriction injury through the TAK1-MAPK/NF-κB signaling pathways.

Cell Commun Signal 2020 04 20;18(1):66. Epub 2020 Apr 20.

Jiangsu Key Laboratory of TCM Evaluation and Translational Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, Jiangsu, China.

Background: Anti-nerve growth factor (NGF) monoclonal antibodies (anti-NGF mAbs) have been reported to significantly attenuate pain, but the mechanism involved has not been fully elucidated, and the serious adverse events associated with mAbs seriously limit their clinical use. This study further investigated the mechanism by which peripheral NGF is involved in neuropathic pain and found safe, natural compounds that target NGF to attenuate neuropathic pain.

Methods: Nociception was assessed by the Von Frey hair and Hargreaves' methods. Western-blotting, qPCR and immunofluorescence were used to detect the cell signaling pathway. RAW264.7 macrophages and RSC96 Schwann cells were cultured for in vitro evaluation.

Results: Intraplantar administration of anti-NGF mAbs suppressed the expression of phosphorylated transforming growth factor-β-activated kinase 1 (TAK1) in the dorsal root ganglion (DRG) and sciatic nerve. Intraplantar administration of a TAK1 inhibitor attenuated CCI-induced neuropathic pain and suppressed the expression of phosphorylated mitogen-activated protein kinases (MAPKs) in the DRG and sciatic nerve. Perisciatic nerve administration of levo-corydalmine (l-CDL) on the operated side obviously attenuated CCI-induced neuropathic pain and suppressed the expression of mNGF and proNGF. In addition, l-CDL-induced antinociception was reversed by intraplantar administration of NGF. Further results indicated that l-CDL-induced suppression of phosphorylated TAK1, MAPKs, and p65 and expression of the proinflammatory cytokines TNF-α and IL-1β in the DRG and sciatic nerve were all abolished by NGF. In addition, in vitro experiments indicated that l-CDL suppressed the secretion of NGF and proNGF in RAW264.7 macrophages and RSC96 Schwann cells, which was abolished by AP-1 and CREB agonists, respectively.

Conclusions: This study showed NGF inhibition suppressed TAK1 in the periphery to attenuate CCI-induced neuropathic pain through inhibition of downstream MAPK and p65 signaling. The natural compound l-CDL inhibited NGF secretion by macrophages and Schwann cells and downstream TAK1-MAPK/NF-κB signaling in the periphery to attenuate CCI-induced neuropathic pain. Video abstract Proposed mechanisms underlying the effect of l-CDL in periphery of CCI rats. In CCI rats, macropahages and Schwann cells could secret NGF to act on the receptors in the periphery to activate TAK1-MAPK/NF-κB axis and promote the release of proinflammatory cytokines, including TNF-α and IL-1β to promote neuropathic pain. l-CDL decreased the secretion of NGF through inhibiting AP-1 and CREB respectively in RAW264.7 and RSC96 Schwann cells to attenuate CCI-induced neuropathic pain by inhibiting the TAK1-p38 MAPK/NF-κB signaling pathway.
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http://dx.doi.org/10.1186/s12964-020-00556-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7171864PMC
April 2020

Dual signal amplification for microRNA-21 detection based on duplex-specific nuclease and invertase.

RSC Adv 2020 Mar 18;10(19):11257-11262. Epub 2020 Mar 18.

State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Research Center for Traceability and Standardization of TCMs, School of Traditional Chinese Pharmacy, China Pharmaceutical University Nanjing 211198 P. R. China

MicroRNA-21 (miRNA-21) is a significant biomarker which is closely related to some kinds of diseases, such as cancer, cardiovascular disease and kidney disease. Therefore, the detection of miRNA-21 is of great importance and can provide essential information for disease diagnosis. In this study, we report a facile, sensitive assay for miRNA-21 detection using personal glucose meters (PGM). Biotinylated DNA strand linked invertase (Inv) is conjugated on the surface of streptavidin-coated magnetic beads (MBs) to form a MBs-DNA-Inv complex. Target miRNA-21 in the detection system is captured by the MBs-DNA-Inv probe through DNA/RNA hybridization. The duplex-specific nuclease (DSN) enzyme specifically cleaves the DNA to recycle the target miRNA and release invertase, thereby triggering the dual signal amplification and ensuring high sensitivity. Besides, we establish a linear relationship between PGM and different concentrations of miRNA-21 in the range of 10 to 200 pM. The limit of detection is 1.8 pM, which is more sensitive than some of the previous reports. In addition, the biosensor exhibits excellent sequence selectivity and single-base mutation can be discriminated. Moreover, the expression of miRNA-21 is confirmed in urine from mice by our method, which is in good accordance with the qRT-PCR result. Therefore, a dependable, low-cost strategy for the detection of miRNA has been established and it meets the latest analytical demands for miRNA determination that is suitable for the public.
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http://dx.doi.org/10.1039/c9ra10657jDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9050473PMC
March 2020

Levocorydalmine attenuates microglia activation and neuropathic pain by suppressing ASK1-p38 MAPK/NF-κB signaling pathways in rat spinal cord.

Reg Anesth Pain Med 2020 03 2;45(3):219-229. Epub 2020 Jan 2.

School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China

Background And Objectives: Neuropathic pain is partially refractory to currently available treatments. Although some studies have reported that apoptosis signal-regulating kinase 1 (ASK1) may inhibit chronic pain, the mechanisms underlying this process have not been fully elucidated.

Methods: Chronic constriction injury (CCI) of the rat sciatic nerve was used to establish a neuropathic pain model. Nociception was assessed using von Frey hair and Hargreaves' methods. Western blot and immunofluorescence were used to detect the cell signaling pathway. BV2 cell line was cultured for in vitro evaluation.

Results: Our results indicated that spinal ASK1 was co-expressed with the microglia marker ionized calcium binding adaptor 1. Additionally, intrathecal administration of ASK1 inhibitor suppressed the activation of spinal microglia and attenuated CCI-induced neuropathic pain. The ASK1 inhibitor also decreased the levels of phosphorylated ASK1 (p-ASK1), p65, p38 mitogen-activated protein kinase (MAPK) and tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) messenger RNA in lipopolysaccharide-stimulated BV2 microglia cells. Intragastric administration of -corydalmine (-CDL) significantly attenuated CCI-induced neuropathic pain and inhibited the expression of p-ASK1 in the spinal cord. -CDL conspicuously suppressed the activation of spinal microglia in vitro and in vivo. Translocation of nuclearfactor-kappa B (NF-κB) and upregulation of p-p65, TNF-α, IL-1β were inhibited by CDL. Further, the analgesic effects of -CDL were associated with reduced levels of phosphorylated protein kinase C (PKC γ), c-JunNH2-terminal kinase, and extracellular signal-regulated kinase.

Conclusions: This study showed that the expression of ASK1 in spinal microglia and ASK1 inhibitor suppressed microglia activation via suppression of p38 MAPK/NF-κB, which ultimately attenuated CCI-induced neuropathic pain. CDL also inhibited the ASK1-P38 MAPK/NF-κB axis to attenuate CCI-induced neuropathic pain.
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http://dx.doi.org/10.1136/rapm-2019-100875DOI Listing
March 2020

Dihydroartemisinin derivative DC32 inhibits inflammatory response in osteoarthritic synovium through regulating Nrf2/NF-κB pathway.

Int Immunopharmacol 2019 Sep 19;74:105701. Epub 2019 Jun 19.

Jiangsu Key Laboratory of TCM Evaluation and Translational Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China. Electronic address:

Synovitis is an aseptic inflammation that leads to joint effusion, pain and swelling. As one of the main drivers of pathogenesis in osteoarthritis (OA), the presence of synovitis contributes to pain, incidence and progression of OA. In our previous study, DC32 [(9α,12α-dihydroartemisinyl) bis(2'-chlorocinnmate)], a dihydroartemisinin derivative, was found to have an antirheumatic ability via immunosuppression, but the effect of DC32 on synovitis has not been fully illuminated. In this study, we chose to evaluate the effect and mechanism of DC32 on attenuating synovial inflammation. Fibroblast-like synoviocytes (FLSs) of papain-induced OA rats were isolated and cultured. And DC32 significantly inhibited the invasion and migration of cultured OA-FLSs, as well as the transcription of IL-6, IL-1β, CXCL12 and CX3CL1 in cultured OA-FLSs measured by qPCR. DC32 remarkably inhibited the activation of ERK and NF-κB pathway, increased the expression of Nrf2 and HO-1 in cultured OA-FLSs detected by western blot. DC32 inhibited the degradation and phosphorylation of IκBα which further prevented the phosphorylation of NF-κB p65 and the effect of DC32 could be relieved by siRNA for Nrf2. In papain-induced OA mice, DC32 significantly alleviated papain-induced mechanical allodynia, knee joint swelling and infiltration of inflammatory cell in synovium. DC32 upregulated the mRNA expression of Type II collagen and aggrecan, and downregulated the mRNA expression of MMP2, MMP3, MMP13 and ADAMTS-5 in the knee joints of papain-induced OA mice measured by qPCR. The level of TNF-α in the serum and secretion of TNF-α in the knee joints were also reduced by DC32 in papain-induced OA mice. In conclusion, DC32 inhibited the inflammatory response in osteoarthritic synovium through regulating Nrf2/NF-κB pathway and attenuated OA. In this way, DC32 may be a potential agent in the treatment of OA.
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http://dx.doi.org/10.1016/j.intimp.2019.105701DOI Listing
September 2019

Determination of the chemical components and phospholipids of velvet antler using UPLC/QTOF-MS coupled with UNIFI software.

Exp Ther Med 2019 May 12;17(5):3789-3799. Epub 2019 Mar 12.

Department of Natural Medicinal Chemistry, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China.

Velvet antler, which exhibits immune and growth enhancing effects, is commonly used in a variety of Asian health care products, but its complex components remain unknown. The current study analyzed extracts using ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight tandem mass spectrometry in the MS mode. Automated detection and data filtering were performed using UNIFI software and peaks were compared with a proprietary scientific library (Traditional Medicine Library; TML). The results obtained using different data processing parameters (including 3D peak detection, target by mass and fragment identification) were evaluated against 87 compounds comprising 1 lignan, 30 terpenoids (including 20 triterpenes), 39 steroids, 8 alkaloids, 4 organic acids and 5 esters in the TML. Using a screening method with a mass accuracy cutoff of ±2 mDa, a retention time cutoff of ±0.2 min, a minimum response threshold of 1,000 counts and an average of 10 false detects per sample analysis, 16 phospholipids were identified in the extracts of velvet antler, three of which were quantified. The results demonstrated that there was 1.07±0.02 µg/g of 1-myristoyl-sn-glycero-3-phosphocholine, 7.05±0.52 ng/g of 1,2-dimyristoyl-sn-glycero-3-phosphocholine and 18.81±0.55 ng/g of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine in velvet antler. The current study successfully identified certain components of velvet antler. Furthermore, the results may provide an experimental basis for further pharmacological and clinical study.
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http://dx.doi.org/10.3892/etm.2019.7372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6447902PMC
May 2019

Selective blockade of spinal D2DR by levo-corydalmine attenuates morphine tolerance via suppressing PI3K/Akt-MAPK signaling in a MOR-dependent manner.

Exp Mol Med 2018 11 14;50(11):1-12. Epub 2018 Nov 14.

Jiangsu Key Laboratory of TCM Evaluation and Translational Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, 211198, China.

Morphine tolerance remains a challenge in the management of chronic pain in the clinic. As shown in our previous study, the dopamine D2 receptor (D2DR) expressed in spinal cord neurons might be involved in morphine tolerance, but the underlying mechanisms remain to be elucidated. In the present study, selective spinal D2DR blockade attenuated morphine tolerance in mice by inhibiting phosphatidylinositol 3 kinase (PI3K)/serine-threonine kinase (Akt)-mitogen activated protein kinase (MAPK) signaling in a μ opioid receptor (MOR)-dependent manner. Levo-corydalmine (l-CDL), which exhibited micromolar affinity for D2DR in D2/CHO-K1 cell lines in this report and effectively alleviated bone cancer pain in our previous study, attenuated morphine tolerance in rats with chronic bone cancer pain at nonanalgesic doses. Furthermore, the intrathecal administration of l-CDL obviously attenuated morphine tolerance, and the effect was reversed by a D2DR agonist in mice. Spinal D2DR inhibition and l-CDL also inhibited tolerance induced by the MOR agonist DAMGO. l-CDL and a D2DR small interfering RNA (siRNA) decreased the increase in levels of phosphorylated Akt and MAPK in the spinal cord; these changes were abolished by a PI3K inhibitor. In addition, the activated Akt and MAPK proteins in mice exhibiting morphine tolerance were inhibited by a MOR antagonist. Intrathecal administration of a PI3K inhibitor also attenuated DAMGO-induced tolerance. Based on these results, l-CDL antagonized spinal D2DR to attenuate morphine tolerance by inhibiting PI3K/Akt-dependent MAPK phosphorylation through MOR. These findings provide insights into a more versatile treatment for morphine tolerance.
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http://dx.doi.org/10.1038/s12276-018-0175-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6235923PMC
November 2018

Rapid identification of urokinase plasminogen activator inhibitors from Traditional Chinese Medicines based on ultrafiltration, LC-MS and in silico docking.

J Pharm Biomed Anal 2019 Feb 25;164:241-248. Epub 2018 Oct 25.

Jiangsu Key Laboratory of TCM Evaluation and Translational Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, 211198, PR China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, 211198, PR China. Electronic address:

The urokinase plasminogen activator (uPA) is regarded as the crucial trigger for plasmin generation, which is involved in several diseases especially for neoplasm metastasis. In this study, an efficient approach integrating ultrafiltration, LC/MS, bioassay and in silico docking, was proposed for rapidly detecting uPA ligands from Traditional Chinese Medicines (TCMs). Forty-two TCMs were initially assessed, and as illustrative case studies, Galla Chinensis and Sanguisorbae Radix, which appeared significant inhibitory activities on uPA, were chosen to develpe and verify the strategy. A total of seven uPA ligands were successfully detected and identified. Two of them, pentagalloylglucose and 28-O-β-d-glucopyranosyl pomolic acid, were demonstrated to be potential inhibitors, with IC at 1.639 μM and 37.82 μM repectively. Furthermore, a combinatorial compound library screening combined with in silico docking assay, was revealed that ursolic acid (IC = 2.623 μM) was also speculated to be a potent parent structure for inhibition of uPA. This approach offers a multidimensional perspective to discover uPA-binding leading compounds from TCMs or other complex mixtures, which would provide an efficient route for drug discovery.
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http://dx.doi.org/10.1016/j.jpba.2018.10.036DOI Listing
February 2019

Novel dihydroartemisinin derivative DHA-37 induces autophagic cell death through upregulation of HMGB1 in A549 cells.

Cell Death Dis 2018 10 15;9(11):1048. Epub 2018 Oct 15.

State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 210009, Nanjing, China.

Dihydroartemisinin (DHA) and its analogs are reported to possess selective anticancer activity. Here, we reported a novel DHA derivative DHA-37 that exhibited more potent anticancer activity on the cells tested. Distinct from DHA-induced apoptosis, DHA-37 triggered excessive autophagic cell death, and became the main contributor to DHA-37-induced A549 cell death. Incubation of the cells with DHA-37 but not DHA produced increased dots distribution of GFP-LC3 and expression ratio of LC3-II/LC3-I, and enhanced the formation of autophagic vacuoles as revealed by TEM. Treatment with the autophagy inhibitor 3-MA, LY294002, or chloroquine could reverse DHA-37-induced cell death. In addition, DHA-37-induced cell death was associated significantly with the increased expression of HMGB1, and knockdown of HMGB1 could reverse DHA-37-induced cell death. More importantly, the elevated HMGB1 expression induced autophagy through the activation of the MAPK signal but not PI3K-AKT-mTOR pathway. In addition, DHA-37 also showed a wonderful performance in A549 xenograft mice model. These findings suggest that HMGB1 as a target candidate for apoptosis-resistant cancer treatment and artemisinin-based drugs could be used in inducing autophagic cell death.
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http://dx.doi.org/10.1038/s41419-018-1006-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6189137PMC
October 2018

A New Strategy for Rapidly Screening Natural Inhibitors Targeting the PCSK9/LDLR Interaction In Vitro.

Molecules 2018 Sep 19;23(9). Epub 2018 Sep 19.

Jiangsu Key Laboratory of TCM Evaluation and Translational Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China.

The interaction between proprotein convertase subtilisin/kexin type 9 (PCSK9) and the low-density lipoprotein receptor (LDLR) is a promising target for the treatment of hyperc-holesterolemia. In this study, a new method based on competitive affinity and tag detection was developed, which aimed to evaluate potent natural inhibitors preventing the interaction of PCSK9/LDLR directly. Herein, natural compounds with efficacy in the treatment of hypercholesterolemia were chosen to investigate their inhibitory activities on the PCSK9/LDLR interaction. Two of them, polydatin () and tetrahydroxydiphenylethylene-2--glucoside (), were identified as potential inhibitors for the PCSK9/LDLR interaction and were proven to prevent PCSK9-mediated LDLR degradation in HepG2 cells. The results suggested that this strategy could be applied for evaluating potential bioactive compounds inhibiting the interaction of PCSK9/LDLR and this strategy could accelerate the discovery of new drug candidates for the treatment of PCSK9-mediated hypercholesterolemia.
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http://dx.doi.org/10.3390/molecules23092397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6225438PMC
September 2018

Identification of active compound combination contributing to anti-inflammatory activity of Xiao-Cheng-Qi Decoction via human intestinal bacterial metabolism.

Chin J Nat Med 2018 Jul;16(7):513-524

Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing 211198, China. Electronic address:

Human intestinal bacteria play an important role in the metabolism of herbal medicines, leading to the variations in their pharmacological profile. The present study aimed to investigate the metabolism of Xiao-Cheng-Qi decoction (XCQD) by human intestinal bacteria and to discover active component combination (ACC) contributing to the anti-inflammatory activity of XCQD. The water extract of XCQD was anaerobically incubated with human intestinal bacteria suspensions for 48 h at 37 °C. A liquid chromatography-hybrid quadrupole time-of-flight mass spectrometry (LC-Q-TOF/MS) method was performed for identification of the metabolites. In addition, the anti-inflammatory effects of XCQD and biotransformed XCQD (XCQD-BT) were evaluated in vitro with cytokines in RAW264.7 cells induced by lipopolysaccharide (LPS). A total of 51 compounds were identified in XCQD and XCQD-BT. Among them, 20 metabolites were proven to be transformed by human intestinal bacteria. Significantly, a combination of 14 compounds was identified as ACC from XCQD-BT, which was as effective as XCQD in cell models of inflammation. In conclusion, this study provided an applicable method, based on intestinal bacterial metabolism, for identifying combinatory compounds responsible for a certain pharmacological activity of herbal medicines.
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http://dx.doi.org/10.1016/S1875-5364(18)30088-8DOI Listing
July 2018

[Sedimentary Phosphorus Speciation in the Coastal Hypoxic Area of Changjiang Estuary and Its Environmental Significance].

Huan Jing Ke Xue 2017 Aug;38(8):3243-3253

Key Laboratory of Marine Sedimentology and Environmental Geology, First Institute of Oceanography, State Oceanic Administration, Qingdao 266061, China.

Phosphorus (P) is a potential limiting nutrient in Changjiang Estuary. Sedimentary P preservation and regeneration play an important role in indicating regional environmental changes and buffering P limitation in the water column. A series of coring experiments was implemented in the hypoxic area of Changjiang Estuary to explore sedimentary P speciation and distribution and their environmental significance. The results showed that the contents and distributions of P in the cores were largely influenced by terrestrial loading, and Detr-P was the dominant P form in the sediments, followed by Org-P, Fe-P, and Auth-P, whereas Exch-P was the minor phase of Tot-P (<5%). Auth-P was predominantly yielded by Org-P and Fe-P transformations. P preservation in Changjiang Estuary was significantly related to terrestrial inputs and environmental changes in the water column. P speciation in cores tracked the regional environmental changes effectively. Distribution of reactive P in the hypoxic area was significantly different from that in the oxic area, with fairly high C/P ratios. The benthic diffusive flux of DRP in the study area ranged from 0.90 to 1.13 μmol·(cm·a). Tot-P burial efficiency (PBE) was higher than 70% and the PBE for Detr-P was nearly 100%, whereas the PBEs for Fe-P and Org-P were 38% and 26%, respectively. Auth-P was the dominant fraction of reactive P preserved in the sediments, and about 51% of Auth-P originated from Fe-P and Org-P transformations. The PBE in the hypoxia area of Changjiang Estuary was fairly lower than that in the continental shelf of the East China Sea. Hypoxia leads to a decrease in the PBE, which would have long-term influence on ecological environmental problems, especially eutrophification. Changes in terrestrial inputs played a key role in P composition in the sediments; the P loads of Changjiang River coupled with primary production and hypoxia greatly affected the P cycling in the Estuary.
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http://dx.doi.org/10.13227/j.hjkx.201701140DOI Listing
August 2017

Computed tomography and magnetic resonance imaging features of cervical chordoma.

Oncol Lett 2018 Jul 16;16(1):861-865. Epub 2018 May 16.

Department of Radiology, Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China.

Computed tomography (CT) and magnetic resonance imaging (MRI) scans of 11 patients with histologically proven cervical chordoma were retrospectively evaluated. Imaging features assessed included location, morphology, association with adjacent structures, vertebral destruction, status of cortical bone, periosteal reaction, attenuation and calcification by CT, and signal intensity and enhancement pattern by MRI. Of 7 cases with CT, 6 exhibited lytic-sclerotic bone destruction. A total of 5 cases exhibited pressure erosion of outer cortex, 3 of which had spiculated periosteal reaction. Calcification was observed in 3 cases. All cases were heterogeneous and hypodense. MRI T2-weighted images (n=10) revealed heterogeneous hyperintense (n=5), intermediate (n=2) and intermediate-hyperintense signal intensity (n=3). Hypointense septa between lobules (n=5) and stripes (n=3) were observed on T2-weighted images. Post-contrast magnetic resonance images (n=6) demonstrated marked heterogeneous (n=3) and ring-like (n=3) enhancement. CT scanning is valuable in revealing the lytic-sclerotic bone destruction, pressure erosion of outer cortex and calcification. MRI is useful in demonstrating the results of soft tissue mass. The two examinations are necessary for differential diagnosis of patients with suspected cervical chordoma.
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http://dx.doi.org/10.3892/ol.2018.8721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6019881PMC
July 2018

Morphological and chemical studies of artificial Andrographis paniculata polyploids.

Chin J Nat Med 2018 Feb;16(2):81-89

Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing 210009, China. Electronic address:

Andrographis paniculata (Burm. f.) Nees (AP) is commonly used for the treatment of many infectious diseases and has been cultivated widely in Asian countries, and has been included in United States Pharmacopoeia as a dietary supplement, but the cultivars of A. paniculata are not abundant due to its self-pollinated. With the aims to enrich AP resources and provide materials for after breeding we explored the polyploidy induction. Different explants, colchicine concentration, and treatment time were tested. After identification by flow cytometry, eleven polyploid plants with different morphologic traits were obtained. The agronomic traits and andrographolide concentration of the polyploids were improved greatly. One of the polyploids (serial 3-7) was chosen for further study. The traits of the second and third generation polyploids (serial 3-7) were stable. Compared with the normal plants, the seeds (2nd generation) weight increased by 31%, and the andrographolide concentration of the leaves increased by 14% (2nd) and 28% (3rd). In conclusion, AP autopolyploids with different morphologic traits were established successfully for the first time, and the polyploids induction might be effective for crop improvement of AP.
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http://dx.doi.org/10.1016/S1875-5364(18)30033-5DOI Listing
February 2018

Clinicopathologic features and outcomes of primary cardiac tumors: a 16-year-experience with 212 patients at a Chinese medical center.

Cardiovasc Pathol 2018 Mar - Apr;33:45-54. Epub 2018 Jan 6.

Department of Pathology, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao 266003, China. Electronic address:

Primary cardiac tumors are uncommon, and the majority of them are benign which are curable but can cause significant morbidity if not diagnosed and treated in a timely fashion. The objective of this study was to review the clinicopathologic features and surgical outcomes of patients with primary cardiac tumors in a single medical center in China. We have retrospectively reviewed 212 consecutive adult patients who underwent surgical resection of primary cardiac tumors at our center from January of 2001 to June of 2017. All available clinicopathological features, imaging characteristics, and disease outcomes were summarized and presented. The present series enrolled 180 cardiac myxomas (84.9%) and 32 non-myxoma cases that included hemangioma, lipoma, papillary fibroelastoma, schwannoma, pericardial cyst, teratoma, paraganglioma, lymphoma, undifferentiated pleomorphic sarcoma, myxofibrosarcoma, angiosarcoma, and liposarcoma. All patients were diagnosed ante-mortem. The most frequent complaint was dyspnea. Benign tumors accounted for 93.9% of cases (199/212) and malignant tumors accounted for 5.7% (12/212), and the remaining one case was intermediate (paraganglioma). The outcome of benign tumors was favorable and only three recurrent cases were documented (1.5%) after surgical resection. All the seven patients with primary cardiac sarcomas (undifferentiated pleomorphic sarcoma, myxofibrosarcoma, angiosarcoma, and liposarcoma) suffered postoperative recurrence or disease related death. Cardiac myxoma represents the most frequent primary cardiac tumors. The clinical presentations, treatment strategies and outcomes of the primary cardiac tumors depend on the tumor location and histopathological type.
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http://dx.doi.org/10.1016/j.carpath.2018.01.003DOI Listing
August 2018

Magnetic Resonance Features and Characteristic Vascular Pattern of Alveolar Soft-Part Sarcoma.

Oncol Res Treat 2017 20;40(10):580-585. Epub 2017 Sep 20.

Department of Radiology, The Affiliated Hospital of Qingdao University, Qingdao, China.

Objective: The aim of this study was to investigate the magnetic resonance (MR) features of alveolar soft-part sarcoma (ASPS).

Methods: We studied 12 patients with ASPS confirmed by pathology in this retrospective study. MR features were analyzed, especially for the location, morphology, signals, and related enhanced features of the tumor vessels.

Results: Flow voids were shown in the central part of the tumor on T2-weighted imaging (T2WI) in all patients; they were arrayed in a radiating mode gathered toward the center (8 cases), designated by us as vascular center-gathered syndrome (VCGS), or scattered like twigs (4 cases). The flow voids were accompanied by high signals in all patients, including tubular (6 cases) and platy (6 cases) signals. Slightly higher signals were shown in the peripheral part of the tumor in all patients. Flow voids in the peripheral part were shown in all patients, and the majority of the flow voids surrounded the tumor (8 cases). The vessels around the tumor in 9 patients showed high signals, and the majority of the vessels were located at the superior and inferior poles (8 cases). 6 patients underwent enhanced scanning, including moderate (5 cases) and significant enhancement (1 case).

Conclusion: Low signals of radiating flow voids accompanied by high signals of slow blood flow or blood sinuses in the center part have high significance for the diagnosis of ASPS.
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http://dx.doi.org/10.1159/000477443DOI Listing
October 2018

The activity of Hou-Po-Da-Huang-Tang is improved through intestinal bacterial metabolism and Hou-Po-Da-Huang-Tang selectively stimulate the growth of intestinal bacteria associated with health.

Biomed Pharmacother 2017 Oct 10;94:794-803. Epub 2017 Aug 10.

Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing 211198, China. Electronic address:

Hou-Po-Da-Huang Tang (HPDHT) was used for the treatment of intestinal tract diseases in China. However, the underlying mechanisms via the intestinal bacteria remain largely unclear. Therefore, the aim of this study was to evaluate the metabolism of HPDHT by the human intestinal bacteria and its modulating effect on the intestinal bacteria. As a result, a total of 34 compounds were identified in HPDHT and transformed HPDHT (T-HPDHT). Among them, 12 metabolites were proved to be transformed by human intestinal bacteria. In vitro assays showed that T-HPDHT exhibited more significant elevation of free radical scavenging activity and suppression on the production of nitric oxide (NO) and TNF-α when comparing to HPDHT. Additionally, in vivo experiment confirmed that HPDHT significantly increased activity of superoxide dismutase (SOD), attenuated the malondialdehyde (MDA) and TNF-α levels in the conventional rats compared with that of pseudo germ-free (PGF) rats. In addition, HPDHT could significantly enhance the mean counts of Bifidobacterium and Lactobacillus and inhibit the growth of Clostridium, and Enterobacteriaceae, relative to controls. Due to the transformation of HPDHT being dependent on the bacterial strain, the effect of HPDHT on the selective growth of Bifidobacterium bifidum 29521 and Lactobacillus plantarum 8014 was evaluated. The kinetic parameters of microbial growth and prebiotic activity scores indicated that HPDHT could selectively stimulate the growth of the strains Bifidobacterium bifidum 29521 and Lactobacillus plantarum 8014. Taken together, metabolism of HPDHT by intestinal bacteria is a critical step towards the emergence of their anti-oxidation, anti-inflammation and prebiotic activities. This study provided valuable information for further pharmacological research on HPDHT.
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http://dx.doi.org/10.1016/j.biopha.2017.08.005DOI Listing
October 2017

Low-grade chondrosarcoma of the cricoid cartilage: a case report and review of the literature.

Skeletal Radiol 2017 Nov 29;46(11):1597-1601. Epub 2017 Jul 29.

Department of Radiology, The Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Qingdao, China.

We report the case of a 60-year-old man with a 12-day history of vomiting whenever he had a meal. Computed tomography revealed a calcified mass in the right cricoid cartilage with intraluminal and extraluminal extension. The patient underwent surgical resection of the trachea with end-to-end anastomosis. Pathological examination of the surgical specimen showed a low-grade chondrosarcoma. Eighteen months after surgery, the patient is alive and disease-free.
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http://dx.doi.org/10.1007/s00256-017-2731-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5599471PMC
November 2017

Metabolic profile and underlying improved bio-activity of Fructus aurantii immaturus by human intestinal bacteria.

Food Funct 2017 Jun;8(6):2193-2201

Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing 211198, China.

Fructus aurantii immaturus (FAI) is the dried young fruit of Citrus aurantium L. or Citrus sinensis L. Osbeck. The purpose of this paper was to investigate the metabolic fate of FAI upon incubation with human intestinal bacteria, meanwhile to evaluate the antioxidant and anti-inflammatory activities of FAI and the transformed Fructus aurantii immaturus (TFAI). The water extract of FAI was anaerobically incubated with human intestinal bacterial suspensions for 48 h at 37 °C. Liquid chromatography-hybridised with quadrupole-time-of-flight mass spectrometry (LC-Q-TOF/MS) was applied to identify FAI metabolites. A total of 45 compounds were identified in FAI, eleven of which were metabolized by human intestinal bacteria. Nine major metabolites were identified as eriodictyol, naringenin, hesperetin, luteolin, apigenin, chryseriol, isosakuranetin, phloretin and diosmetin. The metabolic profile of FAI was elucidated on the basis of metabolite information. We found that the concentrations of acetic, propionic and butyric acids in FAI culture were all increased during fermentation relative to those of the control. Further bioactive evaluations showed that TFAI exhibited more potent antioxidant and anti-inflammatory abilities than FAI in vitro. Additionally, in vivo experiment confirmed that FAI significantly attenuated the blood endotoxin and TNF-α levels in the conventional rats compared to those of pseudo-germ-free (PGF) rats. This study revealed that metabolites may play a key role in the antioxidant and anti-inflammatory capacities of FAI.
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http://dx.doi.org/10.1039/c6fo01851cDOI Listing
June 2017

Simultaneous inhibition of NMDA and mGlu1/5 receptors by levo-corydalmine in rat spinal cord attenuates bone cancer pain.

Int J Cancer 2017 08 29;141(4):805-815. Epub 2017 May 29.

State Key Laboratory of Natural Medicines, Department of Traditional Chinese Medicine, China Pharmaceutical University, Nanjing, Jiangsu, China.

Bone cancer pain is a challenge for its not completely clarified mechanism and broad clinical morbidity. Therefore, novel and more effective drugs are urgent needed for improvement of patients' quality of life. Glutamate receptors have been associated with the development of the central sensitization of chronic pain. Inhibition of N-methyl-d-aspartate (NMDA) and metabotropic glutamate (mGlu) receptors can effectively attenuate bone cancer pain, respectively. Herein, our results indicated that levo-Corydalmine (l-CDL), a compound from Corydalis yanhusuo W.T. Wang, which has been used in traditional Chinese medicine for pain relief could effectively attenuate bone cancer pain induced by tibia bone cavity tumor cell implantation (TCI) through simultaneously inhibiting the NMDA and mGlu1/5 receptors in rat spinal cord without notable side effects. Both intragastric and intrathecal administration of l-CDL significantly alleviated the mechanical hypersensitivity induced by TCI in rats, and the analgesic effect of l-CDL could be reversed by intrathecal administration of NMDA receptor agonist NMDA and mGlu1/5 receptor agonist DHPG but not AMPA receptor agonist AMPA. l-CDL could also selectively suppress NMDA and DHPG induced rapid rise in Ca oscillations in primary cultures neurons of spinal cord in vitro. The antinociception of l-CDL were partially mediated by the reduced phosphorylation of PKC γ and ERK1/2 in spinal cord of TCI rats in a NMDA and mGlu1/5 dependent manner. In conclusion, these results suggested that l-CDL attenuates TCI induced bone cancer pain through simultaneously inhibiting the NMDA and mGlu1/5 receptors and the downstream PKC γ, ERK1/2 signaling pathways in the spinal cord.
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http://dx.doi.org/10.1002/ijc.30780DOI Listing
August 2017

Blockade of neuronal dopamine D2 receptor attenuates morphine tolerance in mice spinal cord.

Sci Rep 2016 12 22;6:38746. Epub 2016 Dec 22.

State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu 210009, China.

Tolerance induced by morphine remains a major unresolved problem and significantly limits its clinical use. Recent evidences have indicated that dopamine D2 receptor (D2DR) is likely to be involved in morphine-induced antinociceptive tolerance. However, its exact effect and molecular mechanism remain unknown. In this study we examined the effect of D2DR on morphine antinociceptive tolerance in mice spinal cord. Chronic morphine treatment significantly increased levels of D2DR in mice spinal dorsal horn. And the immunoreactivity of D2DR was newly expressed in neurons rather than astrocytes or microglia both in vivo and in vitro. Blockade of D2DR with its antagonist (sulpiride and L-741,626, i.t.) attenuated morphine antinociceptive tolerance without affecting basal pain perception. Sulpiride (i.t.) also down-regulated the expression of phosphorylation of NR1, PKC, MAPKs and suppressed the activation of astrocytes and microglia induced by chronic morphine administration. Particularly, D2DR was found to interact with μ opioid receptor (MOR) in neurons, and chronic morphine treatment enhanced the MOR/D2DR interactions. Sulpiride (i.t.) could disrupt the MOR/D2DR interactions and attenuate morphine tolerance, indicating that neuronal D2DR in the spinal cord may be involved in morphine tolerance possibly by interacting with MOR. These results may present new opportunities for the treatment and management of morphine-induced antinociceptive tolerance which often observed in clinic.
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http://dx.doi.org/10.1038/srep38746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5177930PMC
December 2016

Synthesis and cytotoxicity of novel artemisinin derivatives containing sulfur atoms.

Eur J Med Chem 2016 Nov 10;123:763-768. Epub 2016 Aug 10.

Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing, Jiangsu 211198, China. Electronic address:

Ten novel artemisinin derivatives containing sulfur atoms were designed and synthesized and their structures were confirmed by (1)H NMR, (13)C NMR and HRMS technologies in this study. All compounds were reported for the first time. The in vitro cytotoxicity against PC-3, SGC-7901, A549 and MDA-MB-435s cancer cell lines was evaluated by MTT assay. Compounds 4a and 4f displayed potent antitumor activity against PC-3, SGC-7901 and A549 cells with IC50 ranging from 1.6 to 30.5 μM, which values are compared to that of 5-FU (IC50 from 6.8 to 42.5 μM). Compounds 4a and 4f showed high specificity towards human lung cancer A549 cells compared to normal human hepatic L-02 cells with selectivity index of 16.1 and 50.1 respectively. Our promising findings indicated that the compounds 4a and 4f could stand as potential lead compounds for further investigation.
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http://dx.doi.org/10.1016/j.ejmech.2016.08.015DOI Listing
November 2016

Synthesis and in vitro antitumor evaluation of dihydroartemisinin-cinnamic acid ester derivatives.

Eur J Med Chem 2016 Jan 5;107:192-203. Epub 2015 Nov 5.

Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing, Jiangsu 211198, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu 210009, China. Electronic address:

To explore novel high efficiency and low toxicity antitumor agents, a series of dihydroartemisinin-cinnamic acid ester derivatives modified on C-12 and/or C-9 position (s) were synthesized and the in vitro antitumor activities against PC-3, SGC-7901, A549 and MDA-MB-435s cancer cell lines were assessed. The hybrids (3-36) were prepared by esterification of 9α-hydroxyl-dihydroartemisinin (9α-OH DHA), the biotransformation product of dihydroartemisinin (DHA), and cinnamic acid derivatives. Compound 17 (IC50 = 0.20 μM) was the most potent anti-proliferative agent against the human lung carcinoma A549 cells, although it displayed low cytotoxicity on normal hepatic L-02 cells. The mechanism of action of compound 17 was further investigated by analysis of cell apoptosis and intracellular ROS generation. The results indicated that both ROS and ferrous ion contributed to the compound 17-induced cell death. Meanwhile, high intracellular ferrous ion and endogenous oxidative stress in A549 cells made them easier to suffer to compound 17-induced apoptosis. Our promising findings indicated the compound 17 could stand as drug candidate against lung cancer for further investigation.
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http://dx.doi.org/10.1016/j.ejmech.2015.11.003DOI Listing
January 2016

[Preparation and Determination of Insulin-like Growth Factor I in Deer Antler, Heart and Blood].

Zhong Yao Cai 2014 Dec;37(12):2155-8

Objective: To optimize the method for preparation of the insulin-like growth factor I (IGF-I ) in deer antler, and to determine the IGF-I in deer antler, heart and blood.

Methods: Ultrasonic extraction was used to extract IGF-I from different tissues of deer with ammonia-ammonium acetate buffer, followed by ultrafiltration and solid phase extraction to concentrate and purify the samples. At the same time, ethanol precipitation method was carried out in the purification of IGF-I ultrafiltratein deer antler, a parallel test proceeded and radio immune assay (RIA) was set to determine the IGF-I in deer antler, heart and blood.

Results: The IGF-I (60.8 ng/g) in deer antler by solid phase extraction was only existed in 30% methanol aqueous solution which was much higher than that (46.1 ng/g) by ethanol precipitation method. The quantities of IGF-I in deer antler, heart and blood were significantly different, it was 61.9 ng/g in antler and 21.9 ng/mL in blood, while there was no IGF-I tested in deer heart.

Conclusion: Solid phase extraction is superior to ethanol precipitation method in preparing IGF-I in deer antler and it is clear that the IGF-I contained in deer antler is significantly higher than that in deer heart and blood, so it is the best choice to take IGF-I from deer antler.
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December 2014
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