Publications by authors named "Xudong Fu"

32 Publications

Biomimetic Nanoscale Erythrocyte Delivery System for Enhancing Chemotherapy via Overcoming Biological Barriers.

ACS Biomater Sci Eng 2021 Mar 2. Epub 2021 Mar 2.

School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, China.

Overcoming multiple biological barriers, including circulation time , tumor vascular endothelium, reticuloendothelial system (RES), extracellular matrix (ECM), etc., is the key to improve the therapeutic efficacy of drug delivery systems in treating tumors. Inspired by the ability of natural erythrocytes to cross multiple barriers, in this study, a biomimetic delivery system named NE@DOX-Ang2 was developed for enhancing the chemotherapy of breast cancer, which employed nano-erythrocyte (NE) encapsulating doxorubicin (DOX) and surface modification with a targeted angiopep-2 peptide (Ang2). NE@DOX-Ang2 enhanced the capacity to cross biological barriers in a three-dimensional (3D) tumor spheroid model and in mice. Compared with a conventional drug delivery system of liposomes, the half-life of NE@DOX-Ang2 increased approximately 2.5 times. Moreover, NE@DOX-Ang2 exhibited excellent tumor-targeting ability and antitumor effects and . Briefly, the prepared nano-erythrocyte drug carrier has features of favorable biocompatibility and low immunogenicity and the advantage of prolonging the half-life of drugs, which may provide a novel perspective for development of clinically available nanomedicines.
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http://dx.doi.org/10.1021/acsbiomaterials.1c00008DOI Listing
March 2021

Gallic acid-gold nanoparticles enhance radiation-induced cell death of human glioma U251 cells.

IUBMB Life 2021 Feb 28;73(2):398-407. Epub 2020 Dec 28.

Department of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

Glioblastoma multiforme (GBM) is among the most common adult brain tumors with invariably fatal character. Following the limited conventional therapies, almost all patients, however, presented with symptoms at the time of recurrence. It is dire to develop novel therapeutic strategies to improve the current treatment of GBM. Gallic acid is a well-established antioxidant, presenting a promising new selective anti-cancer drug, while gold nanoparticles (GNPs) can be developed as versatile nontoxic carriers for anti-cancer drug delivery. Here, we prepared gallic acid-GNPs (GA-GNPs) by loading gallic acid onto GNPs, reduction products of tetrachloroauric acid by sodium citrate, through physical and agitation adsorption. GA-GNPs, rather than GNPs alone, significantly inhibited the survival of U251 GBM cells, as well as enhanced radiation-induced cell death. Moreover, GA-GNPs plus radiation arrested the cell cycle of U251 at the S and G2/M phases and triggered apoptotic cell death, which is supported by increased BAX protein levels and decreased expression of BCL-2. Thus, GA-GNPs have great potential in the combination with radiation therapy in future studies for GBM treatment.
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http://dx.doi.org/10.1002/iub.2436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898864PMC
February 2021

Epigenetic regulation of mouse preimplantation embryo development.

Curr Opin Genet Dev 2020 10 18;64:13-20. Epub 2020 Jun 18.

Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Division of Hematology/Oncology, Department of Pediatrics, Boston Children's Hospital, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Boston, MA 02115, USA. Electronic address:

After fertilization, mouse embryos go through preimplantation development to give rise to blastocyst. Two key molecular events, zygotic genome activation (ZGA) and the first cell lineage specification, are essential for the process. Recent advances in low-input epigenomics profiling techniques allow the analysis of these events at a molecular level, which revealed a critical role of epigenetic and chromatin reprogramming in ZGA and the first cell lineage specification. Additionally, the establishment of an in vitro embryonic stem cell (ESC) to two-cell embryo-like conversion system have also contributed to the molecular understanding of preimplantation development. In this review, we summarize recent advances in epigenetic regulation of mouse preimplantation development, point out the remaining questions, and propose strategies to tackle these questions.
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http://dx.doi.org/10.1016/j.gde.2020.05.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641911PMC
October 2020

How canyons evolve by incision into bedrock: Rainbow Canyon, Death Valley National Park, United States.

Proc Natl Acad Sci U S A 2020 06 15;117(26):14730-14737. Epub 2020 Jun 15.

Department of Civil & Environmental Engineering, University of Illinois Urbana-Champaign, Urbana, IL 61801;

Incising rivers may be confined by low-slope, erodible hillslopes or steep, resistant sidewalls. In the latter case, the system forms a canyon. We present a morphodynamic model that includes the essential elements of a canyon incising into a plateau, including 1) abrasion-driven channel incision, 2) migration of a canyon-head knickpoint, 3) sediment feed from an alluvial channel upstream of the knickpoint, and 4) production of sediment by sidewall collapse. We calculate incision in terms of collision of clasts with the bed. We calculate knickpoint migration using a moving-boundary formulation that allows a slope discontinuity where the channel head meets an alluvial plateau feeder channel. Rather than modeling sidewall collapse events, we model long-term behavior using a constant sidewall slope as the channel incises. Our morphodynamic model specifically applies to canyon, rather than river-hillslope evolution. We implement it for Rainbow Canyon, CA. Salient results are as follows: 1) Sediment supply from collapsing canyon sidewalls can be substantially larger than that supplied from the feeder channel on the plateau. 2) For any given quasi-equilibrium canyon bedrock slope, two conjugate slopes are possible for the alluvial channel upstream, with the lower of the two corresponding to a substantially lower knickpoint migration rate and higher preservation potential. 3) Knickpoint migration occurs at a substantially faster time scale than regrading of the bedrock channel itself, underlying the significance of disequilibrium processes. Although implemented for constant climactic conditions, the model warrants extension to long-term climate variation.
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http://dx.doi.org/10.1073/pnas.1911040117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334490PMC
June 2020

A transcriptional roadmap for 2C-like-to-pluripotent state transition.

Sci Adv 2020 May 29;6(22):eaay5181. Epub 2020 May 29.

Howard Hughes Medical Institute, Boston, MA, USA.

In mouse embryonic stem cell (ESC), a small cell population displays totipotent features by expressing a set of genes that are transiently active in 2-cell-stage embryos. These 2-cell-like (2C-like) cells spontaneously transit back into the pluripotent state. We previously dissected the transcriptional dynamics of the transition from pluripotency to the totipotent 2C-like state and identified factors that modulate the process. However, how 2C-like cells transit back into the pluripotent state remains largely unknown. In this study, we analyzed the transcriptional dynamics from the 2C-like state to pluripotent ESCs and identified an intermediate state. The intermediate state characterized by two-wave step up-regulation of pluripotent genes is different from the one observed during the 2C-like entry transition. Nonsense-mediated Dux mRNA decay plays an important role in the 2C-like state exit. Thus, our study not only provides a transcriptional roadmap for 2C-like-to-pluripotent state transition but also reveals a key molecular event driving the transition.
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http://dx.doi.org/10.1126/sciadv.aay5181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7259939PMC
May 2020

The chromatin remodeler Snf2h is essential for oocyte meiotic cell cycle progression.

Genes Dev 2020 02 9;34(3-4):166-178. Epub 2020 Jan 9.

Howard Hughes Medical Institute, Boston Children's Hospital, Boston, Massachusetts 02115, USA.

Oocytes are indispensable for mammalian life. Thus, it is important to understand how mature oocytes are generated. As a critical stage of oocytes development, meiosis has been extensively studied, yet how chromatin remodeling contributes to this process is largely unknown. Here, we demonstrate that the ATP-dependent chromatin remodeling factor Snf2h (also known as Smarca5) plays a critical role in regulating meiotic cell cycle progression. Females with oocyte-specific depletion of are infertile and oocytes lacking fail to undergo meiotic resumption. Mechanistically, depletion of results in dysregulation of meiosis-related genes, which causes failure of maturation-promoting factor (MPF) activation. ATAC-seq analysis in oocytes revealed that Snf2h regulates transcription of key meiotic genes, such as , by increasing its promoter chromatin accessibility. Thus, our studies not only demonstrate the importance of Snf2h in oocyte meiotic resumption, but also reveal the mechanism underlying how a chromatin remodeling factor can regulate oocyte meiosis.
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http://dx.doi.org/10.1101/gad.331157.119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000916PMC
February 2020

Universal relation with regime transition for sediment transport in fine-grained rivers.

Proc Natl Acad Sci U S A 2020 01 18;117(1):171-176. Epub 2019 Dec 18.

Department of Civil and Environmental Engineering, Ven Te Chow Hydrosystems Laboratory, University of Illinois at Urbana-Champaign, IL 61801;

Fine-grained sediment (grain size under 2,000 μm) builds floodplains and deltas, and shapes the coastlines where much of humanity lives. However, a universal, physically based predictor of sediment flux for fine-grained rivers remains to be developed. Herein, a comprehensive sediment load database for fine-grained channels, ranging from small experimental flumes to megarivers, is used to find a predictive algorithm. Two distinct transport regimes emerge, separated by a discontinuous transition for median bed grain size within the very fine sand range (81 to 154 μm), whereby sediment flux decreases by up to 100-fold for coarser sand-bedded rivers compared to river with silt and very fine sand beds. Evidence suggests that the discontinuous change in sediment load originates from a transition of transport mode between mixed suspended bed load transport and suspension-dominated transport. Events that alter bed sediment size near the transition may significantly affect fluviocoastal morphology by drastically changing sediment flux, as shown by data from the Yellow River, China, which, over time, transitioned back and forth 3 times between states of high and low transport efficiency in response to anthropic activities.
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http://dx.doi.org/10.1073/pnas.1911225116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6955285PMC
January 2020

Stimulation of Hair Growth by Small Molecules that Activate Autophagy.

Cell Rep 2019 06;27(12):3413-3421.e3

Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address:

Hair plays important roles, ranging from the conservation of body heat to the preservation of psychological well-being. Hair loss or alopecia affects millions worldwide, but methods that can be used to regrow hair are lacking. We report that quiescent (telogen) hair follicles can be stimulated to initiate anagen and hair growth by small molecules that activate autophagy, including the metabolites α-ketoglutarate (α-KG) and α-ketobutyrate (α-KB), and the prescription drugs rapamycin and metformin, which impinge on mTOR and AMPK signaling. Stimulation of hair growth by these agents is blocked by specific autophagy inhibitors, suggesting a mechanistic link between autophagy and hair regeneration. Consistently, increased autophagy is detected upon anagen entry during the natural hair follicle cycle, and oral α-KB prevents hair loss in aged mice. Our finding that anagen can be pharmacologically activated in telogen skin when natural anagen-inducing signal(s) are absent has implications for the treatment of hair loss patients.
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http://dx.doi.org/10.1016/j.celrep.2019.05.070DOI Listing
June 2019

Myc and Dnmt1 impede the pluripotent to totipotent state transition in embryonic stem cells.

Nat Cell Biol 2019 07 17;21(7):835-844. Epub 2019 Jun 17.

Howard Hughes Medical Institute, Boston, MA, USA.

Totipotency refers to the ability of a cell to generate all of the cell types of an organism. Unlike pluripotency, the establishment of totipotency is poorly understood. In mouse embryonic stem cells, Dux drives a small percentage of cells into a totipotent state by expressing 2-cell-embryo-specific transcripts. To understand how this transition takes place, we performed single-cell RNA-seq, which revealed a two-step transcriptional reprogramming process characterized by downregulation of pluripotent genes in the first step and upregulation of the 2-cell-embryo-specific elements in the second step. To identify factors controlling the transition, we performed a CRISPR-Cas9-mediated screen, which revealed Myc and Dnmt1 as two factors preventing the transition. Mechanistic studies demonstrate that Myc prevents downregulation of pluripotent genes in the first step, while Dnmt1 impedes 2-cell-embryo-specific gene activation in the second step. Collectively, the findings of our study reveal insights into the establishment and regulation of the totipotent state in mouse embryonic stem cells.
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http://dx.doi.org/10.1038/s41556-019-0343-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7137718PMC
July 2019

Stereotactic aspiration for hypertensive intracerebral haemorrhage in a Chinese population: a retrospective cohort study.

Stroke Vasc Neurol 2019 Mar 2;4(1):14-21. Epub 2019 Mar 2.

Department of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

Objective: We aimed to compare the therapeutic effects of stereotactic aspiration and best medical management in patients who developed supratentorial hypertensive intracerebral haemorrhage (HICH) with a volume of haemorrhage between 20 and 40 mL.

Methods: The clinical data of 220 patients with supratentorial HICH with a volume between 20 and 40 mL were retrospectively analysed. Among them, 142 received stereotactic aspiration surgery (stereotactic aspiration group) and 78 received best medical management (conservative group). All were followed up for 6 months. Multivariate logistic regression and Kaplan-Meier survival curves were used to compare the outcome between the two groups.

Results: The rebleeding rate was lower in the group that had stereotactic aspiration when compared with the group with medical treatment (6 [4.2%] vs 9 [11.5%], χ=4.364, p=0.037). After 6 months, although the mortality rate did not differ significantly between the two groups (8 cases [5.6%] vs 10 cases [12.8%], χ=3.461, p=0.063), the rate of a favourable outcome was higher in the group who received stereotactic aspiration (χ=15.870, p=0.000). Logistic regression identified that medical treatment (OR=1.64, p=0.000) was an independent risk factor for an unfavourable outcome. The Kaplan-Meier curves indicated that the median favourable outcome time in the stereotactic aspiration group was 59.5 days compared with that in the medically treated group (87.0 days). The log-rank test indicated that the prognosis at 6 months was better for those treated with stereotactic haematoma aspiration (χ=29.866, p=0.000). However, the 6-month survival rate was similar between the two groups (χ=3.253, p=0.068).

Conclusions: Stereotactic haematoma aspiration significantly improved the quality of life, although did not effectively reduce the rate of mortality. When selected appropriately, patients with HICH may benefit from this type of surgical intervention.
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http://dx.doi.org/10.1136/svn-2018-000200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6475080PMC
March 2019

Bedrock-alluvial streams with knickpoint and plunge pool that migrate upstream with permanent form.

Sci Rep 2019 04 16;9(1):6176. Epub 2019 Apr 16.

Department of Civil & Environmental Engineering, University of Illinois Urbana-Champaign, Urbana, 61801, USA.

Purely alluvial rivers cannot sustain knickpoints along their long profiles, as they would be obliterated by diffusional morphodynamics. Bedrock streams with a partial alluvial cover, however, form and sustain slope breaks over long periods of time. Here we consider the case of an initial profile of a bedrock-alluvial stream with a sharp slope break, or knickpoint, from high to low midway. We show that if the initial flow is sufficiently Froude-supercritical in the upstream reach and Froude-subcritical in the downstream reach, a three-tiered structure can evolve at the slope break: a hydraulic jump at the water surface; a scour hole in the alluvium above the bedrock, and a plunge pool carved into bedrock. Once the profile adjusts to balance uplift, it can migrate upstream without changing form.
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http://dx.doi.org/10.1038/s41598-019-42389-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467923PMC
April 2019

Effect of simvastatin on expression of VEGF and TGF-β1 in atherosclerotic animal model of type 2 diabetes mellitus.

Exp Ther Med 2018 Oct 7;16(4):2889-2894. Epub 2018 Aug 7.

Department of Cadre Health Protection, Liaocheng People's Hospital, Liaocheng, Shandong 252000, P.R. China.

Expression of vascular endothelial growth factor (VEGF) and transforming growth factor-β1 (TGF-β1) in atherosclerosis animal model of type 2 diabetes mellitus treated with simvastatin was investigated. Clean grade mature Sprague Dawley (SD) rats were divided into three groups: Normal control (n=10), model (n=13) and treatment group (n=13); low-dose simvastatin was administered. The changes of VEGF and TGF-β1 levels were analyzed by tail vein blood sampling. The relationship between levels of VEGF, TGF-β1 and treatment time was analyzed. The expression level of VEGF in the treatment group after 4 and 8 weeks of intervention was lower compared with the model group (P<0.05). The expression level of TGF-β1 in the treatment group after 8 weeks of intervention was higher than that in the model group (P<0.05). The expression level of VEGF in the treatment group after 8 weeks of intervention was lower than that after 1 week of intervention (P<0.05). The expression level of TGF-β1 was increased in the model group after 8 weeks of intervention compared with 1 week before and after the intervention (P<0.05). The expression level of TGF-β1 in the treatment group at 2, 4 and 8 weeks after intervention were significantly higher than that before intervention (P<0.05). The expression of TGF-β1 increased after 4 and 8 weeks after intervention compared with 1 week after intervention (P<0.05). The expression of VEGF was negatively correlated with TGF-β1 expression in the treatment group; negative correlation was found between VEGF and treatment time. There was a positive correlation between TGF-β1 and treatment time. VEGF and TGF-β1 may be involved in the development of type 2 diabetes (T2MD) atherosclerosis (AS). Simvastatin may play a therapeutic role in T2MD AS by downregulating VEGF and upregulating the expression of TGF-β1.
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http://dx.doi.org/10.3892/etm.2018.6583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6143897PMC
October 2018

K237-modified thermosensitive liposome enhanced the delivery efficiency and cytotoxicity of paclitaxel in vitro.

J Liposome Res 2019 Mar 19;29(1):86-93. Epub 2018 Apr 19.

a Department of Pharmacy , Wuhan General Hospital of Chinese PLA , Wuhan , China.

This study aimed to develop novel temperature-sensitive liposomes loading paclitaxel (PTX-TSL) and evaluate them in vitro to improve the delivery efficiency and targeting of PTX. K237 peptide was conjugated to the terminal NHS of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[hydroxyl succinimidyl (polyethylene glycol)-(DSPE-PEG-NHS), and K237-modified PTX-TSL (K237-PTX-TSL) was prepared using a film dispersion method. K237-TSL encapsulation with calcein was synthesized and used to determine the cellular uptake of TSL. The morphology of K237-PTX-TSL was observed using a transmission electron microscope. The particle size and potential were measured using a laser particle size analyzer. The phase transition temperature was detected using the differential scanning calorimetry. The Cell Counting Kit-8 assay and flow cytometry were used to evaluate the effects of K237-PTX-TSL on the proliferation and cell cycle of cell lines SKOV-3 and human umbilical vein endothelial cell (HUVEC). The encapsulation efficiency of K237-PTX-TSL was 94.23% ± 0.76%. The particle diameter was 88.3 ± 4.7 nm. K237-PTX-TSL showed a fast release profile at 42 °C, while it was stable at 37 °C. PTX-TSL combined with hyperthermia significantly inhibited the cell proliferation of SKOV-3 cells and HUVECs due to increased cell arrest in the G2/M phase. The half-minimal inhibitory concentration value of K237-PTX-TSL on SKOV-3 cells and HUVECs was 13.61 ± 1.81 and 5.54 ± 0.95 nmol/L, respectively, which were significantly lower than those with PTX-TSL (p < 0.01). K237 modification could increase the targeting efficiency of TSL to cancer cells and vascular endothelial cells, thus resulting in higher cytotoxicities compared with PTX-TSL, which might be a potential formulation for targeting cancer therapy.
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http://dx.doi.org/10.1080/08982104.2018.1458863DOI Listing
March 2019

Chemical Foaming Coupled Self-Etching: A Multiscale Processing Strategy for Ultrahigh-Surface-Area Carbon Aerogels.

ACS Appl Mater Interfaces 2018 Jan 10;10(3):2819-2827. Epub 2018 Jan 10.

Division of Fuel Cell & Battery, Dalian National Laboratory for Clean Energy, Dalian Institute of Chemical Physics, Chinese Academy of Sciences , Dalian 116023, China.

Due to the unique structure, carbon aerogels have always shown great potential for multifunctional applications. At present, it is highly desirable but remains challenging to tailor the microstructures with respect to porosity and specific surface area to further expand its significance. A facile chemical foaming coupled self-etching strategy is developed for multiscale processing of carbon aerogels. The strategy is directly realized via the pyrolysis of a multifunctional precursor (pentaerythritol melamine phosphate) without any special drying process and multiple steps. In the micrometer scale, the macroporous scaffold structures with interconnected and strutted carbon nanosheets are built up by chemical foaming from decomposition of melamine, whereas the meso/microporous nanosheets are formed via self-etching by phosphorus-containing species. The delicately hierarchical structures and record-breaking specific surface area of 2668.4 m g render the obtained carbon aerogels great potentials for absorption (324.1-593.6 g g of absorption capacities for varied organic solvents) and energy storage (338 F g of specific capacitance). The construction of such novel carbon nanoarchitecture will also shed light on the design and synthesis of multifunctional materials.
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http://dx.doi.org/10.1021/acsami.7b16556DOI Listing
January 2018

Dipotassium phosphate improves the molecular weight stability of polysialic acid in Escherichia coli K235 culture broth.

Bioresour Technol 2018 Jan 24;247:30-35. Epub 2017 Aug 24.

Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi 214122, China. Electronic address:

This work elucidated the intrinsic mechanism underlying the influence of KHPO on PSA production and molecular weight (MW) stability. Among the different potassium salts mixed with KHPO in the initial medium, those with buffering capacity were favorable for PSA production. In the bioreactor culture with pH control, adding an appropriate concentration of KHPO could enhance PSA production. A dual-phase pH control strategy with ammonia water and KOH could also increase the yield and maintain the MW stability of PSA. Zeta potential test, UV/circular dichroism spectra, and transmission electric microscopy were utilized to explore the configuration of KHPO-PSA complex. The results from this study can serve a good basis for the industrial-scale production of PSA with stable MW.
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http://dx.doi.org/10.1016/j.biortech.2017.08.142DOI Listing
January 2018

IONP-doped nanoparticles for highly effective NIR-controlled drug release and combination tumor therapy.

Int J Nanomedicine 2017 16;12:3751-3766. Epub 2017 May 16.

School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, People's Republic of China.

Despite advances in controlled drug delivery, drug delivery systems (DDSs) with controlled activated drug release and high spatial and temporal resolution are still required. Theranostic nanomedicine is capable of diagnosis, therapy, and monitoring the delivery and distribution of drug molecules and has received growing interest. In this study, a near-infrared light-controlled "off-on" DDS with magnetic resonance imaging and magnetic targeting properties was developed using a hybrid nanoplatform (carbon nanotubes [CNTs]-iron oxide nanoparticle). Doxorubicin (DOX) and distearoyl--glycero-3-phosphoethanolamine-PEG were adsorbed onto CNTs-iron oxide nanoparticle, and then to avoid the unexpected drug release during circulation, 1-myristyl alcohol was used to encapsulate the CNTs-drug complex. Herein, multifunctional DOX-loaded nanoparticles (NPs) with "off-on" state were developed. DOX-NPs showed an obvious "off-on" effect (temperature increase, drug release) controlled by near-infrared light in vitro and in vivo. In the in vivo and in vitro studies, DOX-NPs exhibited excellent magnetic resonance imaging ability, magnetic targeting property, high biosafety, and high antitumor combined therapeutic efficacy (hyperthermia combined with chemotherapy). These results highlight the great potential of DOX-NPs in the treatment of cancer.
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http://dx.doi.org/10.2147/IJN.S113963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5440031PMC
September 2017

The exceptional sediment load of fine-grained dispersal systems: Example of the Yellow River, China.

Sci Adv 2017 May 12;3(5):e1603114. Epub 2017 May 12.

Ven Te Chow Hydrosystems Laboratory, Department of Civil and Environmental Engineering, University of Illinois at Urbana-Champaign, Champaign, IL 61801, USA.

Sedimentary dispersal systems with fine-grained beds are common, yet the physics of sediment movement within them remains poorly constrained. We analyze sediment transport data for the best-documented, fine-grained river worldwide, the Huanghe (Yellow River) of China, where sediment flux is underpredicted by an order of magnitude according to well-accepted sediment transport relations. Our theoretical framework, bolstered by field observations, demonstrates that the Huanghe tends toward upper-stage plane bed, yielding minimal form drag, thus markedly enhancing sediment transport efficiency. We present a sediment transport formulation applicable to all river systems with silt to coarse-sand beds. This formulation demonstrates a remarkably sensitive dependence on grain size within a certain narrow range and therefore has special relevance to silt-sand fluvial systems, particularly those affected by dams.
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http://dx.doi.org/10.1126/sciadv.1603114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5429038PMC
May 2017

A PLGA-PEG-PLGA Thermosensitive Gel Enabling Sustained Delivery of Ropivacaine Hydrochloride for Postoperative Pain Relief.

Chem Pharm Bull (Tokyo) 2017 ;65(3):229-235

Department of Pharmacy, Wuhan General Hospital of Chinese PLA.

Postoperative pain is a complex physiological response to disease and tissue injury. Moderate-to-severe pain typically occurs within 48 h after surgery. Amino amide local anesthetics are widely applied to manage postoperative pain, and they have high efficacy, a low risk for addiction and limited side effects. However, these anesthetics also have short half-lives, often necessitating continuous injection to obtain satisfactory pain relief. In the current work, we used a poly(lactic-co-glycolic acid) (PLGA)-polyethylene glycol (PEG)-PLGA (PLGA-PEG-PLGA) temperature-sensitive gel to deliver a local anesthetic, ropivacaine hydrochloride (RP), to prolong its analgesic effect. We investigated the influence of polymer and drug concentration on gelation temperature and the in vitro drug release rate from the temperature-sensitive gel. RP-loaded PLGA-PEG-PLGA solution is a liquid at room temperature and forms a gel at temperatures slightly lower than body temperature. With regard to the gel's drug release rate, 37.5, 51.3 and 72.6% of RP was released at 12, 24 and 48 h, respectively. This in vitro drug release profile conformed to the Higuchi equation. To assess pain control efficacy when using the gel, we evaluated the mechanical paw withdrawal reflex threshold, thermal pain threshold and incision cumulative pain scores in a rat incisional model. The results showed that the anti-pain effect of a single injection of RP-loaded gel at the incision site lasted for 48 h, which is significantly longer than the effect produced by injection of RP solution alone. The use of RP-loaded thermosensitive gels could provide a promising method for managing postoperative pain.
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http://dx.doi.org/10.1248/cpb.c16-00471DOI Listing
April 2017

Thermosensitive magnetic liposomes with doxorubicin cell-penetrating peptides conjugate for enhanced and targeted cancer therapy.

Drug Deliv 2016 Nov 7;23(9):3436-3443. Epub 2016 Jun 7.

a Department of Clinical Laboratory , Huangshi Love & Health Hospital of Hubei Province , Huangshi , P.R. China.

To specifically deliver cytotoxic drug to tumor cells and enhance cellular uptake is the key for effective cancer therapy. In this paper, we described a novel drug targeting system, which is designed to combine features of biological (cell-penetrating peptides, CPPs) and physical (magnetic) drug targeting for use in the magnetic hyperthermia-triggered release. A doxorubicin-CPPs conjugate (DOX-CPPs) was loaded into thermosensitive magnetic liposomes (TSMLs) (DOX-CPPs/TSMLs), and in vitro DOX-CPPs thermosensitive release activity, anti-proliferation effect, in vivo targeted delivery as well as in vivo antitumor activity were determined. The results demonstrated that the DOX-CPPs/TSMLs showed good physicochemical properties, effective anti-proliferation effect in MCF-7 cells in vitro. Additionally, in vivo study, DOX-CPPs/TSMLs under AC magnetic field displayed superior in vivo targeted delivery efficacy, antitumor efficacy in an MCF-7 xenograft murine model. In conclusion, the application of DOX-CPPs/TSMLs under AC magnetic field may provide a strategy for the selective and efficient delivery of drug.
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http://dx.doi.org/10.1080/10717544.2016.1189983DOI Listing
November 2016

Efficient siRNA Delivery Using Novel Cell-Penetrating Peptide-siRNA Conjugate-Loaded Nanobubbles and Ultrasound.

Ultrasound Med Biol 2016 06;42(6):1362-74

State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Because of the absence of tolerable and effective carriers for in vivo delivery, the applications of small interfering RNA (siRNA) in the clinic for therapeutic purposes have been limited. In this study, development of a novel siRNA delivery system based on ultrasound-sensitive nanobubbles (NBs, nano-sized echogenic liposomes) and cell-permeable peptides (CPPs) is described. A CPP-siRNA conjugate was entrapped in an NB, (CPP-siRNA)-NB, and the penetration of CPP-siRNA was temporally masked; local ultrasound stimulation triggered the release of CPP-siRNA from the NBs and activated its penetration. Subsequent research revealed that the (CPP-siRNA)-NBs had a mean particle size of 201 ± 2.05 nm and a siRNA entrapment efficiency >85%. In vitro release results indicated that >90% of the encapsulated CPP-siRNA was released from NBs in the presence of ultrasound, whereas <1.5% (30 min) was released in the absence of ultrasound. Cell experiments indicated higher cellular CPP-siRNA uptake of (CPP-siRNA)-NBs with ultrasound among the various formulations in human breast adenocarcinoma cells (HT-1080). Additionally, after systemic administration in mice, (CPP-siRNA)-NBs accumulated in the tumor, augmented c-myc silencing and delayed tumor progression. In conclusion, the application of (CPP-siRNA)-NBs with ultrasound may constitute an approach to selective targeted delivery of siRNA.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2016.01.017DOI Listing
June 2016

On spatial pattern of concentration distribution for Taylor dispersion process.

Sci Rep 2016 Feb 12;6:20556. Epub 2016 Feb 12.

State Key Laboratory of Hydroscience and Engineering; Department of Hydraulic Engineering, Tsinghua University, Beijing 100084, China.

Taylor dispersion is a key concept in many fields. In the present paper, we characterize the pattern of the complete spatial concentration distribution for laminar tube flow; the obtained simple description is shown to represent the nature of Taylor dispersion. Importantly, we find that during the approach to the longitudinal normality of the transverse mean concentration at the time scale of R(2)/D (R is the tube radius and D is the molecular diffusivity), the solute concentration becomes uniformly distributed across a family of invariant curved transverse surfaces instead of the flat cross-sections in the traditional view. The family of curved surfaces is analytically determined, and a transformation is devised for the previously obtained analytical solution to discuss the decay of the concentration difference across the curved surfaces. The approach to a uniform concentration across the flat cross-sections to the same degree (~3% by concentration difference percentage), achieved at a time-scale of 100 R(2)/D, is shown to be the natural consequence of the longitudinal separation of the concentration contours on the curved surfaces.
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http://dx.doi.org/10.1038/srep20556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4751533PMC
February 2016

M1 of Murine Gamma-Herpesvirus 68 Induces Endoplasmic Reticulum Chaperone Production.

Sci Rep 2015 Nov 30;5:17228. Epub 2015 Nov 30.

Department of Molecular and Medical Pharmacology, University of California, Los Angeles, California 90095.

Viruses rely on host chaperone network to support their infection. In particular, the endoplasmic reticulum (ER) resident chaperones play key roles in synthesizing and processing viral proteins. Influx of a large amount of foreign proteins exhausts the folding capacity in ER and triggers the unfolded protein response (UPR). A fully-executed UPR comprises signaling pathways that induce ER folding chaperones, increase protein degradation, block new protein synthesis and may eventually activate apoptosis, presenting both opportunities and threats to the virus. Here, we define a role of the MHV-68M1 gene in differential modulation of UPR pathways to enhance ER chaperone production. Ectopic expression of M1 markedly induces ER chaperone genes and expansion of ER. The M1 protein accumulates in ER during infection and this localization is indispensable for its function, suggesting M1 acts from the ER. We found that M1 protein selectively induces the chaperon-producing pathways (IRE1, ATF6) while, interestingly, sparing the translation-blocking arm (PERK). We identified, for the first time, a viral factor capable of selectively intervening the initiation of ER stress signaling to induce chaperon production. This finding provides a unique opportunity of using viral protein as a tool to define the activation mechanisms of individual UPR pathways.
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http://dx.doi.org/10.1038/srep17228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4663489PMC
November 2015

Bio-inspired Construction of Advanced Fuel Cell Cathode with Pt Anchored in Ordered Hybrid Polymer Matrix.

Sci Rep 2015 Nov 5;5:16100. Epub 2015 Nov 5.

Division of Fuel Cell &Battery, Dalian National Laboratory for Clean Energy, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.

The significant use of platinum for catalyzing the cathodic oxygen reduction reactions (ORRs) has hampered the widespread use of polymer electrolyte membrane fuel cells (PEMFCs). The construction of well-defined electrode architecture in nanoscale with enhanced utilization and catalytic performance of Pt might be a promising approach to address such barrier. Inspired by the highly efficient catalytic processes in enzymes with active centers embedded in charge transport pathways, here we demonstrate for the first time a design that allocates platinum nanoparticles (Pt NPs) at the boundaries with dual-functions of conducting both electrons by aid of polypyrrole and protons via Nafion(®) ionomer within hierarchical nanoarrays. By mimicking enzymes functionally, an impressive ORR activity and stability is achieved. Using this brand new electrode architecture as the cathode and the anode of a PEMFC, a high mass specific power density of 5.23 W mg(-1)Pt is achieved, with remarkable durability. These improvements are ascribed to not only the electron decoration and the anchoring effects from the Nafion(®) ionomer decorated PPy substrate to the supported Pt NPs, but also the fast charge and mass transport facilitated by the electron and proton pathways within the electrode architecture.
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http://dx.doi.org/10.1038/srep16100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4633593PMC
November 2015

Cell-penetrating peptide-siRNA conjugate loaded YSA-modified nanobubbles for ultrasound triggered siRNA delivery.

Colloids Surf B Biointerfaces 2015 Dec 24;136:641-50. Epub 2015 Oct 24.

Department of Clinical Laboratory, Huangshi Love & Health Hospital of Hubei Province, Huangshi 435000, PR China. Electronic address:

Due to the absence of effective in vivo delivery systems, the employment of small interference RNA (siRNA) in the clinic has been hindered. In this paper, a new siRNA targeting system for EphA2-positive tumors was developed, based on ultrasound-sensitive nanobubbles (NBs) and cell-permeable peptides (CPPs). Here, a CPP-siRNA conjugate (CPP-siRNA) was entrapped in an ephrin mimetic peptide (YSA peptide)-modified NB (CPP-siRNA/YSA-NB) and the penetration of the CPP-siRNA was temporally masked; local ultrasound stimulation triggered the release of CPP-siRNA from the NBs and activated its penetration. Subsequent research demonstrated that the CPP-siRNA/YSA-NBs had particle sizes of approximately 200 nm and a siRNA entrapment efficiency of more than 85%. The in vitro release results showed that over 90% of the encapsulated CPP-siRNA released from the NBs in the presence of ultrasound, while less than 1.5% of that (30 min) released without ultrasound. Cell experiments showed a the higher CPP-siRNA cellular uptake of CPP-siRNA/YSA-NB among the various formulations in human breast adenocarcinoma cells (MCF-7, EphA2 positive cells). Additionally, after systemic administration in mice, CPP-siRNA/YSA-NB accumulated in the tumor, augmented c-Myc silencing and delayed tumor progression. In conclusion, the application of CPP-siRNA/YSA-NB with ultrasound may provide a strategy for the selective and efficient delivery of siRNA.
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http://dx.doi.org/10.1016/j.colsurfb.2015.10.004DOI Listing
December 2015

Ultrasound-responsive nanobubbles contained with peptide-camptothecin conjugates for targeted drug delivery.

Drug Deliv 2016 Oct 14;23(8):2756-2764. Epub 2015 Aug 14.

c Beijing Institute of Pharmacology and Toxicology , Beijing , PR China.

To improve the targeting delivery efficiency of anticancer drug to tumor sites, a new strategy combining cell-permeable peptide (CPP) and ultrasound was reported in this article. In this study, we devised and tested a strategy for functional payload delivery to cells by loading CPP-camptothecin conjugate (CPP-CPT) into nanobubble (CPP-CPT NB). Here, CPP existing in the conjugation form of CPP and CPT was hidden in nanobubble to cloak the penetration activity of CPP. Meanwhile, local tumor ultrasound was utilized to achieve specific targeting of CPP-CPT to the tumor cells. The mean particle size of the prepared CPP-CPT NB was ∼200 nm, and the drug entrapment efficiency was >80%. Stimulated by ultrasound, over 90% of the entrapped CPP-CPTs would release from the nanobubbles. Subsequent research demonstrated that the CPP-CPT NB showed effective cellular uptake and significant cytotoxic activity in HeLa cells in vitro. Additionally, after systemic administration in mice, CPP-CPT NB with ultrasound showed a higher tumor inhibition effect in nude mice xenografted HeLa cells tumors and excellent body safety when compared with normal CPT injection group. In conclusion, the carrier constructed in this study would be a safe and efficiently drug delivery system for specific cancer treatment.
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http://dx.doi.org/10.3109/10717544.2015.1077289DOI Listing
October 2016

2-Hydroxyglutarate Inhibits ATP Synthase and mTOR Signaling.

Cell Metab 2015 Sep 16;22(3):508-15. Epub 2015 Jul 16.

Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA. Electronic address:

We discovered recently that the central metabolite α-ketoglutarate (α-KG) extends the lifespan of C. elegans through inhibition of ATP synthase and TOR signaling. Here we find, unexpectedly, that (R)-2-hydroxyglutarate ((R)-2HG), an oncometabolite that interferes with various α-KG-mediated processes, similarly extends worm lifespan. (R)-2HG accumulates in human cancers carrying neomorphic mutations in the isocitrate dehydrogenase (IDH) 1 and 2 genes. We show that, like α-KG, both (R)-2HG and (S)-2HG bind and inhibit ATP synthase and inhibit mTOR signaling. These effects are mirrored in IDH1 mutant cells, suggesting a growth-suppressive function of (R)-2HG. Consistently, inhibition of ATP synthase by 2-HG or α-KG in glioblastoma cells is sufficient for growth arrest and tumor cell killing under conditions of glucose limitation, e.g., when ketone bodies (instead of glucose) are supplied for energy. These findings inform therapeutic strategies and open avenues for investigating the roles of 2-HG and metabolites in biology and disease.
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http://dx.doi.org/10.1016/j.cmet.2015.06.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4663076PMC
September 2015

Cell-penetrating peptide-doxorubicin conjugate loaded NGR-modified nanobubbles for ultrasound triggered drug delivery.

J Drug Target 2016 15;24(2):134-46. Epub 2015 Jul 15.

c Department of Pharmacy , Beijing Institute of Pharmacology and Toxicology , Beijing , People's Republic of China.

A new drug-targeting system for CD13(+) tumors has been developed, based on ultrasound-sensitive nanobubbles (NBs) and cell-permeable peptides (CPPs). Here, the CPP-doxorubicin conjugate (CPP-DOX) was entrapped in the asparagine-glycine-arginine (NGR) peptide modified NB (CPP-DOX/NGR-NB) and the penetration of CPP-DOX was temporally masked; local ultrasound stimulation could trigger the CPP-DOX release from NB and activate its penetration. The CPP-DOX/NGR-NBs had particle sizes of about 200 nm and drug entrapment efficiency larger than 90%. In vitro release results showed that over 85% of the encapsulated DOX or CPP-DOX would release from NBs in the presence of ultrasound, while less than 1.5% of that (30 min) without ultrasound. Cell experiments showed the higher cellular CPP-DOX uptake of CPP-DOX/NGR-NB among the various NB formulations in Human fibrosarcoma cells (HT-1080, CD13(+)). The CPP-DOX/NGR-NB with ultrasound treatment exhibited an increased cytotoxic activity than the one without ultrasound. In nude mice xenograft of HT-1080 cells, CPP-DOX/NGR-NB with ultrasound showed a higher tumor inhibition effect (3.1% of T/C%, day 24), longer median survival time (50 days) and excellent body safety compared with the normal DOX injection group. These results indicate that the constructed vesicle would be a promising drug delivery system for specific cancer treatment.
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http://dx.doi.org/10.3109/1061186X.2015.1058802DOI Listing
October 2016

Enhanced small interfering RNA delivery into cells by exploiting the additive effect between photo-sensitive peptides and targeting ligands.

J Pharm Pharmacol 2015 Sep 16;67(9):1215-31. Epub 2015 Apr 16.

Department of Pharmaceutics, Beijing Institute of Pharmacology and Toxicology, Beijing, China.

Objectives: To enhance the targeting delivery efficiency of small interfering RNA (siRNA) to tumour cells, a novel multifunctional liposome (PSP/NGR-L) comodified with photo-sensitive cell-penetrating peptides (PSP) and asparagine-glycine-arginine peptide (NGR) was constructed and investigated.

Methods: PSP was conjugated to 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-maleimide(polyethylene glycol)-2000 (DSPE-PEG2000 -MAL) to generate DSPE-PEG2000 -PSP and used to form PSP/NGR-L, the features of the liposomes were determined. HT-1080 and MCF-7 cells were used for cellular uptake tests, and the cellular uptake pathways were identified. Intracellular trafficking and endosomal escape were also evaluated. In-vitro siRNA transfection evaluations were carried out in HT-1080 cells.

Key Findings: The encapsulation efficiencies of liposomes were about 80%, and the mean particle sizes were around 100 nm. The targeting specificity of PSP/NGR-L was significantly enhanced via NGR navigation and ultraviolet (UV) light illumination. The internalization of PSP/NGR-L in HT-1080 cells was mediated by more than one cellular uptake mechanisms. The constructed nanocarrier could escape from the endosome to produce its effects in the cellular cytoplasm with the help of UV illumination. PSP/NGR-L could down-regulate expression of c-myc and augmented cell apoptosis in HT-1080 cells.

Conclusions: The application of combined PSP and NGR modifications may be a new approach for the selectively targeted delivery of siRNA to cancer cells.
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http://dx.doi.org/10.1111/jphp.12425DOI Listing
September 2015

MicroRNA-185 targets SOCS3 to inhibit beta-cell dysfunction in diabetes.

PLoS One 2015 6;10(2):e0116067. Epub 2015 Feb 6.

Research Department, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, China.

Diabetes is the most common and complex metabolic disorder, and one of the most important health threats now. MicroRNAs (miRNAs) are a group of small non-coding RNAs that have been suggested to play a vital role in a variety of physiological processes, including glucose homeostasis. In this study, we investigated the role of miR-185 in diabetes. MiR-185 was significantly downregulated in diabetic patients and mice, and the low level was correlated to blood glucose concentration. Overexpression of miR-185 enhanced insulin secretion of pancreatic β-cells, promoted cell proliferation and protected cells from apoptosis. Further experiments using in silico prediction, luciferase reporter assay and western blot assay demonstrated that miR-185 directly targeted SOCS3 by binding to its 3'-UTR. On the contrary to miR-185's protective effects, SOCS3 significantly suppressed functions of β-cell and inactivated Stat3 pathway. When treating cells with miR-185 mimics in combination with SOCS3 overexpression plasmid, the inhibitory effects of SOCS3 were reversed. While combined treatment of miR-185 mimics and SOCS3 siRNA induced synergistically promotive effects compared to either miR-185 mimics or SOCS3 siRNA treatment alone. Moreover, we observed that miR-185 level was inversely correlated with SOCS3 expression in diabetes patients. In conclusion, this study revealed a functional and mechanistic link between miR-185 and SOCS3 in the pathogenesis of diabetes. MiR-185 plays an important role in the regulation of insulin secretion and β-cell growth in diabetes. Restoration of miR-185 expression may serve a potentially promising and efficient therapeutic approach for diabetes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0116067PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4319748PMC
January 2016

Contributions of purinergic P2X3 receptors within the midbrain periaqueductal gray to diabetes-induced neuropathic pain.

J Physiol Sci 2015 Jan 1;65(1):99-104. Epub 2014 Nov 1.

Department of Endocrinology, Liaocheng People's Hospital, 67 West Dongchang Road, Liaocheng, 252000, Shandong, China.

Hyperalgesia and allodynia are commonly observed in patients with diabetic neuropathy. The mechanisms responsible for neuropathic pain are not well understood. Thus, in this study, we examined the role played by purinergic P2X3 receptors of the midbrain periaqueductal gray (PAG) in modulating diabetes-induced neuropathic pain because this brain region is an important component of the descending inhibitory system to control central pain transmission. Our results showed that mechanical withdrawal thresholds were significantly increased by stimulation of P2X3 receptors in the dorsolateral PAG of rats (n = 12, P < 0.05 vs. vehicle control) using α,β-methylene-ATP (α,β-meATP, a P2X3 receptor agonist). In addition, diabetes was induced by an intraperitoneal injection of streptozotocin (STZ) in rats, and mechanical allodynia was observed 3 weeks after STZ administration. Notably, the excitatory effects of P2X3 stimulation on mechanical withdrawal thresholds were significantly blunted in STZ-induced diabetic rats (n = 12, P < 0.05 vs. control animals) as compared with control rats (n = 12). Furthermore, the protein expression of P2X3 receptors in the plasma membrane of the dorsolateral PAG of STZ-treated rats was significantly decreased (n = 10, P < 0.05 vs. control animals) compared to that in control rats (n = 8), whereas the total expression of P2X3 receptors was not significantly altered. Overall, data of our current study suggest that a decrease in the membrane expression of P2X3 receptors in the PAG of diabetic rats is likely to impair the descending inhibitory system in modulating pain transmission and thereby contributes to the development of mechanical allodynia in diabetes.
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http://dx.doi.org/10.1007/s12576-014-0344-5DOI Listing
January 2015