Search

Improved curative effects with reduced toxicity has always been the ultimate goal of gene delivery vectors for tumor immunotherapy. Panax notoginseng polysaccharide (PNP), a natural plant-derived macromolecule, not only has antitumor immune activity but also has the typical structural characteristics useful for gene delivery. In this work, positively charged polyethyleneimine (PEI) was directly grafted to the backbone of PNP to induced its charge reversal and generate a functional gene vector (PNP-PEI). Moreover, a short hairpin RNA targeting the programmed death-ligand 1 (PD-L1) was loaded into PNP-PEI to generate a potentially therapeutic nanoparticle (PNP-PEI/shPD-L1). In vitro and in vivo experiments demonstrated that PNP-PEI could efficiently carry the therapeutic shPD-L1 into tumor cells and that PNP-PEI/shPD-L1 could significantly inhibit the expression of PD-L1 and growth of B16-F10 cells. Noteworthily, treatment with PNP-PEI reversed the phenotype of macrophages from M2 to M1 subtype and promoted dendritic cell maturation, which encouraged the host immunity and enhanced the therapeutic antitumor effects. In summary, this study describes a PNP-based gene delivery vector and highlights the beneficial immunopotentiating therapeutic outcomes of PNP-PEI for tumor immunotherapy.

There is growing empirical evidence that certain types of chemotherapy and phototherapy trigger immunogenic cell death and enhance the therapeutic anticancer efficacy of genetic immunotherapy. However, the main challenge is spatiotemporally co-delivering different drugs to maximize the therapeutic index of the combination therapy. In this study, a drug delivery system (HTCP-Au/shPD-L1/DOX) was designed with a polysaccharide-wrapped shell and a condensed DNA core. To construct the HTCP-Au vector, dodecyl side chains with a polyethylenimine (PEI) head were grafted onto hyaluronic acid, and AuNPs were grafted via Au-S bonds. During drug loading, PEI arrested shRNA plasmid DNA targeting programmed cell death ligand 1 (shPD-L1) via electrostatic interactions. It also formed a PEI-DNA core that was automatically enclosed when aliphatic hydrocarbons pulled the hyaluronic acid backbone. A hydrophobic interlayer consisting of dodecyl bridge chains between the PEI-DNA core and the hyaluronic acid shell was required to accommodate hydrophobic doxorubicin. In vitro and in vivo assays demonstrated that this core-shell drug delivery system could efficiently load and transport three different drugs and effectively target tumors. Moreover, it could activate the immune system, thereby providing promising therapeutic efficacy against tumor growth and metastasis., Graphical abstract HTCP-Au/shPD-L1/DOX was composed of gold nanoparticles (AuNPs)-modified hyaluronic acid shell, shPD-L1 plasmid core compressed by cationic polyethyleneimine and doxorubicin (DOX) encapsulated in hydrophobic layer. It could target to tumor cells by the CD44 receptor which is over-expressed in tumor microenvironment, followed by drug releasing responsively at 808 nm laser and the low pH in lysosome. Then the PD-L1 gene silencing induced by shPD-L1 and immunogenic cell death effect triggered by DOX and AuNPs will eliminate the tumor synergisticallyImage, graphical abstract

"Black Copper Walking on Silver ", the unique copper production process in Yunnan, as an important part of the excellent traditional Chinese culture, its inheritance has far-reaching significance for us to establish cultural confidence and rebuild cultural identity. However, the current development of black copper and silver walking technology is difficult, and the traditional sense of protection has been unable to solve the root problem. Nowadays, the protection of black copper and silver walking skills should break the traditional static single protection mode, combine the traditional inheritance with modern protection, and grasp the intangible cultural heritage elements from the perspective of productive protection. On the basis of objectively analyzing the characteristics and development status, the article effectively connects the living inheritance with industrialization, and explores the new development mode of folk custom industrialization under the live inheritance mode, so as to promote the live inheritance of black copper walking on silver and the common development of folk economy industry.

Near-infrared (NIR) persistent luminescence nanoparticles (PLNPs) with high brightness, small sizes, good hydro-dispersivity, and intrinsic surface-functional groups are desirable in biological applications. In this work, Cr3+-doped zinc gallogermanates Zn1+x Ga2−2x Ge x O4:Cr (ZGGC) PLNPs were hydrothermally synthesized via 3-aminopropyltriethoxysilane (APTES) as an additive, or APTES and cetyltrimethylammonium bromide (CTAB) as two co-additives. Addition of APTES not only dramatically enhances the 696 nm NIR luminescence intensity, but also obviously decreases the particle size and introduces amino groups. In particular, the x = 0.1 series ZGGC (ZGGC0.1) with the addition of n moles equivalent APTES (ZGGC0.1-nA) had smaller particle sizes than the x = 0.2 counterpart (ZGGC0.2-nA). The NIR afterglow intensities increased with the APTES introduction. The ZGGC0.2-2.5A sample (also named as ZGGC, Si, -NH2) exhibited maximum luminescence intensities both in solid and aqueous states. With APTES, Si atom is doped and –NH2 groups are modified, the trap depth and density become larger, and the afterglow intensities and decay time are significantly enhanced. More notably, co-addition of CTAB (ZGGC0.2-2.5A-C) (also named as ZGGC, Si, −NH2’) further enhances hydro-dispersivity and luminescence intensity, decreases particle sizes, and results in more prominent amino groups. The trap density is drastically higher than that without CTAB (i.e. ZGGC0.2-2.5A). Change of Cr3+ microenvironment in the crystal and more defects introduction contribute to the enhanced brightness. As expected, the ZGGC,Si,-NH2’ PLNPs possess excellent biocompatibility, deep tissue penetration and distinguished bioimaging properties, and rechargeability with orange LED light. The ZGGC,Si,-NH2’ PLNPs should provide to be an excellent nanomaterial for various functionalization and bioimaging applications.

The aim of this work was to develop a simple and rapid analytical method for the simultaneous determination of a wide range of drug residues in milk by UHPLC-MS/MS. A total of 25 typical veterinary drugs investigated belong to six families including β-lactams, quinolones, β-agonists, phenicols, glucocorticoids and nitrofurans. The samples were extracted by acetonitrile and defatted with n-hexane twice. Electrospray ionization and positive/negative polarity switching were utilized for the analysis of 25 veterinary drugs in a single chromatographic run. The linearity, recovery, precision and matrix effects of the method were fully validated. The intra- and inter-precision were in the range of 1.7-11.1% and 2.5-10.4%, respectively. The average recoveries ranged from 65.9% to 123.5% with RSD less than 10.8% at three concentration levels. The proposed method was demonstrated to be simple, economical and reliable for the fast monitoring of these drug residues in milk samples.

Microthrix parvicella (M. parvicella) is a filamentous bacterium that induces bulking in activated sludge. Here, we used the affinity of long-chain fatty acids (LCFA) for M. parvicella to create a novel fluorescent probe of carbazole modified by LCFA. The structure was characterized by 1H NMR spectroscopy and mass spectrometry. The spectral properties, photostability, and hydrophobic properties of the probe were also characterized. Fluorescent-labeling results showed that it can label M. parvicella in situ and could be biodegraded via metabolism. The stable docking mode of carbazole probes with different fatty acid chains and lipases was also docked by the density functional tight-binding (DFTB) method.

A novel near-infrared (NIR) ratiometric colorimetric ICT-based fluorescence probe for hydrazine has been synthesized and characterized. The probe DCM-LX selectively distinguished hydrazine with other analyses with a wide pH range. Once hydrazine is added to the solution of probe DCM-LX, the color of solution changed to orange from yellow immediately. It means probe can be used for “naked-eye” detection of hydrazine. DCM-LX exhibits high selectivity and excellent sensitivity towards hydrazine with detection limit as low as 7.71 nM. Furthermore, DCM-LX was successfully applied in living cellular imaging with low toxicity and hydrazine detection in H 2 O sample.

Xueling Ren, Jing Lin, Xuefang Wang, Xiao Liu, Erjuan Meng, Rui Zhang, Yanxiao Sang, Zhenzhong Zhang Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, People’s Republic of China Abstract: The efficacy of RNA interference (RNAi)-based cancer gene therapy is limited by its unexpected side effects, thus necessitating a strategy to precisely trigger conditional gene knockdown. In this study, we engineered a novel photoactivatable RNAi system, named as polyetherimide-modified single-wall carbon nanotube (PEI-SWNT)/pHSP-shT, that enables optogenetic control of targeted gene suppression in tumor cells. PEI-SWNT/pHSP-shT comprises a stimulus-responsive nanocarrier (PEI-SWNT), and an Hsp70B'-promoter-driven RNAi vector (pHSP-shT). In response to near-infrared (NIR) light irradiation, heating of PEI-SWNT in breast MCF-7 cells triggered gene knockdown targeting human telomerase reverse transcriptase through RNAi, with the gene-knockdown activity capable of being switched off by extinguishing the NIR. Furthermore, we demonstrated that the photoactivatable RNAi system exhibited higher antitumor activity by combining gene therapy and photothermal therapy, both in vitro and in vivo. Optogenetic control of RNAi based on an NIR-activated nanocarrier will potentially facilitate improved understanding of molecular-targeted gene therapy in human malignant tumors. Keywords: near-infrared light response, SWNT, RNAi, Hsp70B' promoter

Hydrogen sulfide (H2S) is very important for humans and is involved in many physiological processes. Here, we designed and reported a new naked-eye colorimetric fluorescent probe Z1 for detecting H2S in absolute HEPES solution. The fluorescence intensity, after the reaction of the probe and H2S, is about 32 times that of the probe alone. When the concentration of H2S is 0-100 μM, the detection limit (DL) is rather low at about 0.15 μM (3σ/slope). The response mechanism is based on the leaving of the 2,4-dinitrobenzene moiety, followed by intramolecular cyclization to give a fluorescent iminocoumarin-benzothiazole group. Moreover, Z1 was applied to endogenous and exogenous H2S imaging in living cells. The high overlap coefficient proved that probe Z1 has good ER-tracker localization in living cells.

We present a novel luminescent metal–organic framework (LMOF) based on zirconium metal oxide cluster Zr6O8 bonding with a new tetratopic linker 1,3,6,8-tetrakis(4′-carboxy[1,1′-biphenyl]-4-yl-)pyrene. This (4,12)-connected ftw-a-type net is composed of a large solvent-accessible volume of 79.5% volume per unit cell with a BET surface area up to 3540.5 m2 g−1. The activated LMOF exhibits an unprecedented fluorescence quenching effect triggered by nitrobenzene (NB) with quench percentage up to 99.5%, and could reversibly take up 14.7 mmol g−1 of NB under atmospheric conditions. The breakthrough curve of CH4 and C2H6 at 298 K and 2.0 MPa demonstrates that the activated LMOF has high-performance selective adsorption for CH4 with a selectivity of 25.45, which is an unusually high value as compared with those of reported materials.

A two-photon reversible fluorescent probe L1 was designed and synthesized. The fluorescence intensity of the probe solution was strong, while the fluorescence of the solution was obviously quenched and the color of the solution was changed after the addition of hypochlorous acid, indicating this is “naked-eye sensor” for the detection of HClO. The probe showed great selectivity for hypochlorous acid over other reactive oxygen species (ROS) and anions. Fluorescence titration experiments showed that the probe has a low detection limit of 0.674 μM. Because of a morpholine group introduced to the naphathalimide framework, probe L1 was successfully applied to detect intracellular HClO in lysosome.

Liver-specific gene knockdown cannot be achieved by short hairpin RNA (shRNA) generated by RNA polymerase III promoter. Here we constructed, modified and evaluated apolipoprotein A-I (ApoA-I) promoter-driven shRNA expression vectors against human telomerase reverse transcriptase (hTERT) in SMMC-7721 cells. The roles of the cis-acting hammerhead ribozyme and the specific pausing site MAZ, the liver-specific promoter ApoA-I, as well as SV40 and CMV enhancers were first individually evaluated, and then they were incorporated to construct a liver-specific shRNA expression plasmid against hTERT, and the inhibitory effects on hTERT were examined in SMMC-7721 cells. The results showed that the introduction of the cis-acting hammerhead ribozyme and the specific pausing site MAZ did not change gene knockdown efficiency significantly, but eliminated the off-target effect. Green fluorescent protein (GFP) expressing plasmid under the control of ApoA-I promoter can produce liver-specific GFP expression, but at a much lower level compared to the CMV promoter. The CMV or SV40 enhancer-modified ApoA-I promoter caused a four or two folds increase in mRNA expression of GFP relative to ApoA-I alone, respectively. The liver-specific shRNA expression plasmid against hTERT under the control of CMV enhancer-modified ApoA-I promoter with the sequences of the cis-acting hammerhead ribozyme and MAZ, induced significant inhibitory effect on hTERT at both mRNA and protein levels in SMMC-7721 cells. Therefore, liver-specific gene therapy is made possible by utilizing shRNA expression vector under the control of CMV enhancer-modified ApoA-I promoter.

By studying on the little cotton textures from relics excavation, there is not a clear answer to when the China cotton planting started. Although Qiru area was the north weaving center, there were not so much unearthed fabrics. “The lion rolling ball” parcel cloth of Qing Dynasty is one of the seldom printed cottons. It contains rich culture, life custom and the information of weaving technology with cotton in the Qilu region. From the view of history, this paper analyzes the pattern model, fiber material, weaving technology of “The lion rolling ball” parcel cloth of Qing Dynasty. By comparing it with modern Lu brocade using empirical analysis method, we found that the yarns in fabric is cotton, one of ancient Asia cottons, which showed “The lion rolling ball” parcel cloth of Qing Dynasty played an important role in the history of cotton clothes.

Due to the difference in the physical and mechanical properties between the optical fiber, protective layer, adhesive layer, and the host material, the strains measured by a fiber Bragg grating (FBG) sensor may not be the actual strains of the host material, which impedes the reliable applications of FBG sensors. To overcome this problem, in this paper, the strain transfer formula was derived by using elastic analysis, the shear-lag method, and several reasonable assumptions taking into account temperature variations and nonaxial stresses, which was an improvement to an existing study (Li, H. N., Zhou, G. D., Ren, L., and Li, D. S., “Strain Transfer Analysis of Embedded Fiber Bragg Grating Sensor Under Nonaxial Stress,” Optic. Eng., Vol. 46, No. 5, 2007, 054402). The analytical results were validated by simulating the behavior of a bare optical fiber through finite element analysis. The data enabled the identification of the parameters that influence the strain transfer from the host material to the embedded FBG sensors and the impact of the temperature variation and sensor alignment angle on the measurement accuracy. This work provided additional knowledge for the improvement of the existing strain transfer theory of FBG sensors in order to achieve a more accurate strain measurement with this sensing technology.

The purpose of this study is to explore the possibility and feasibility of liver-specific gene therapy. A shRNA expression plasmid against human telomerase reverse transcriptase (hTERT) was constructed under the control of liver-specific promoter apolipoprotein A-I (ApoAI), designated as pApoAI-shTERT, and its liver-specific cytotoxicity and inhibition of telomerase activity were first evaluated in different cell lines, and its therapeutic effect was further studied in SMMC-7721 human liver tumor-bearing mice in vivo. The results showed that compared to pU6-shTERT, a shRNA expression plasmid against hTERT under the control of U6 promoter, pApoAI-shTERT only significantly diminished the cell viability in the telomerase positive hepatocarcinoma cells and showed no cytotoxicity in the telomerase negative cell lines as well as in the telomerase positive cell line of non-liver origin. Besides, pApoAI-shTERT only significantly reduced telomerase activity in the telomerase positive cell lines of liver origin. Intravenous administration of pegylated immuno-lipopolyplexes (PILP) formulated green fluorescent protein (GFP) expression plasmid under the control of ApoAI into liver tumor-bearing mice resulted in restricted GFP expression in liver and liver tumor. The treatment of pApoAI-shTERT formulated as PILP caused a 56% increase in the life span of SMMC-7721 tumor-bearing mice in vivo relative to the control, which was in agreement with the reduced tumor size and down-regulated hTERT mRNA level in the tumors. We conclude that the vector pApoAI-shTERT was able to cause liver-specific and hTERT target-specific cytotoxicity, and utilizing PILP to deliver pApoAI-shTERT is a promising strategy for liver-specific gene therapy.

Liver-specific gene therapy is advantageous to minimize the possible adverse effects caused by non-target gene expression. The CMV promoter of the enhanced green fluorescent protein (EGFP) expressing plasmid pCMV-EGFP was replaced with the liver-specific promoter apolipoprotein A-I (ApoAI) generating pApoAI-EGFP plasmid. In vitro expression experiments performed in various cell lines including HepG2, SMMC-7721, MCF7, ACC-2 and Lo2 indicated that pCMV-EGFP treatment caused gene expression in all the cell lines, whereas pApoAI-EGFP treatment only induced EGFP expression in cells of liver origin including the liver cancer cells HepG2 and SMMC-7721 and the normal liver cells Lo2. Either pCMV-EGFP or pApoAI-EGFP was formulated as pegylated immuno-lipopolyplexes (PILP), a novel and efficient gene delivery system. Following intravenous administration of the PILP in H22 tumor-bearing mice, there was significant EGFP expression in liver, tumor, spleen, brain and lung in the pCMV-EGFP treated mice, whereas in the pApoAI-EGFP treated mice there was only gene expression in liver and tumor and the non-liver organ gene expression was eliminated. This study suggests that the use of the PILP technology and liver-specific promoter enables efficient and liver-specific expression of an exogenous gene.