New antimicrobial strategies are urgently needed to meet the challenges posed by the emergence of drug-resistant bacteria and bacterial biofilms.This work reports the facile synthesis of antimicrobial dynamic covalent...New antimicrobial strategies are urgently needed to meet the challenges posed by the emergence of drug-resistant bacteria and bacterial biofilms.This work reports the facile synthesis of antimicrobial dynamic covalent nano-networks(aDCNs)composing antibiotics bearing multiple primary amines,polyphenols,and a cross-linker acylphenylboronic acid.Mechanistically,the iminoboronate bond drives the formation of aDCNs,facilitates their stability,and renders them highly responsive to stimuli,such as low pH and high H2O2 levels.Besides,the representative A1B1C1 networks,composed of polymyxin B1(A1),2-formylphenylboronic acid(B1),and quercetin(C1),inhibit biofilm formation of drug-resistant Escherichia coli,eliminate the mature biofilms,alleviate macrophage inflammation,and minimize the side effects of free polymyxins.Excellent bacterial eradication and inflammation amelioration efficiency of A1B1C1 networks are also observed in a peritoneal infection model.The facile synthesis,excellent antimicrobial performance,and biocompatibility of these aDCNs potentiate them as a much-needed alternative in current antimicrobial pipelines.展开更多
Eleven biogenetically related polyprenylated acylphloroglucinols(PPAPs),including four novel skeletons(1-4)and five new com-pounds(5-9),were isolated from the flowers of Hypericum monogynum.Hypermonones A-D(1-4)repres...Eleven biogenetically related polyprenylated acylphloroglucinols(PPAPs),including four novel skeletons(1-4)and five new com-pounds(5-9),were isolated from the flowers of Hypericum monogynum.Hypermonones A-D(1-4)represented the first example of a unique dilactone structure containing carbonyl bonded single 5-lactone and tricyclic γ-lactone moieties.Their structures were elucidated by NMR analysis,X-ray crystallography,and ECD calculations.Moreover,we revised the structure of hyperibrin B to hy perm on one I(9)via NMR an alysis,a qua ntum computational chemistry method,and hypothetic bios yn thetic con siderations.Three compounds(5,6,and 9)with significant MDR reversal activity(RF ranging from 61 to 223)were superior to the positive control verapamil(MCF-7/ADR,RF:53;HepG2/ADRz RF:124).Mechanism study for compound 5 indicated that this compound could inhibit the function of P-gp tran sport rather tha n its expressi on,and the possible recog nition mechanism betwee n compo und 5 and P-gp was predicted by molecular docking.展开更多
The multidrug resistance P-glycoprotein (P-gp) expression and func-tion in hematopoietic stem/progenitor cells were studied to investigate whether the inhibition of hematopoietic cell P-gp function by multidrug resist...The multidrug resistance P-glycoprotein (P-gp) expression and func-tion in hematopoietic stem/progenitor cells were studied to investigate whether the inhibition of hematopoietic cell P-gp function by multidrug resistance reversal agent increases the cytotoxicity of chemotherapy drugs on the hematopoietic cells.The expression of P-gp on the surface of CD cells from healthy human marrow was examined by flow cytometry. The multidrug resistance reversal agent MS-209 was used to measure the effects of MS-209 on the Rhodamin-123 uptaking o fCD hematopoietic cells. By using methylcellulose semi-solid culture, normal human granulocyte-macrophage clonal formation unit (CFU-GM) was cultured. The changes in CFU-GM inhibitory rate caused by daunorubicin were determined in the presence or absence of MS-2O9. The results showed that the P-gp expression rate of bone marrow CDL cells was 13. 3 %. MS-209 obviously increased the Rhodamin-123 uptake of CD positive cells. The mean inhibitory rate of daunorubicin for CFU-GM was 29. 6 %, but it was increased to 43. 3 % in the presence of MS-209 with the difference being significant (P< 0. 05). It was concluded that hematopoietic cells expressed P-gp protein and possessed active function- MS-209could inhibit the membrane efflux pump and increase the cytotoxicity of chemotherapy drugs to the clonal growth of hematopoeitic stem cells, suggesting the side effects of these drugs on the hematopoietic system should be taken into consideration in the clinical use.展开更多
Chemotherapy plays a crucial role in triple-negative breast cancer (TNBC) treatment as it not only directly kills cancer cells but also induces immunogenic cell death. However, the chemotherapeutic efficacy was strong...Chemotherapy plays a crucial role in triple-negative breast cancer (TNBC) treatment as it not only directly kills cancer cells but also induces immunogenic cell death. However, the chemotherapeutic efficacy was strongly restricted by the acidic and hypoxic tumor environment. Herein, we have successfully formulated PLGA-based nanoparticles concurrently loaded with doxorubicin (DOX), hemoglobin (Hb) and CaCO3 by a CaCO3-assisted emulsion method, aiming at the effective treatment of TNBC. We found that the obtained nanomedicine (DHCaNPs) exhibited effective drug encapsulation and pH-responsive drug release behavior. Moreover, DHCaNPs demonstrated robust capabilities in neutralizing protons and oxygen transport. Consequently, DHCaNPs could not only serve as oxygen nanoshuttles to attenuate tumor hypoxia but also neutralize the acidic tumor microenvironment (TME) by depleting lactic acid, thereby effectively overcoming the resistance to chemotherapy. Furthermore, DHCaNPs demonstrated a notable ability to enhance antitumor immune responses by increasing the frequency of tumor-infiltrating effector lymphocytes and reducing the frequency of various immune-suppressive cells, therefore exhibiting a superior efficacy in suppressing tumor growth and metastasis when combined with anti-PD-L1 (αPD-L1) immunotherapy. In summary, this study highlights that DHCaNPs could effectively attenuate the acidic and hypoxic TME, offering a promising strategy to figure out an enhanced chemo-immunotherapy to benefit TNBC patients.展开更多
Objective: To investigate the Reversal Effect of Irisquinone (ANKA) on Cisplatin-resistant Human Lung Adenocarcinoma Cell Line (A 549 DDP ) and the change of MRP expression. Methods: MTT assay, flow cytometry, glutath...Objective: To investigate the Reversal Effect of Irisquinone (ANKA) on Cisplatin-resistant Human Lung Adenocarcinoma Cell Line (A 549 DDP ) and the change of MRP expression. Methods: MTT assay, flow cytometry, glutathione reductase recycling assay, RT-PCR were used. Results: None or low cytotoxic concentration of ANKA (10, 20, 30 μmol/L) could increase the sensitivity of A 549 DDP cells to CDDP by 8.2, 7.9 and 8.9-fold in a dose independent manner. After A 549 DDP cells was pretreated with 10 μmol/L ANKA for 12 h, CDDP cytotoxicity was increased 9.41-fold. The GSH content of the cells treated by ANKA is reduced significantly (P<0.001). The GSTπ protein expression was reduced by ANKA depended on its doses. ANKA also reduced expression of MRP protein, dependent on its dose and treating time (P<0.001). MRP mRNA expression was reduced only by 30μmol/L ANKA (P<0.05). Conclusion: The reversal effect of ANKA on A 549 DDP cell was relative to intracellular glutathione system.展开更多
Construction of multifunctional stimuli-responsive nanotherapeutics enabling improved intratumoral penetration of therapeutics and reversal of multiple-drug resistance(MDR)is potent to achieve effective cancer treatme...Construction of multifunctional stimuli-responsive nanotherapeutics enabling improved intratumoral penetration of therapeutics and reversal of multiple-drug resistance(MDR)is potent to achieve effective cancer treatment.Herein,we report a general method to synthesize pH-dissociable calcium carbonate(CaCO_(3))hollow nanoparticles with amorphous CaCO_(3)as the template,gallic acid(GA)as the organic ligand,and ferrous ions as the metallic center via a one-pot coordination reaction.The obtained GA–Fe@CaCO_(3)exhibits high loading efficiencies to both oxidized cisplatin prodrug and doxorubicin,yielding drug loaded GA-Fe@CaCO_(3)nanotherapeutics featured in pH-responsive size shrinkage,drug release,and Fenton catalytic activity.Compared to nonresponsive GA-Fe@silica nanoparticles prepared with silica nanoparticles as the template,such GA-Fe@CaCO_(3)confers significantly improved intratumoral penetration capacity.Moreover,both types of drug-loaded GA–Fe@CaCO_(3)nanotherapeutics exhibit synergistic therapeutic efficacies to corresponding MDR cancer cells because of the GA–Fe mediated intracellular oxidative stress amplification that could reduce the efflux of engulfed drugs by impairing the mitochondrial-mediated production of adenosine triphosphate(ATP).As a result,it is found that the doxorubicin loaded GA-Fe@CaCO_(3)exhibits superior therapeutic effect towards doxorubicin-resistant 4T1 breast tumors via combined chemodynamic and chemo-therapies.This work highlights the preparation of pH-dissociable CaCO_(3)-based nanotherapeutics to enable effective tumor penetration for enhanced treatment of drug-resistant tumors.展开更多
We demonstrate the polarization of resistive switching for a Cu/VOx/Cu memory cell.The switching behaviors of Cu/VOx/Cu cell are tested by using a semiconductor device analyzer(Agilent B1500A),and the relative micro...We demonstrate the polarization of resistive switching for a Cu/VOx/Cu memory cell.The switching behaviors of Cu/VOx/Cu cell are tested by using a semiconductor device analyzer(Agilent B1500A),and the relative micro-analysis of I-V characteristics of VOx/Cu is characterized by using a conductive atomic force microscope(CAFM).The I-V test results indicate that both the forming and the reversible resistive switching between low resistance state(LRS) and high resistance state(HRS) can be observed under either positive or negative sweep.The CAFM images for LRS and HRS directly exhibit evidence for the formation and rupture of filaments based on positive or negative voltage.The Cu/VOx/Cu sandwiched structure exhibits reversible resistive switching behavior and shows potential applications in the next generation of nonvolatile memory.展开更多
Non-antibiotics affect bacterial susceptibility towards antibiotics in a multifactorial manner, including perturbation of membrane energetic and a possibly direct interaction with drug efflux transporters themselves. ...Non-antibiotics affect bacterial susceptibility towards antibiotics in a multifactorial manner, including perturbation of membrane energetic and a possibly direct interaction with drug efflux transporters themselves. Thus, efflux inhibiting compounds affect susceptibilities to antibiotics that act either intracellular or at the bacterial wall. Therefore they may be applied as helper compounds to conventional antibiotic treatments. A valid definition of the effect of these compounds is crucial. Conventional microbiological quotations such as checkerboard or MIC definition do not discriminate the complexity of a system where several compounds interact with several targets both on the bacterial membrane and soma. We presume the fact, that certain resistance mechanisms, such as efflux, are neither adequately nor precisely monitored, utilizing the established microbiologic screening tools, such as agar- or microdilution techniques. In this context this paper may contribute as an innovative step, utilizing mathematic modeling in order to describe interactions on the surface of microorganisms. Thus, mathematical modeling might be a tool which can be adopted to optimize the description of certain forms of bacterial resistance, as well as the influence of antibacterial drugs on such targets which interact with bacterial outer-membrane transport mechanisms. This paper presents modeling of bacterial population dynamics as an attempt to precise complex compound target interaction. Furthermore, the importance of a synergetic coupling term in the model is exemplified by comparison with experimental data of Kumar et al. [1]. A specific procedure for extraction of model coefficients is devised for further experimental studies of the coupling between an antibiotics and a helper compound. In particular, it is found that the scarce experimental data of Kumar et al. [1] can be fitted to the mathematical model demonstrating synergetic effects of non-antibiotics.展开更多
Multidrug resistance remains a serious clinical problem in the successful therapy of malignant diseases. It occurs in cultured tumor cell lines, as well as in human cancers. Therefore, it is critical to develop novel ...Multidrug resistance remains a serious clinical problem in the successful therapy of malignant diseases. It occurs in cultured tumor cell lines, as well as in human cancers. Therefore, it is critical to develop novel anticancer drugs with multidrug-resistance modulating potential to increase the survival rate of leukemia patients. Plant-derived natural products have been used for the treatment of various diseases for thousands of years. This review summarizes the anticancer and multidrug-resistance reversing properties of the extracts and bioactive compounds from traditional medicinal plants in different leukemia cell lines. Further mechanistic studies will pave the road to establish the anticancer potential of plant-derived natural compounds.展开更多
Multidrug-resistance(MDR)featuring complicated and poorly defined mechanisms is a major obstacle to the success of cancer chemotherapy in the clinic.Compound nanoparticles comprising multiple cytostatics with differen...Multidrug-resistance(MDR)featuring complicated and poorly defined mechanisms is a major obstacle to the success of cancer chemotherapy in the clinic.Compound nanoparticles comprising multiple cytostatics with different mechanisms of action are commonly developed to tackle the multifaceted nature of clinical MDR.However,the different pharmacokinetics and release profiles of various drugs result in inconsistent drug internalization and suboptimal drug synergy at the tumor sites.In the present study,a type of self-targeting hyaluronate(HA)nanogels((CDDPH)^ANG/DOX)to reverse drug resistance through the synchronized pharmacokinetics,intratumoral distribution,and intracellular release of topoisomerase II inhibitor doxorubicin(DOX)and DNA-crosslinking agent cisplatin(CDDP)is developed.With prolonged circulation time and enhanced intratumoral accumulation in vivo,(CDDP)^HANG/DOX shows efficient drug delivery into the drug-resistant MCF-7/ADR breast cancer cells and enhanced antitumor activity.Besides,fluorescence imaging of DOX combined with the micro-computed tomography(micro-CT)imaging of CDDP facilitates the visualization of this combination tumor chemotherapy.With visualizable synchronized drug delivery,the self-targeting in situ crosslinked nanoplatform may hold good potential in future clinical therapy of advanced cancers.展开更多
A high accuracy frequency synchronization method is proposed for the 3rd generation partnership project (3GPP) long term evolution advanced (LTE-A) downlink receiver in time division duplexing (TDD) mode. In gen...A high accuracy frequency synchronization method is proposed for the 3rd generation partnership project (3GPP) long term evolution advanced (LTE-A) downlink receiver in time division duplexing (TDD) mode. In general, cyclic prefix (CP) correlation based fractional frequency offset (FFO) estimation method and primary synchronization signal (PSS) differential correlation based integer frequency offset (IFO) estimation method are applied for LTE-A frequency synchronization. However, the polarity of CP based FFO estimation result may get reversed when system FFO is closer to the edge of frequency estimation range on account of noise interference; PSS based IFO estimation has performance degradation in low signal noise ratio (SNR). We propose polarity detection aided CP based FFO estimation and frequency domain enhanced differential correlation based IFO estimation to obtain higher accuracy of frequency synchronization. Computer simulation shows that the proposed method greatly outperforms the conventional methods, especially in low SNR scenario.展开更多
A total synthesis of 17-membered macrocyclolipopeptide dysoxylactam A,a potent agent reversing P-glycoprotein(P-gp)-mediated multidrug resistance(MDR)in cancer cells,was developed from the starting material(S)-2-methy...A total synthesis of 17-membered macrocyclolipopeptide dysoxylactam A,a potent agent reversing P-glycoprotein(P-gp)-mediated multidrug resistance(MDR)in cancer cells,was developed from the starting material(S)-2-methylbutanal in a linear sequence of 12 steps with 23.2%overall yield.The key steps include proline-catalyzed asymmetric aldol reaction,Evans aldol reaction and Krische allylation to construct the multiple stereocenters containing fragment,and ring-closing metathesis to furnish the macrocycle.This total synthesis facilitates the preparation of large amount samples of dysoxylactam A and the side chain simplified derivatives for further biological tests and preliminary structure-activity relationship exploration.展开更多
In the fabrication of a 48 mm×48 mm silicon micro-strip nuclear radiation detector with 96 strips on each side, a perfect P-N junction cannot be formed consistently by the one-step implantation process, and thus ...In the fabrication of a 48 mm×48 mm silicon micro-strip nuclear radiation detector with 96 strips on each side, a perfect P-N junction cannot be formed consistently by the one-step implantation process, and thus over 50% of strips produced do not meet application requirements. However, the method of stratified implantation not only avoids the P region between the surface of wafers and the P+ region, but also overcomes the shadow effect. With the help of the stratified implantation process, a perfect functional P-N junction can be formed, and over 95% of strips meet application requirements.展开更多
The annealing process for boron implantation is a crucial step during large size nuclear radiation detector fabrication. It can reduce the lattice defects and the projection straggling. A two-step annealing process fo...The annealing process for boron implantation is a crucial step during large size nuclear radiation detector fabrication. It can reduce the lattice defects and the projection straggling. A two-step annealing process for boron implantation was developed instead of a one-step annealing process, and the reverse body resistance of a silicon micro-strip detector was significantly increased, which means that the performance of the detector was improved.展开更多
基金supported by the National Natural Science Foundation of China(Grant Nos.52203184,22275043,51773099,52293380,and 52293383)Startup Fund of Wenzhou Institute,University of Chinese Academy of Sciences(Grant No.WIUCASQD2021022)+1 种基金Key Laboratory of Functional Polymer Materials,Ministry of Education(Grant No.KLFPM202202)Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province(Grant No.2022E10022).
文摘New antimicrobial strategies are urgently needed to meet the challenges posed by the emergence of drug-resistant bacteria and bacterial biofilms.This work reports the facile synthesis of antimicrobial dynamic covalent nano-networks(aDCNs)composing antibiotics bearing multiple primary amines,polyphenols,and a cross-linker acylphenylboronic acid.Mechanistically,the iminoboronate bond drives the formation of aDCNs,facilitates their stability,and renders them highly responsive to stimuli,such as low pH and high H2O2 levels.Besides,the representative A1B1C1 networks,composed of polymyxin B1(A1),2-formylphenylboronic acid(B1),and quercetin(C1),inhibit biofilm formation of drug-resistant Escherichia coli,eliminate the mature biofilms,alleviate macrophage inflammation,and minimize the side effects of free polymyxins.Excellent bacterial eradication and inflammation amelioration efficiency of A1B1C1 networks are also observed in a peritoneal infection model.The facile synthesis,excellent antimicrobial performance,and biocompatibility of these aDCNs potentiate them as a much-needed alternative in current antimicrobial pipelines.
基金supported by the National Natural Science Foundation of China(Nos.U1812403,81872772,and 81960546)the Scie nee and Tech no logy Departme nt of Guizhou Province(Nos.QKH 2020-1Z076,QKHZC[2020]4Y203z QKHJC[2018]1409,QKHZC[2019]2762,and QKHPTRC[2020]5008)+3 种基金the High-level Innovative Talents in Guizhou Provinee(Thousand Levels of Talent for Chunmao Yuan in 2018)the"Light of the West"Talent Cultivation Program of Chinese Academy of Sciences for Chunmao Yuan(No.RZ[2020]82)the 100 Leading Talents of Guizhou Provinee(fund for Y.M.L)the Guizhou Provincial Engineering Research Center for Natural Drugs.
文摘Eleven biogenetically related polyprenylated acylphloroglucinols(PPAPs),including four novel skeletons(1-4)and five new com-pounds(5-9),were isolated from the flowers of Hypericum monogynum.Hypermonones A-D(1-4)represented the first example of a unique dilactone structure containing carbonyl bonded single 5-lactone and tricyclic γ-lactone moieties.Their structures were elucidated by NMR analysis,X-ray crystallography,and ECD calculations.Moreover,we revised the structure of hyperibrin B to hy perm on one I(9)via NMR an alysis,a qua ntum computational chemistry method,and hypothetic bios yn thetic con siderations.Three compounds(5,6,and 9)with significant MDR reversal activity(RF ranging from 61 to 223)were superior to the positive control verapamil(MCF-7/ADR,RF:53;HepG2/ADRz RF:124).Mechanism study for compound 5 indicated that this compound could inhibit the function of P-gp tran sport rather tha n its expressi on,and the possible recog nition mechanism betwee n compo und 5 and P-gp was predicted by molecular docking.
文摘The multidrug resistance P-glycoprotein (P-gp) expression and func-tion in hematopoietic stem/progenitor cells were studied to investigate whether the inhibition of hematopoietic cell P-gp function by multidrug resistance reversal agent increases the cytotoxicity of chemotherapy drugs on the hematopoietic cells.The expression of P-gp on the surface of CD cells from healthy human marrow was examined by flow cytometry. The multidrug resistance reversal agent MS-209 was used to measure the effects of MS-209 on the Rhodamin-123 uptaking o fCD hematopoietic cells. By using methylcellulose semi-solid culture, normal human granulocyte-macrophage clonal formation unit (CFU-GM) was cultured. The changes in CFU-GM inhibitory rate caused by daunorubicin were determined in the presence or absence of MS-2O9. The results showed that the P-gp expression rate of bone marrow CDL cells was 13. 3 %. MS-209 obviously increased the Rhodamin-123 uptake of CD positive cells. The mean inhibitory rate of daunorubicin for CFU-GM was 29. 6 %, but it was increased to 43. 3 % in the presence of MS-209 with the difference being significant (P< 0. 05). It was concluded that hematopoietic cells expressed P-gp protein and possessed active function- MS-209could inhibit the membrane efflux pump and increase the cytotoxicity of chemotherapy drugs to the clonal growth of hematopoeitic stem cells, suggesting the side effects of these drugs on the hematopoietic system should be taken into consideration in the clinical use.
基金supported by the Key R&D Program of Lishui City(2021ZDYF12,2022ZDYF07,2023zdyf14)Natural Science Foundation of China(82072026,82072025 and 82272090)+1 种基金Zhejiang Provincial Natural Science Foundation(LY23H180003,LQ22H180010)Provincial and Ministerial Joint Construction of Key Projects(WKJ-ZJ-2317).
文摘Chemotherapy plays a crucial role in triple-negative breast cancer (TNBC) treatment as it not only directly kills cancer cells but also induces immunogenic cell death. However, the chemotherapeutic efficacy was strongly restricted by the acidic and hypoxic tumor environment. Herein, we have successfully formulated PLGA-based nanoparticles concurrently loaded with doxorubicin (DOX), hemoglobin (Hb) and CaCO3 by a CaCO3-assisted emulsion method, aiming at the effective treatment of TNBC. We found that the obtained nanomedicine (DHCaNPs) exhibited effective drug encapsulation and pH-responsive drug release behavior. Moreover, DHCaNPs demonstrated robust capabilities in neutralizing protons and oxygen transport. Consequently, DHCaNPs could not only serve as oxygen nanoshuttles to attenuate tumor hypoxia but also neutralize the acidic tumor microenvironment (TME) by depleting lactic acid, thereby effectively overcoming the resistance to chemotherapy. Furthermore, DHCaNPs demonstrated a notable ability to enhance antitumor immune responses by increasing the frequency of tumor-infiltrating effector lymphocytes and reducing the frequency of various immune-suppressive cells, therefore exhibiting a superior efficacy in suppressing tumor growth and metastasis when combined with anti-PD-L1 (αPD-L1) immunotherapy. In summary, this study highlights that DHCaNPs could effectively attenuate the acidic and hypoxic TME, offering a promising strategy to figure out an enhanced chemo-immunotherapy to benefit TNBC patients.
基金the grant from the National 9th five-year program for Scientific Research of China (96-906-01-23).
文摘Objective: To investigate the Reversal Effect of Irisquinone (ANKA) on Cisplatin-resistant Human Lung Adenocarcinoma Cell Line (A 549 DDP ) and the change of MRP expression. Methods: MTT assay, flow cytometry, glutathione reductase recycling assay, RT-PCR were used. Results: None or low cytotoxic concentration of ANKA (10, 20, 30 μmol/L) could increase the sensitivity of A 549 DDP cells to CDDP by 8.2, 7.9 and 8.9-fold in a dose independent manner. After A 549 DDP cells was pretreated with 10 μmol/L ANKA for 12 h, CDDP cytotoxicity was increased 9.41-fold. The GSH content of the cells treated by ANKA is reduced significantly (P<0.001). The GSTπ protein expression was reduced by ANKA depended on its doses. ANKA also reduced expression of MRP protein, dependent on its dose and treating time (P<0.001). MRP mRNA expression was reduced only by 30μmol/L ANKA (P<0.05). Conclusion: The reversal effect of ANKA on A 549 DDP cell was relative to intracellular glutathione system.
基金supported by the National Natural Science Foundation of China(No.51802209),the National Research Programs from Ministry of Science and Technology(MOST)of China(No.2016YFA0201200)the Natural Science Foundation of Jiangsu Province(No.BK20180848)+1 种基金the China Postdoctoral Science Foundation(No.2018T110545)the Collaborative Innovation Center of Suzhou Nano Science and Technology,and the 111 Program from the Ministry of Education of China.
文摘Construction of multifunctional stimuli-responsive nanotherapeutics enabling improved intratumoral penetration of therapeutics and reversal of multiple-drug resistance(MDR)is potent to achieve effective cancer treatment.Herein,we report a general method to synthesize pH-dissociable calcium carbonate(CaCO_(3))hollow nanoparticles with amorphous CaCO_(3)as the template,gallic acid(GA)as the organic ligand,and ferrous ions as the metallic center via a one-pot coordination reaction.The obtained GA–Fe@CaCO_(3)exhibits high loading efficiencies to both oxidized cisplatin prodrug and doxorubicin,yielding drug loaded GA-Fe@CaCO_(3)nanotherapeutics featured in pH-responsive size shrinkage,drug release,and Fenton catalytic activity.Compared to nonresponsive GA-Fe@silica nanoparticles prepared with silica nanoparticles as the template,such GA-Fe@CaCO_(3)confers significantly improved intratumoral penetration capacity.Moreover,both types of drug-loaded GA–Fe@CaCO_(3)nanotherapeutics exhibit synergistic therapeutic efficacies to corresponding MDR cancer cells because of the GA–Fe mediated intracellular oxidative stress amplification that could reduce the efflux of engulfed drugs by impairing the mitochondrial-mediated production of adenosine triphosphate(ATP).As a result,it is found that the doxorubicin loaded GA-Fe@CaCO_(3)exhibits superior therapeutic effect towards doxorubicin-resistant 4T1 breast tumors via combined chemodynamic and chemo-therapies.This work highlights the preparation of pH-dissociable CaCO_(3)-based nanotherapeutics to enable effective tumor penetration for enhanced treatment of drug-resistant tumors.
基金Project supported by the Program for New Century Excellent Talents in University of Ministry of Education of China (Grant No. NCET-11-1064)the Young Scientists Fund of the National Natural Science Foundation of China (Grant Nos. 61101055,61274113,and 11204212)+1 种基金the Specialized Research Fund for the Doctoral Program of Higher Education of China (Grant No. 20100032120029)Tianjin Natural Science Foundation of China (Grant No. 10SYSYJC27700)
文摘We demonstrate the polarization of resistive switching for a Cu/VOx/Cu memory cell.The switching behaviors of Cu/VOx/Cu cell are tested by using a semiconductor device analyzer(Agilent B1500A),and the relative micro-analysis of I-V characteristics of VOx/Cu is characterized by using a conductive atomic force microscope(CAFM).The I-V test results indicate that both the forming and the reversible resistive switching between low resistance state(LRS) and high resistance state(HRS) can be observed under either positive or negative sweep.The CAFM images for LRS and HRS directly exhibit evidence for the formation and rupture of filaments based on positive or negative voltage.The Cu/VOx/Cu sandwiched structure exhibits reversible resistive switching behavior and shows potential applications in the next generation of nonvolatile memory.
基金the COST Action BM0701(ATENS)network for stimulating discussions
文摘Non-antibiotics affect bacterial susceptibility towards antibiotics in a multifactorial manner, including perturbation of membrane energetic and a possibly direct interaction with drug efflux transporters themselves. Thus, efflux inhibiting compounds affect susceptibilities to antibiotics that act either intracellular or at the bacterial wall. Therefore they may be applied as helper compounds to conventional antibiotic treatments. A valid definition of the effect of these compounds is crucial. Conventional microbiological quotations such as checkerboard or MIC definition do not discriminate the complexity of a system where several compounds interact with several targets both on the bacterial membrane and soma. We presume the fact, that certain resistance mechanisms, such as efflux, are neither adequately nor precisely monitored, utilizing the established microbiologic screening tools, such as agar- or microdilution techniques. In this context this paper may contribute as an innovative step, utilizing mathematic modeling in order to describe interactions on the surface of microorganisms. Thus, mathematical modeling might be a tool which can be adopted to optimize the description of certain forms of bacterial resistance, as well as the influence of antibacterial drugs on such targets which interact with bacterial outer-membrane transport mechanisms. This paper presents modeling of bacterial population dynamics as an attempt to precise complex compound target interaction. Furthermore, the importance of a synergetic coupling term in the model is exemplified by comparison with experimental data of Kumar et al. [1]. A specific procedure for extraction of model coefficients is devised for further experimental studies of the coupling between an antibiotics and a helper compound. In particular, it is found that the scarce experimental data of Kumar et al. [1] can be fitted to the mathematical model demonstrating synergetic effects of non-antibiotics.
基金supported by the National Natural Science Foundation of P.R.China(Nos.81170492,81370673)National High Technology Research and Development Program 863 of P.R.China(No.2012AA022703)+2 种基金National Key Basic Research Program 973 of P.R.China(No.2010CB732404)Key Medical Projects of Jiangsu Province(No.BL2014078)Key Discipline of Jiangsu Province(2011-2015)
文摘Multidrug resistance remains a serious clinical problem in the successful therapy of malignant diseases. It occurs in cultured tumor cell lines, as well as in human cancers. Therefore, it is critical to develop novel anticancer drugs with multidrug-resistance modulating potential to increase the survival rate of leukemia patients. Plant-derived natural products have been used for the treatment of various diseases for thousands of years. This review summarizes the anticancer and multidrug-resistance reversing properties of the extracts and bioactive compounds from traditional medicinal plants in different leukemia cell lines. Further mechanistic studies will pave the road to establish the anticancer potential of plant-derived natural compounds.
基金This study was financially supported by the National Key Research and Development Program of China(No.2016YFC1100701)the National Natural Science Foundation of China(Nos.52022095,51973216,and 51873207)+1 种基金the Science and Technology Development Program of jilin Province(No.20200404182YY)the Youth Innovation Promotion Association of Chinese Academy of Sciences(No.2019005)。
文摘Multidrug-resistance(MDR)featuring complicated and poorly defined mechanisms is a major obstacle to the success of cancer chemotherapy in the clinic.Compound nanoparticles comprising multiple cytostatics with different mechanisms of action are commonly developed to tackle the multifaceted nature of clinical MDR.However,the different pharmacokinetics and release profiles of various drugs result in inconsistent drug internalization and suboptimal drug synergy at the tumor sites.In the present study,a type of self-targeting hyaluronate(HA)nanogels((CDDPH)^ANG/DOX)to reverse drug resistance through the synchronized pharmacokinetics,intratumoral distribution,and intracellular release of topoisomerase II inhibitor doxorubicin(DOX)and DNA-crosslinking agent cisplatin(CDDP)is developed.With prolonged circulation time and enhanced intratumoral accumulation in vivo,(CDDP)^HANG/DOX shows efficient drug delivery into the drug-resistant MCF-7/ADR breast cancer cells and enhanced antitumor activity.Besides,fluorescence imaging of DOX combined with the micro-computed tomography(micro-CT)imaging of CDDP facilitates the visualization of this combination tumor chemotherapy.With visualizable synchronized drug delivery,the self-targeting in situ crosslinked nanoplatform may hold good potential in future clinical therapy of advanced cancers.
基金supported by the Natural Science Foundation of Shanghai (11ZR1435100)Chinese National Key Project (2009ZX03003002,2011ZX0300100703,and 2012ZX03001008-004)
文摘A high accuracy frequency synchronization method is proposed for the 3rd generation partnership project (3GPP) long term evolution advanced (LTE-A) downlink receiver in time division duplexing (TDD) mode. In general, cyclic prefix (CP) correlation based fractional frequency offset (FFO) estimation method and primary synchronization signal (PSS) differential correlation based integer frequency offset (IFO) estimation method are applied for LTE-A frequency synchronization. However, the polarity of CP based FFO estimation result may get reversed when system FFO is closer to the edge of frequency estimation range on account of noise interference; PSS based IFO estimation has performance degradation in low signal noise ratio (SNR). We propose polarity detection aided CP based FFO estimation and frequency domain enhanced differential correlation based IFO estimation to obtain higher accuracy of frequency synchronization. Computer simulation shows that the proposed method greatly outperforms the conventional methods, especially in low SNR scenario.
基金support from the National Natural Science Foundation of China(Nos.81861138045,22177121)the CAMS Innovation Fund forMedical Sciences(2019-12M-5-080)+1 种基金the Biological Resources Program,CAS(KFJ-BRP-008-001)of People's Republicof China isgratefully acknowledgedsupport of Science and Technology Commission of Shanghai Municipality(20ZR1467800).
文摘A total synthesis of 17-membered macrocyclolipopeptide dysoxylactam A,a potent agent reversing P-glycoprotein(P-gp)-mediated multidrug resistance(MDR)in cancer cells,was developed from the starting material(S)-2-methylbutanal in a linear sequence of 12 steps with 23.2%overall yield.The key steps include proline-catalyzed asymmetric aldol reaction,Evans aldol reaction and Krische allylation to construct the multiple stereocenters containing fragment,and ring-closing metathesis to furnish the macrocycle.This total synthesis facilitates the preparation of large amount samples of dysoxylactam A and the side chain simplified derivatives for further biological tests and preliminary structure-activity relationship exploration.
基金Supported by National Natural Science Foundation of China(11175223,11305231,11205220)
文摘In the fabrication of a 48 mm×48 mm silicon micro-strip nuclear radiation detector with 96 strips on each side, a perfect P-N junction cannot be formed consistently by the one-step implantation process, and thus over 50% of strips produced do not meet application requirements. However, the method of stratified implantation not only avoids the P region between the surface of wafers and the P+ region, but also overcomes the shadow effect. With the help of the stratified implantation process, a perfect functional P-N junction can be formed, and over 95% of strips meet application requirements.
文摘The annealing process for boron implantation is a crucial step during large size nuclear radiation detector fabrication. It can reduce the lattice defects and the projection straggling. A two-step annealing process for boron implantation was developed instead of a one-step annealing process, and the reverse body resistance of a silicon micro-strip detector was significantly increased, which means that the performance of the detector was improved.