Synthesis and Biological Activities of a 3′-Azido Analogue of Doxorubicin Against Drug-Resistant Cancer Cells

Doxorubicin (DOX), an anthracycline antibiotic, is one of the most active anticancer chemotherapeutic agents. The clinical use of DOX, however, is limited by the dose-dependant P-glycoprotein (P-gp)-mediated resistance. Herein, a 3′-azido analogue of DOX (ADOX) was prepared from daunorubicin (DNR). ADOX exhibited potent antitumor activities in drug-sensitive (MCF-7 and K562) and drug-resistant cell lines (MCF-7/DNR, K562/DOX), respectively. The drug resistance index (DRI) values of ADOX were much lower than that of DOX. The cytotoxicity experiments of ADOX or DOX against K562/DOX, with or without P-gp inhibitor, indicated that ADOX circumvents resistance by abolishing the P-gp recognition. This conclusion was further supported by drug influx/efflux flow cytometry experiments, as well as by molecular docking of ADOX to P-gp. In vivo animal tests, ADOX exhibited higher activity and less toxicity than DOX. The current data warranted ADOX for additional pre-clinical evaluations for new drug development

Light-Controlled Nanosystem with Size-Flexibility Improves Targeted Retention for Tumor Suppression

Although great promise has been achieved with nanomedicines in cancer therapy, limitations are still encountered, such as short retention time in the tumor. Herein, a nanosystem that can modulate the particle size in situ by near-infrared (NIR) light is self-assembled by cross-linking the surface-modified poly(lactic-co-glycolic acid) from the up-conversion nanoparticle with indocyanine green and doxorubicin-nitrobenezene-polyethylene glycol (DOX-NB-PEG). The nanosystem with its small size (approximate to 100 nm) achieves better tumor targeting, while the PEG on the surface of the nanosystem can effectively shield the adsorption of proteins during blood circulation, maintaining a stable nanostructure and achieving good tumor targeting. Moreover, the nanosystem at the tumor realizes the rapid shedding of PEG on its surface by NIR irradiation, and the enhanced cellular uptake. At the same time, aggregation occurs inside the nanosystem to form bigger particles (approximate to 600 nm) in situ, prolonging the retention time at the tumor and producing enhanced targeted therapeutic effects. In vitro data show higher cellular uptake and a higher rate of apoptosis after irradiation, and the in vivo data prove that the nanosystem have a longer residence time at the tumor site after NIR irradiation. This nanosystem demonstrates an effective therapeutic strategy in targeted synergistic tumors

Organic acids enhance the uptake of lead by wheat roots

Abstract The uptake and bioavailability of lead (Pb) in soil-plant systems remain poorly understood. This study indicates that acetic and malic acids enhance the uptake of Pb by wheat (Triticum aestivum L.) roots under hydroponic conditions. The net concentration-dependent uptake influx of Pb in the presence and absence of organic acids was characterized by Michaelis-Menten type nonsaturating kinetic curves that could be resolved into linear and saturable components. Fitted maximum uptake rates (V max ) of the Michaelis-Menton saturable component in the presence of acetic and malic acids were, respectively, 2.45 and 1.63 times those of the control, while the Michaelis-Menten K m values of 5.5, 3.7 and 2.2 lM, respectively, remained unchanged. Enhanced Pb uptake by organic acids was partially mediated by Ca 2+ and K + channels, and also depended upon the physiological function of the plasma membrane P-type ATPase. Uptake may have been further enhanced by an effectively thinner unstirred layer of Pb adjacent to the roots, leading to more rapid diffusion towards roots. X-ray absorption spectroscopic studies provided evidence that the coordination environment of Pb in wheat roots was similar to that of Pb(CH 3 COO) 2 Á3H 2 O in that one Pb atom was coordinated to four oxygen atoms via the carboxylate group. Keywords Ca 2+ and K + channels Á Organic acids Á P-type ATPase Á Uptake of lead (Pb) Á Wheat (Triticum aestivum L.) Á X-ray absorption spectroscop

Ferroelectricity in layered bismuth oxide down to 1 nanometer

Atomic-scale ferroelectrics are of great interest for high-density electronics, particularly field-effect transistors, low-power logic, and nonvolatile memories. We devised a film with a layered structure of bismuth oxide that can stabilize the ferroelectric state down to 1 nanometer through samarium bondage. This film can be grown on a variety of substrates with a cost-effective chemical solution deposition. We observed a standard ferroelectric hysteresis loop down to a thickness of ~1 nanometer. The thin films with thicknesses that range from 1 to 4.56 nanometers possess a relatively large remanent polarization from 17 to 50 microcoulombs per square centimeter. We verified the structure with first-principles calculations, which also pointed to the material being a lone pair-driven ferroelectric material. The structure design of the ultrathin ferroelectric films has great potential for the manufacturing of atomic-scale electronic devices.This work was supported by the National Key Research and Development Program of China (2018YFA0703700, 2017YFE0119700, and 2020YFA0406202), the National Natural Science Foundation of China (21801013, 51774034, 51961135107, 62104140, 12175235, 22090042, 12074016, 11704041, and 12274009), the Fundamental Research Funds for the Central Universities (FRF-IDRY-19-007 and FRF-TP-19-055A2Z), the National Program for Support of Top-notch Young Professionals, the Young Elite Scientists Sponsorship Program by CAST (2019-2021QNRC), and Lingang Laboratory Open Research Fund (grant LG-QS-202202-11). Use of the Beijing Synchrotron Radiation Facility (1W1A beamlines, China) of the Chinese Academy of Sciences is acknowledged. Y.-W.F. acknowledges the support of Masaki Azuma’s group during his stay at the Tokyo Institute of Technology. Y.L. acknowledges the support of the Beijing Innovation Team Building Program (grant no. IDHT20190503), the Beijing Natural Science Foundation (Z210016), the Research and Development Project from the Shanxi-Zheda Institute of Advanced Materials and Chemical Engineering (2022SX-TD001), and the General Program of Science and Technology Development Project of Beijing Municipal Education Commission (KM202110005003).Peer reviewe

Giant polarization in super-tetragonal ferroelectric thin films through interphase strain

Strain engineering has emerged as a powerful tool to enhance the performance of known functional materials. Here we demonstrate a general and practical method to obtain super-tetragonality and giant polarization using interphase strain. We use this method to create an out-of-plane–to–in-plane lattice parameter ratio of 1.238 in epitaxial composite thin films of tetragonal lead titanate (PbTiO3), compared to 1.065 in bulk. These thin films with super-tetragonal structure possess a giant remanent polarization, 236.3 microcoulombs per square centimeter, which is almost twice the value of known ferroelectrics. The super-tetragonal phase is stable up to 725°C, compared to the bulk transition temperature of 490°C. The interphase-strain approach could enhance the physical properties of other functional materials.PostprintPeer reviewe

Clinical Study on efficacy of allopurinol in patients with acute coronary syndrome and its functional mechanism

Objective: To investigate the therapeutic effect of allopurinol treatment on acute coronary syndrome and to elucidate its possible mechanism. Methods: Patients with acute coronary syndrome (n = 100) were recruited as research subjects in our hospital. The patients were randomly divided into two groups, an allopurinol group (n = 50) and a control group (n = 50). These two groups were treated with conventional antiplatelet, anticoagulation and anti-ischemic therapy; allopurinol therapy was added to the allopurinol group based on conventional treatment indications. Biochemical markers such as serum creatinine, uric acid, BNP, blood glucose and blood lipid were compared between the two groups. Indicators of oxidative stress and inflammatory response (MDA, OX-LDL, NO, hs-CRP and TNF-α), as well as cardiovascular events during 2-years follow-up, were recorded. Results: On admission, there was no difference in serum creatinine, uric acid, BNP, blood glucose or lipid levels between the two groups (P > 0.05). However, after 1 month of treatment, these levels were improved in patients in the allopurinol group compared to the control group (P < 0.05). MDA, OX-LDL, hs-CRP and TNF-α decreased after treatment periods of 14 days and 1 month. They were also decreased at 3 month, 6 month, 1 year, and 2 year follow-up visits. However, data from the allopurinol group demonstrated significantly lower levels than in the control group (P < 0.05). Additionally, compared with the control group, allopurinol treatment significantly elevated the level of NO (P < 0.05). The total effective rates of the allopurinol group are much higher than in the control group for both angina pectoris (93.2% and 76%, respectively) and ECG (96% and 82%, respectively). Most patients in the allopurinol group (n = 40) and the control group (n = 41) received stent implantation with no significant difference shown between them. The incidence of cardiovascular events during 2 years of follow-up in the allopurinol group was 10%; it was 30% in the control group. Conclusion: Allopurinol has a remarkable effect in the treatment of ACS and can improve the oxidative stress and inflammatory reaction indicators of patients. The protective mechanism of allopurinol might be achieved by suppressing the secretion and release of inflammatory mediators such as TNF-α, hs-CRP, OX-LDL and MDA while increasing levels of NO

Panax ginseng Inhibits Metabolism of Diester Alkaloids by Downregulating CYP3A4 Enzyme Activity via the Pregnane X Receptor

To investigate the effects of P. ginseng C.A. Mey (P. ginseng) on the metabolism of diester alkaloids and explore the potential mechanism. P. ginseng was administered orally to rats for 7 days, after which liver microsome samples were prepared and then incubated with diester alkaloids. Ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry was used to determinate the concentration of diester alkaloids to calculate the clearance rate. The cocktail method was used to evaluate the effects of oral administration of P. ginseng extracts on the activities of cytochrome P450 (CYP) isoforms in rats through the changes in the pharmacokinetic parameters of the probe drugs. The protein and gene expression of CYP3A2 and pregnane X receptor (PXR) in rats were evaluated by western blotting and quantitative PCR. The specific enzyme inhibitor method and human recombinant enzyme method were used to identify the involvement of sub-CYPs in the metabolism of diester alkaloids in human liver microsomes (HLMs). The clearances of aconitine, mesaconitine, and hypaconitine in the P. ginseng groups were lower than those of the control group. The areas under the curve of midazolam were 2.37 ± 1.05, 4.96 ± 0.51, and 6.23 ± 1.30 mg·L−1·h for the low-, medium-, and high-dose P. ginseng groups, respectively, which were higher than that of the control (2.23 ± 0.64 mg·L−1·h). The clearances of midazolam for the medium- (1.87 ± 0.16 L·h−1·kg−1) and high-dose (1.60 ± 0.34 L·h−1·kg−1) P. ginseng groups were lower than that of the control group (4.66 ± 1.43 L·h−1·kg−1). After exposure to P. ginseng extracts, the gene and protein expression levels of CYP3A4 and PXR were decreased. The hepatic metabolism rates of aconitine, mesaconitine, and hypaconitine in HLMs were decreased to 60.37%, 21.67%, and 10.11%, respectively, when incubated with ketoconazole, a specific inhibitor for CYP3A. The kinetic plots indicated that the KM and Vmax values of CYP3A4 were 10.08 ± 3.26 μM and 0.12 ± 0.01nmol·mg protein−1·min−1 for aconitine, 131.3 ± 99.75 μM and 0.73 ± 0.44 nmol·mg protein−1·min−1 for mesaconitine, and 17.05 ± 9.70 μM and 0.16 ± 0.04 nmol·mg protein−1·min−1 for hypaconitine, respectively. The in vitro mean intrinsic clearance rates by CYP3A4 were 0.0119, 0.0056, and 0.0091 mL·nmol CYP−1·min−1 for aconitine, mesaconitine, and hypaconitine, respectively. Therefore we implied that P. ginseng inhibited the metabolism of diester alkaloids in vitro and decreased the CYP3A4 enzyme activity as well as the gene and protein expression of CYP3A4 and PXR in vivo. CYP3A4 had a larger effect on diester alkaloid metabolism than the other human CYP isoforms, CYP1A2, CYP2C9, and CYP2E1

Controllable hydrothermal synthesis of Cu-doped \u3b4-MnO2 films with different morphologies for energy storage and conversion using supercapacitors

The \u3b4-MnO2 and Cu-doped \u3b4-MnO2 grown on Ni foams are synthesized by a simple hydrothermal method for supercapacitor electrode application. The samples are characterized by XRD, ICP-AES, SEM, and BET for its composition, structure/morphology, and BET surface area. The electrochemical properties of the electrodes are studied by cyclic voltammetry (CV), galvanostatic charge/discharge and electrochemical impedance spectroscopy (EIS) in 1M Na2SO4 solution. The results show that copper addition can vary the self-assembly of \u3b4-MnO2 nanosheets, inducing the formation of flower-like structure. The morphology and electrochemical performance of the formed \u3b4-MnO2 electrodes can be controlled by simply tuning the copper doping concentration. The 2at.% Cu-doped \u3b4-MnO2 film obtains the maximum specific capacitance as high as 296Fg-1 at 1Ag-1, which is 80% higher than that of the pure \u3b4-MnO2 film. Furthermore, it also shows a better cyclic stability than undoped \u3b4-MnO2 film. The enhanced electrochemical properties may be attributed to its optimized hybrid nanosheet network and flow-like structure. A possible explanation for such enhancement in electrochemical properties of Cu-doped \u3b4-MnO2 films has been discussed in this paper.Peer reviewed: YesNRC publication: Ye