Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 55
Filter
1.
J Colloid Interface Sci ; 674: 361-369, 2024 Jun 24.
Article in English | MEDLINE | ID: mdl-38941930

ABSTRACT

To achieve high-performance Zn-air batteries (ZABs), the development of bifunctional air electrodes capable of efficiently mediating both the oxygen reduction reaction (ORR) and the oxygen evolution reaction (OER) is imperative. In this study, we present an N-doped carbon hollow nanorod encapsulating a semi-coherent Co-Ni/Co6Mo6C heterojunction, tailored for reversible oxygen catalysis. This nanohybrid demonstrated an ORR half-wave potential of 0.907 V alongside an OER overpotential of η10 = 352 mV. When incorporated into ZABs, this catalyst exhibited extraordinary performance metrics, including a high-power density of 343.7 mW/cm2, a specific capacity of 681 mAh/gZn, and enhanced durability. The distinctive electric field within the heterojunction facilitated electron transfer across the semi-coherent interface during reversible oxygen electrocatalysis, enhancing the adsorption and release of active intermediates. Thus, this heightened ORR-OER catalytic efficiency culminated in superior ZABs performance. Our findings afford a pivotal design paradigm for the advancement of productive bifunctional catalysts within the field of energy conversion technologies.

2.
Proc Natl Acad Sci U S A ; 121(16): e2321665121, 2024 Apr 16.
Article in English | MEDLINE | ID: mdl-38593078

ABSTRACT

Different mechanisms driving a linear temperature dependence of the resistivity ρ ∼ T at van Hove singularities (VHSs) or metal-insulator transitions when doping a Mott insulator are being debated intensively with competing theoretical proposals. We experimentally investigate this using the exceptional tunability of twisted bilayer (TB) WSe2 by tracking the parameter regions where linear-in-T resistivity is found in dependency of displacement fields, filling, and magnetic fields. We find that even when the VHSs are tuned rather far away from the half-filling point and the Mott insulating transition is absent, the T-linear resistivity persists at the VHSs. When doping away from the VHSs, the T-linear behavior quickly transitions into a Fermi liquid behavior with a T2 relation. No apparent dependency of the linear-in-T resistivity, besides a rather strong change of prefactor, is found when applying displacement fields as long as the filling is tuned to the VHSs, including D ∼ 0.28 V/nm where a high-order VHS is expected. Intriguingly, such non-Fermi liquid linear-in-T resistivity persists even when magnetic fields break the spin-degeneracy of the VHSs at which point two linear in T regions emerge, for each of the split VHSs separately. This points to a mechanism of enhanced scattering at generic VHSs rather than only at high-order VHSs or by a quantum critical point during a Mott transition. Our findings provide insights into the many-body consequences arising out of VHSs, especially the non-Fermi liquid behavior found in moiré materials.

3.
Biochem Genet ; 2024 Feb 20.
Article in English | MEDLINE | ID: mdl-38376577

ABSTRACT

The aim of this study was to investigate the role and mechanism of circ-RNF111 in the human ovarian cancer cell line SKOV-3. First, qRT-PCR was used to detect circ-RNF111 and miR-556-5p expression levels in human normal ovarian epithelial cells IOSE80 and human ovarian cancer cells SKOV-3. CCK-8 and colony formation assays were adopted to determine the proliferation rate and cell viability of SKOV-3 cells, respectively. Additionally, in an attempt to reveal the mechanism of circ-RNF111, we predicted the targeting relationship between miR-556-5p and circ-RNF111 as well as miR-556-5p and CCND1 using the circinteractome and TargetScan databases, respectively, and validated their relationship by dual-luciferase reporter assay. The protein expression levels of CCND1 in SKOV-3 cells were detected by Western blot. Based on the above experiments, the expression of circ-RNF111 was found to be up-regulated in SKOV-3, and the knockdown of circ-RNF111 significantly inhibited the proliferation and viability of SKOV-3 cells. Then we confirmed that circ-RNF111 sponged miR-556-5p in SKOV-3 cells to up-regulate CCND1 expression. In addition, simultaneous inhibition of miR-556-5p or overexpression of CCND1 in SKOV-3 cells with knockdown of circ-RNF111 reversed the inhibitory effect of knockdown of circ-RNF111 on the protein expression level of CCND1, cell proliferation rate, and cell viability. In summary, circ-RNF111 promotes the proliferation of SKOV-3 cells by targeting the miR-556-5p/CCND1 axis. Circ-RNF111 may serve as a potential target for ovarian cancer therapy.

4.
Nat Commun ; 15(1): 1825, 2024 Feb 28.
Article in English | MEDLINE | ID: mdl-38418816

ABSTRACT

Monolayer molybdenum disulfide (MoS2), an emergent two-dimensional (2D) semiconductor, holds great promise for transcending the fundamental limits of silicon electronics and continue the downscaling of field-effect transistors. To realize its full potential and high-end applications, controlled synthesis of wafer-scale monolayer MoS2 single crystals on general commercial substrates is highly desired yet challenging. Here, we demonstrate the successful epitaxial growth of 2-inch single-crystal MoS2 monolayers on industry-compatible substrates of c-plane sapphire by engineering the formation of a specific interfacial reconstructed layer through the S/MoO3 precursor ratio control. The unidirectional alignment and seamless stitching of MoS2 domains across the entire wafer are demonstrated through cross-dimensional characterizations ranging from atomic- to centimeter-scale. The epitaxial monolayer MoS2 single crystal shows good wafer-scale uniformity and state-of-the-art quality, as evidenced from the ~100% phonon circular dichroism, exciton valley polarization of ~70%, room-temperature mobility of ~140 cm2v-1s-1, and on/off ratio of ~109. Our work provides a simple strategy to produce wafer-scale single-crystal 2D semiconductors on commercial insulator substrates, paving the way towards the further extension of Moore's law and industrial applications of 2D electronic circuits.

5.
Nano Lett ; 23(17): 7921-7926, 2023 Sep 13.
Article in English | MEDLINE | ID: mdl-37585490

ABSTRACT

Moiré superlattices of twisted van der Waals heterostructures provide a promising and tunable platform for simulating correlated two-dimensional physical models. In twisted bilayer transition-metal dichalcogenides with twist angles close to 0°, the Γ and K valley moiré bands are described by the honeycomb and the triangular effective lattice models, respectively, with distinct physics. Using large-scale first-principles calculations, we show that in-plane biaxial strain and out-of-plane pressure provide effective knobs for switching the moiré lattice models that emerged at the band edges in twisted bilayer WSe2 by shifting the energy positions of the Γ and K valley minibands. The shifting mechanism originates from the differences in the orbital characters of the Γ and K valley states and their responses to strain and pressure. The critical strain and pressure for switching the Γ/K valleys are 2.11% and 2.175 GPa, respectively.

6.
J Phys Chem Lett ; 14(10): 2455-2462, 2023 Mar 16.
Article in English | MEDLINE | ID: mdl-36867121

ABSTRACT

A J-type dimer PMI-2, two perylene monoimides linked by butadiynylene bridger was prepared, and its excited-state dynamics was studied using ultrafast femtosecond transient absorption spectroscopy, along with steady-state spectroscopy and quantum chemical calculations. It is evidently demonstrated that the symmetry-breaking charge separation (SB-CS) process in PMI-2 is positively mediated by an excimer, which is mixed by localized Frenkel excitation (LE) and an interunit charge transfer (CT) state. Kinetic studies show that, with the polarity increasing of the solvent, the transformation of excimer from a mixture to the CT state (SB-CS) is accelerated, and the recombination time of the CT state is reduced obviously. Theoretical calculations indicate that these are due to PMI-2 obtaining more negative free energy (ΔGcs) and lower CT state energy levels in highly polar solvents. Our work suggests that the mixed excimer can be formed in a J-type dimer with suitable structure, in which the charge separation the process is sensitive to the solvent environment.

7.
J Colloid Interface Sci ; 630(Pt A): 688-697, 2023 Jan 15.
Article in English | MEDLINE | ID: mdl-36279834

ABSTRACT

Developing transition metal electrocatalysts, especially single-atom catalysts (SACs), is significant. However, most of the synthesis procedures of SACs involve the formation of nanoparticles (NPs), and the produced NPs always play an influential role during electrocatalytic processing, so exploring the synergistic effects between metallic and isolated metal species is of great interest. Herein, we report a Zn/Fe-metal-organic framework (MOF)-derived Fe3C coupling FeNx catalyst constructed via coordination confinement pyrolysis effect successfully. Compared with the Pt/C catalyst and most precious metal-free catalysts, the optimized catalyst Fe3C-FeNx/NC-7 demonstrates superior oxygen reduction reaction (ORR) activity in 0.1 M KOH. The half-wave potential (E1/2) reaches up to 0.93 V with the limiting current density (jL) of 5.65 mA/cm2 at 5 mV/s scanning rate and 1600 rpm. The excellent performance originates from the synergistic effect of FeNx and Fe3C active units combined with wide-distributed nitrogen atoms. The Fe3C NPs further optimize the electronic structure and adsorption/desorption free energy of the catalyst. The assembled primary Zn-air battery (ZAB) displays a satisfying open-circuit potential of 1.53 V and an excellent specific capacity of 835 mA·h·g-1. The maximum power density achieves 283 mW/cm2, outclassing the commercial Pt/C-based ZAB. This result demonstrates the promising application prospect of the catalyst-cooperated metallic NPs with isolated single metal species.

8.
Phys Rev Lett ; 131(25): 256201, 2023 Dec 22.
Article in English | MEDLINE | ID: mdl-38181343

ABSTRACT

Moiré superlattices have emerged as an exciting condensed-matter quantum simulator for exploring the exotic physics of strong electronic correlations. Notable progress has been witnessed, but such correlated states are achievable usually at low temperatures. Here, we report evidence of possible room-temperature correlated electronic states and layer-hybridized SU(4) model simulator in AB-stacked MoS_{2} homobilayer moiré superlattices. Correlated insulating states at moiré band filling factors v=1, 2, 3 are unambiguously established in twisted bilayer MoS_{2}. Remarkably, the correlated electronic state at v=1 shows a giant correlated gap of ∼126 meV and may persist up to a record-high critical temperature over 285 K. The realization of a possible room-temperature correlated state with a large correlated gap in twisted bilayer MoS_{2} can be understood as the cooperation effects of the stacking-specific atomic reconstruction and the resonantly enhanced interlayer hybridization, which largely amplify the moiré superlattice effects on electronic correlations. Furthermore, extreme large nonlinear Hall responses up to room temperature are uncovered near correlated electronic states, demonstrating the quantum geometry of moiré flat conduction band.

9.
ACS Nano ; 16(9): 15063-15071, 2022 Sep 27.
Article in English | MEDLINE | ID: mdl-36036963

ABSTRACT

Metal oxides are the most efficient electron transport layers (ETLs) in perovskite solar cells (PSCs). However, issues related to the bulk (i.e., insufficient electron mobility, unfavorable energy level position) and interface of metal oxide/perovskite (detrimental surface hydroxyl groups) limit the transport kinetics of photoinduced electrons and prevent PSCs from unleashing their theoretical efficiency potential. Herein, the inorganic InP colloid quantum dots (CQDs) with outstanding electron mobility (4600 cm2 V-1 s-1) and carboxyl (-COOH) terminal ligands were uniformly distributed into the metal oxide ETL to form consecutive electron transport channels. The hybrid InP CQD-based ETL demonstrates a more N-type characteristic with more than 3-fold improvement in electron mobility. The formation of the Sn-O-In bond facilitates electron extraction due to suitable energy level alignment between the ETL and perovskite. The strong interaction between uncoordinated Pb2+ at the perovskite/ETL interface and the -COO- in the ligand of InP CQDs reduces the density of defects in perovskite. As a result, the hybrid InP CQD-based ETL with an optimized InP ratio (18 wt %) boosts the power conversion efficiency of PSCs from 22.38 to 24.09% (certified efficiency of 23.43%). Meanwhile, the device demonstrates significantly improved photostability and atmospheric storage stability.

10.
Org Lett ; 24(23): 4292-4297, 2022 06 17.
Article in English | MEDLINE | ID: mdl-35658457

ABSTRACT

Bicyclo[1.1.1]pentanes (BCPs) are widely utilized in drug design as sp3-rich bioisosteres for tert-butyl, internal alkynes, and aryl groups. A general and mild method for radical acylation of [1.1.1]propellane with aldehydes has been developed. The protocol provides straightforward access to bicyclo[1.1.1]pentane ketones with a broad substrate scope. The synthetic utility of this methodology is demonstrated by the late-stage modification of bioactive molecules and the versatile transformation of bicyclo[1.1.1]pentane ketones, making it useful for drug discovery.


Subject(s)
Aldehydes , Ketones , Acylation , Aldehydes/chemistry , Ketones/chemistry , Pentanes
11.
In Vivo ; 36(2): 753-763, 2022.
Article in English | MEDLINE | ID: mdl-35241531

ABSTRACT

BACKGROUND/AIM: The development of colon cancer is influenced by the tumour immune microenvironment, in which specific immune cell subsets may be useful predictors for patient's clinical outcome and devising treatment strategies. MATERIALS AND METHODS: The distribution of tumour-infiltrating immune cell subpopulations of three cohorts of The Cancer Genome Atlas (n=225), GSE39582 (n=493), and GSE17536 (n=137) datasets were analysed on the basis of single cell RNA sequencing data via the Cibersortx software. A prognostic model was constructed via a penalised Cox regression model with least absolute shrinkage and selection operator (LASSO) penalty according to the one standard error rule. RESULTS: Conventional type 2 dendritic cells were correlated with a good prognosis, whereas NLRP3-expressing macrophages, C1QC-expressing tumour-associated macrophages, and GALTB-expressing B cells were correlated with a poor prognosis. We constructed a prognostic model based on prognosis related cell subsets including nine specific immune cell subsets. By using the LASSO method, we found that the model had a superior prediction ability in all three cohorts of patients. CONCLUSION: Multiple immune cell subpopulations in the tumour microenvironment are associated with the prognosis of colon cancer. The established prognostic model has important clinical value in predicting the clinical outcome of patients with colon cancer and in treatment decision.


Subject(s)
Biomarkers, Tumor , Colonic Neoplasms , Biomarkers, Tumor/genetics , Colonic Neoplasms/genetics , Colonic Neoplasms/pathology , Humans , Prognosis , Proportional Hazards Models , Tumor Microenvironment/genetics
12.
BMC Cancer ; 22(1): 216, 2022 Feb 28.
Article in English | MEDLINE | ID: mdl-35227236

ABSTRACT

OBJECTIVE: Neuroblastoma is a common extracranial solid tumor of childhood. Recently, multiple treatments have been practiced including Iodine-131-metaiodobenzylguanidine radiation (131I-MIBG) therapy. However, the outcomes of efficacy and safety vary greatly among different studies. The aim of this meta-analysis is to evaluate the efficacy and safety of 131I-MIBG in the treatment of neuroblastoma and to provide evidence and hints for clinical decision-making. METHODS: Medline, EMBASE database and the Cochrane Library were searched for relevant studies. Eligible studies utilizing 131I-MIBG in the treatment of neuroblastoma were included. The pooled outcomes (response rates, adverse events rates, survival rates) were calculated using either a random-effects model or a fixed-effects model considering of the heterogeneity. RESULTS: A total of 26 clinical trials including 883 patients were analyzed. The pooled rates of objective response, stable disease, progressive disease, and minor response of 131I-MIBG monotherapy were 39%, 31%, 22% and 15%, respectively. The pooled objective response rate of 131I-MIBG in combination with other therapies was 28%. The pooled 1-year survival and 5-year survival rates were 64% and 32%. The pooled occurrence rates of thrombocytopenia and neutropenia in MIBG monotherapy studies were 53% and 58%. In the studies of 131I-MIBG combined with other therapies, the pooled occurrence rates of thrombocytopenia and neutropenia were 79% and 78%. CONCLUSION: 131I-MIBG treatment alone or in combination of other therapies is effective on clinical outcomes in the treatment of neuroblastoma, individualized 131I-MIBG is recommended on a clinical basis.


Subject(s)
3-Iodobenzylguanidine/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Iodine Radioisotopes/therapeutic use , Neuroblastoma/drug therapy , Child, Preschool , Female , Humans , Infant , Male , Neuroendocrine Tumors/drug therapy , Neutropenia/chemically induced , Survival Rate , Treatment Outcome
13.
J Org Chem ; 87(5): 3135-3144, 2022 Mar 04.
Article in English | MEDLINE | ID: mdl-35029406

ABSTRACT

Herein, we developed palladium-catalyzed regio- and diastereoselective difluoromethylthiolation of acrylamides to form the Z-isomer product at room temperature. Using 8-aminoquinoline as a directing group, this protocol resulted in a high efficiency under mild reaction conditions and showed good functional group tolerances, which opens a novel synthetic methodology for accessing SCF2H-containing skeletons. Moreover, mechanistic studies were conducted to obtain insights into the reaction mechanism, and post-functionalization of the product reactions was performed.

14.
Spectrochim Acta A Mol Biomol Spectrosc ; 228: 117783, 2020 Mar 05.
Article in English | MEDLINE | ID: mdl-31753660

ABSTRACT

Polycyclic aromatic hydrocarbons (PAHs) are one of the most widespread and dangerous group of pollutants existing in the environment. Trace detection of PAHs is essential and important. Surface-enhanced Raman scattering (SERS) is a powerful analytical tool for ultrasensitive chemical analysis. However, the direct detection of PAHs by SERS is difficult due to poor affinity of PAHs to metal surfaces. In this work, we present a SERS platform based on the Ag-nanoparticles/graphene hybrid for the direct detection of PAHs with graphene as PAHs assemblies. The target PAHs are captured by the graphene through π-π electronic stacking, and brought close to the hot spots generated by dense Ag-nanoparticles decorated on the graphene. Sensitive detection of PAHs has been realized using this SERS substrate without further surface modification. The limit of detection for the three typical PAHs including pyrene, anthracene and phenanthrene was as low as 0.73 ppb, 1.1 ppb and 0.57 ppb, respectively. Our results indicate that the immobilization of PAHs on graphene is a process that can be applied in the design of sensitive sensors for these aromatic pollutants. This functional SERS sensor shows a great potential application in food safety inspection and environment pollutants monitoring.

15.
Bioorg Med Chem Lett ; 29(19): 126630, 2019 10 01.
Article in English | MEDLINE | ID: mdl-31466809

ABSTRACT

FMS-like tyrosine kinase 3 (FLT3) was an important therapeutic target in acute myeloid leukemia (AML). We synthesized two series of 4-((6,7-dimethoxyquinoline-4-yl)oxy)aniline derivatives possessing the semicarbazide moiety and 2,2,2-trifluoro-N,N'-dimethylacetamide moiety as the linker. The cell proliferation assay in vitro against HL-60 and MV4-11 cell lines demonstrated that most series I compounds containing semicarbazide moiety had more potent than Cabozantinib. Furthermore, the enzyme assay showed that compound 12c and 12g were potent FLT3 inhibitors with IC50 values of 312 nM and 384 nM, respectively. Following that, molecular docking analysis was also performed to determine possible binding mode between FLT3 and the target compound.


Subject(s)
Aniline Compounds/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Drug Design , Leukemia, Myeloid, Acute/drug therapy , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , fms-Like Tyrosine Kinase 3/antagonists & inhibitors , Apoptosis , Cell Proliferation , Humans , Leukemia, Myeloid, Acute/enzymology , Leukemia, Myeloid, Acute/pathology , Semicarbazides/chemistry , Structure-Activity Relationship , Tumor Cells, Cultured
16.
Water Environ Res ; 91(12): 1661-1668, 2019 Dec.
Article in English | MEDLINE | ID: mdl-31237380

ABSTRACT

Three vertical flow constructed wetlands, that is, system A (planted with Pennisetum sinese Roxb), system B (planted with Pennisetum purpureum Schum.), and system C (without plants as the control) were constructed to estimate the contribution of substrates, plants, and microorganisms to organic matter removal. The organic compounds accumulated in the substrate in systems A, B, and C were 12.03%, 11.91%, and 9.4%, respectively. Synergistic utilization of organic compounds by microorganisms and plants in systems A, B, and C were 80.95%, 81.58%, and 80.11%, respectively. Substrate interception and adsorption of organic compounds in plant systems A and B were more extensive than in the nonplant control system C. The total accumulative and absorptive capacity of systems A, B, and C was as follows: B (2,713 g) > A (2,698 g) > C (2,076 g). The amounts of insoluble organic accumulated on the upper substrates of the three systems showed the order C > A > B. No constructed wetland clogging occurred for A and B systems during the experiment, while system C suffered clogging in early September. Therefore, substrate blockage may be related to the type of organic compound accumulated. Accumulation of insoluble organic matter is the direct cause of system blockage. PRACTITIONER POINTS: Substrate interception and adsorption of organic compounds in plant systems were more extensive than those in the nonplant control system. Distribution characteristics of the surface layer were significantly higher than those of the middle and bottom layers. Substrate blockage is related to the type of organic compound accumulated. Accumulation of insoluble organic compounds may be the direct cause of system blockage. The upper substrate is the main site for organic compound removal.


Subject(s)
Wastewater , Wetlands , Organic Chemicals , Plants , Waste Disposal, Fluid
17.
Sci Bull (Beijing) ; 64(21): 1608-1616, 2019 Nov 15.
Article in English | MEDLINE | ID: mdl-36659573

ABSTRACT

Formamidinium lead triiodide (HC(NH2)2PbI3 or FAPbI3) is a promising light absorber for high-efficiency perovskite solar cells because of its superior light absorption range and thermal stability to CH3NH3PbI3 (MAPbI3). Unfortunately, it is difficult to fabricate high-quality FAPbI3 thin films to surpass the MAPbI3-based cells due to easily forming unwanted but more stable yellow δ-phase and thus requiring high annealing-temperature for wanted photovoltaic-active black α-phase. Herein, we reported a novel low-temperature fabrication of highly crystallized α-FAPbI3 film exhibiting uniaxial-oriented nature with large grain sizes up to 2 µm. First-principles energetic calculations predicted that this novel deposition should be ascribed to the formation of a high-energy metastable two-dimensional (2D) intermediate of MAFAPbI3Cl followed by a spontaneous conversion to α-FAPbI3. The ions exchange reaction during this MAFAPbI3Cl-FAPbI3 conversion account for the perovskite film uniaxial-oriented grown along the (1 1 1) direction. This large-grain and uniaxial-oriented grown α-FAPbI3 based solar cells exhibited an efficiency up to 20.4% accompanying with low density-voltage (J-V) hysteresis and high stability.

18.
Eur J Med Chem ; 163: 690-709, 2019 Feb 01.
Article in English | MEDLINE | ID: mdl-30572179

ABSTRACT

To develop novel therapeutic agents with anticancer activities, two series of novel 7-amino-[1,2,4]triazolo[4,3-f]pteridinone, and 7-aminotetrazolo[1,5-f]pteridinone derivatives were designed and synthesized. All compounds were tested for anti-proliferative activities against five cancer cell lines. The structure-activity relationships (SARs) studies were conducted through the variation in two regions, the moiety of A ring and the terminal aniline B on pteridinone core. 1-Methyl-1,2,4-triazole derivative L7 with 2,6-dimethylpiperazine showed the most potent antiproliferative activity against A549, PC-3, HCT116, MCF-7 and MDA-MB-231 cell lines with IC50 values of 0.16 µM, 0.30 µM, 0.51 µM, 0.30 µM, and 0.70 µM, respectively. Combined with the results of the molecular docking and enzymatic studies, the PLK1 was very likely to be one of the drug targets of compound L7. Furthermore, to clarify the anticancer mechanism of compound L7, further explorations in the bioactivity were conducted. The results showed that compound L7 obviously inhibited proliferation of A549 cell lines, induced a great decrease in mitochondrial membrane potential leading to apoptosis of cancer cells, suppressed the migration of tumor cells, and arrested G1 phase of A549 cells.


Subject(s)
Antineoplastic Agents/chemistry , Drug Design , Pteridines/pharmacology , Tetrazoles/pharmacology , Triazoles/pharmacology , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Humans , Inhibitory Concentration 50 , Membrane Potential, Mitochondrial/drug effects , Molecular Docking Simulation , Pteridines/chemical synthesis , Structure-Activity Relationship , Tetrazoles/chemical synthesis , Triazoles/chemical synthesis
19.
Bioorg Med Chem ; 26(9): 2621-2631, 2018 05 15.
Article in English | MEDLINE | ID: mdl-29681484

ABSTRACT

The hepatitis C virus (HCV) NS5B polymerase is an attractive target for the development of novel and selective inhibitors of HCV replication. In this paper, the design, synthesis, and preliminary SAR studies of novel inhibitors of HCV NS5B polymerase based on the structure of tegobuvir have been described. The efforts to optimize the antiviral potency and reduce the treatment side effects with respect to genotype 1b resulted in the discovery of compound 3, which exhibited an EC50 of 1.163 nM and a CC50 >200 nM in a cell-based HCV replicon system assay. Additionally, testing for inhibition of the hERG channel showed a marked improvement over tegobuvir and the pharmacokinetic properties of compound 3 indicated that it was worthy of further investigation as a non-nucleoside inhibitor of HCV NS5B polymerase.


Subject(s)
Antiviral Agents/pharmacology , Imidazoles/pharmacology , Pyridines/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Cell Line , Hepacivirus/drug effects , Imidazoles/chemical synthesis , Imidazoles/chemistry , Imidazoles/pharmacokinetics , Male , Purines/pharmacology , Pyridazines/pharmacology , Pyridines/chemical synthesis , Pyridines/chemistry , Pyridines/pharmacokinetics , Rats, Sprague-Dawley , Sofosbuvir/pharmacology , Structure-Activity Relationship
20.
Bone ; 108: 10-19, 2018 03.
Article in English | MEDLINE | ID: mdl-29229438

ABSTRACT

Pulsed electromagnetic fields (PEMF) has been investigated as a noninvasive alternative method to prevent bone loss for postmenopausal osteoporosis (OP), and the bone tissue involved in these studies are usually long bones such as femur and tibia in OP patients or rat models. However, few studies have investigated the effects of PEMF on the vertebral bone in mice with OP. This study aimed to investigate whether PEMF preserve lumbar vertebral bone mass, microarchitecture and strength in ovariectomized (OVX) mouse model of OP and its associated mechanisms. Thirty 3-month-old female BALB/c mice were randomly divided into three groups (n=10): sham-operated control (Sham), ovariectomy (OVX), and ovariectomy with PEMF treatment (OVX+PEMF). The OVX+PEMF group was exposed to 15Hz, 1.6 mT PEMF for 8h/day, 7days/week. After 8weeks, the mice were sacrificed. The OVX+PEMF group showed lower body weight gain of mice induced by estrogen deficiency compared with OVX group. Biochemical analysis of serum demonstrated that serum bone formation markers including bone specific alkaline phosphatase (BALP), serum osteocalcin (OCN), osteoprotegerin (OPG) and N-terminal propeptide of type I procollagen (P1NP) were markedly higher in OVX+PEMF group compared with OVX group. Besides, serum bone resorption markers including tartrate-resistant acid phosphatase 5b (TRAP-5b) and C-terminal crosslinked telopeptides of type I collagen (CTX-I) were markedly lower in OVX+PEMF group compared with OVX group. Biomechanical test observed that OVX+PEMF group showed higher compressive maximum load and stiffness of the lumbar vertebrae compared with OVX group. Micro-computed tomography (µCT) and histological analysis of lumbar vertebrae revealed that PEMF partially prevented OVX-induced decrease of trabecular bone mass and deterioration of trabecular bone microarchitecture in lumbar vertebrae. Real-time PCR showed that the canonical Wnt signaling pathway of the lumbar vertebrae, including Wnt3a, LRP5 and ß-catenin were markedly up-regulated in OVX+PEMF group compared with OVX group. Moreover, the mRNA expressions of RANKL and OPG were markedly up-regulated in OVX+PEMF group compared with OVX group, whereas no statistical difference in RANKL/OPG mRNA ratio was found between OVX+PEMF group and OVX group. Besides, our study also found that the RANK mRNA expression was down-regulated in OVX+PEMF group compared with OVX group. Taken together, we reported that long-term stimulation with PEMF treatment was able to alleviate lumbar vertebral OP in postmenopausal mice through a combination of increased bone formation and suppressed bone resorption related to regulating the skeletal gene expressions of Wnt3a/LRP5/ß-catenin and OPG/RANKL/RANK signaling pathways.


Subject(s)
Electromagnetic Fields , Lumbar Vertebrae/anatomy & histology , Ovariectomy , Animals , Biomechanical Phenomena , Body Weight , Cancellous Bone/anatomy & histology , Female , Gene Expression Regulation , Lumbar Vertebrae/diagnostic imaging , Lumbar Vertebrae/physiology , Mice, Inbred BALB C , Organ Size , Serum/metabolism , X-Ray Microtomography
SELECTION OF CITATIONS
SEARCH DETAIL