HIF-1α mediates CXCR4 transcription to activate the AKT/mTOR signaling pathway and augment the viability and migration of activated B cell-like diffuse large B-cell lymphoma cells.

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy with a high relapse rate. We previously found that C-X-C motif chemokine receptor 4 (CXCR4) was highly expressed in DLBCL and associated with poor prognosis. This study focused on the effect of hypoxia-inducible factor-1α (HIF-1α) on CXCR4 expression and the DLBCL progression. Two activated B cell-like DLBCL cell lines Ly-3 and SUDHL2 were transfected with overexpression and knockdown plasmids or HIF-1α. The viability and migration of DLBCL cells were significantly increased under hypoxic conditions, or upon HIF-1α overexpression under normoxic conditions, but the HIF-1α downregulation led to inverse trends. However, the promoting effects of HIF-1α overexpression on DLBCL cells were suppressed by Plerixafor (a CXCR4 inhibitor). The luciferase and chromatin immunoprecipitation assays revealed that HIF-1α bound to the functional site HRE1 on CXCR4 promoter to activate its transcription. HIF-1α-mediated CXCR4 activation further led to increased phosphorylation of AKT/mTOR under hypoxic conditions. Taken together, this work reports that HIF-1α promotes viability and migration of activated B cell-like cells under hypoxia, which might involve the transcription of CXCR4 and the activation of the AKT/mTOR pathway. The finding may provide novel lights in the management of DCBCL.

A Novel Electrochemical Immunosensor Based on COF-LZU1 as Precursor to Form Heteroatom-Doped Carbon Nanosphere for CA19-9 Detection.

Porous carbon sphere materials have a large variety of applications in several fields due to the large surface area, adaptable porosity, and good conductivity they possess. Obtaining a steady carbon sphere using the green synthesis method remains a significant challenge. In this experiment, covalent organic frameworks (COFs) were used as a precursor and Fe3O4NPs were integrated into the precursor in order to synthesize a porous carbon sphere material using the one-step pyrolysis method. COFs have an ordered porous structure, perpetual porosity, large surface area, and low density and display good environmental tolerance. These properties make them an excellent precursor for synthesizing porous carbon sphere, which maintains good morphology at high temperatures, and it is not involved in the removal of dangerous reagent and small size restrictions during the synthesis process. In addition to the formation of a porous carbon sphere, transition metal carbon material that contains N element can be an active catalyst. The composites exhibit better activity when Fe is doped into carbon materials containing N element than that of other doped transition metals including Mn and Co. In this situation, the integration of Fe3O4NPs and N element in the COF precursor exposed the active sites of the composites and the two substances synergistically improved the electrocatalytic properties, and the composites were named Fe3O4@NPCS. The constructed Fe3O4@NPCS/GCE immunosensor was applied as a means of detecting CA19-9 antigen and presented a wide linear range from 0.00001 to 10 U/mL with a low detection limit of 2.429 µU/mL (S/N = 3). In addition, the prepared immunosensor was utilized for detecting CA19-9 antigen in the real human serum, and the recovery rates were in the range from 95.24% to 106.38%. Therefore, a porous carbon sphere prepared by COFs as a precursor can be applied for the detection of CA19-9 antigen in real samples, which could be an excellent strategy for CA19-9 antigen detection and could potentially promote the development of COF materials in various electrochemical fields.

Dual function metal-organic frameworks based ratiometric electrochemical sensor for detection of doxorubicin.

Cancer is one of the main diseases threatening human health in the world. Doxorubicin (DOX) is a common anti-cancer drug that can be used for chemotherapy to extend a cancer patient's life. It is our common wish that treatment process of cancer is efficient and secure. Therefore, it is of great significance to develop sensitive, rapid and accurate techniques for anti-cancer drug doxorubicin (DOX) detection. Herein, in our work, a ratiometric electrochemical sensor for DOX detection was designed, which based on MB@MWCNTs/UiO-66-NH2 composites. The porous materials UiO-66-NH2 magically shoulder double function in our ratiometric electrochemical strategy, which can reduce the interior error caused by the various complex materials. Specifically, on the one hand, it can be used to catalyze DOX, which can provide a great current signal to be detected, on the other hand, its special property of absorbing molecules was utilized to load materials as internal reference. Consequently, we chose methylene blue (MB) as the substance that can generate an internal reference signal, because it is a specific and stable electroactive substance. Then, we added MWCNTs as a part of the material modified on the ratiometric electrochemical platform to enhance the signal of the target due to its feature of good electrical conductivity. Under the optimized conditions, the ratiometric electrochemical sensor displayed a wide linear detection with the range from 0.1 µM to 75 µM and the limit of detection (LOD) of 0.051 µM. The applicability of this method in the analysis of actual human saliva samples has been confirmed by the results of selectivity, stability, and reproducibility tests, which was prospective in clinical application.

A sandwich-configuration electrochemiluminescence immunoassay based on Cu2O@OMC-Ru nanocrystals and OMC-MoS2 nanocomposites for determination of alpha-fetoprotein.

A sandwich-format electrochemiluminescence (ECL) immunosensor has been developed for alpha-fetoprotein (AFP) detection based on the use of ordered mesoporous carbon-molybdenum disulfide (OMC-MoS2) as a sensor platform and cuprous oxide @ ordered mesoporous carbon-Ru(bpy)32+ (Cu2O@OMC-Ru) composites as signal tags. OMC alongside MoS2 plays a synergistic role in improving the electrochemical performance of the electrode in the electron transfer process. The uniform cubic-shaped Cu2O@OMC-Ru nanocrystals display excellent luminous efficiency, with a signal amplification strategy of OMC-MoS2 synergistic enhancement and Cu2O@OMC which is capable of immobilizing more Ru(bpy)32+ serving as a tracing tag to label antibodies. A detectable ECL emission at a Cu2O@OMC-Ru nanocrystals modified electrode is initiated at an applied voltage of +1.15 V (scanning range: 0-1.2 V), in the presence of the tripropylamine (TPA) as coreactant. With the increase in AFP concentration, the loading of Cu2O@OMC-Ru at the electrode increases. Afterward, the ECL detection of AFP shows a wide linear range from 0.1 pg/mL to 10 ng/mL with a correlation coefficient of 0.9964 and a detection limit of 0.011 pg/mL (S/N = 3) under the optimal experimental conditions. The recoveries were in the range 91.2-97.1% with RSD varying from 4.8 to 8.5%. Overall, the novel immunosensor has been successfully applied to the analysis of human serum samples, indicating a great potential for application in clinical diagnostics.

Spherical carrier amplification strategy for electrochemical immunosensor based on polystyrene-gold nanorods @L-cysteine/MoS2 for determination of tacrolimus.

A novel sensitive electrochemical immunosensor has been designed for determination of tacrolimus (Tac) based on spherical carrier amplification strategy. In this work, a spherical signal carrier was prepared by conjugating gold nanorods (AuNRs) functionalized L-cysteine (AuNRs@L-Cys) onto polystyrene nanoparticles (PS) to form a nanostructure, greatly increasing the amount of loaded capture antibodies. The PS was a stable spherical functional polymer with large specific surface area and was labeled with AuNRs@L-Cys via coupling reagent to increase active groups, biocompatibility and conductivity. The capture antibodies could be attached on the PS- AuNRs@L-Cys via linkage reagent glutaraldehyde (GA). Furthermore, single-layer molybdenum disulfide (MoS2) fixed by chitosan were utilized to construct the base of this immunosensor, increasing the carrying capacity and stability of the electrode. After electrochemical reduction, the conductivity and electron transfer rate of MoS2 were obviously improved, which offered a platform for this immunosensor and further amplified the signal. Under the optimized conditions, the proposed immunosensor revealed a linear Tac-concentration behavior from 1.0 to 30 ng mL-1 with a detection limit of 0.17 ng mL-1 (S/N = 3). The immunoassay was successfully applied to the quantification of Tac in serum samples with acceptable precision. The results indicated that a potentially analytical platform may be used to recognize the concentration of other drugs.

All-trans retinoic acid and arsenic trioxide fail to derepress the monocytic differentiation driver Irf8 in acute promyelocytic leukemia cells.

All-trans retinoic acid (ATRA) and/or arsenic trioxide (ATO) administration leads to granulocytic maturation and/or apoptosis of acute promyelocytic leukemia (APL) cells mainly by targeting promyelocytic leukemia/retinoic acid receptor alpha (PML/RARα). Yet, ~10-15% of APL patients are not cured by ATRA- and ATO-based therapies, and a potential failure of ATRA and ATO in completely reversing PML/RARα-driven oncogenic alterations has not been comprehensively examined. Here we characterized the in vivo primary responses of dysregulated genes in APL cells treated with ATRA and ATO using a GFP-labeled APL model. Although induced granulocytic differentiation of APL cells was evident after ATRA or ATO administration, the expression of the majority of dysregulated genes in the c-Kit+ APL progenitors was not consistently corrected. Irf8, whose expression increased along with spontaneous differentiation of the APL progenitors in vivo, represented such a PML/RARα-dysregulated gene that was refractory to ATRA/ATO signaling. Interestingly, Irf8 induction, but not its knockdown, decreased APL leukemogenic potential through driving monocytic maturation. Thus, we reveal that certain PML/RARα-dysregulated genes that are refractory to ATRA/ATO signaling are potentially crucial regulators of the immature status and leukemogenic potential of APL cells, which can be exploited for the development of new therapeutic strategies for ATRA/ATO-resistant APL cases.