Rational Design of PARP1/c-Met Dual Inhibitors for Overcoming PARP1 Inhibitor Resistance Induced by c-Met Overexpression.

The emergence of resistance to PARP1 inhibitors poses a current therapeutic challenge, necessitating the development of novel strategies to overcome this obstacle. The present study describes the design and synthesis of a series of small molecules that target both PARP1 and c-Met. Among them, compound 16 is identified as a highly potent dual inhibitor, exhibiting excellent inhibitory activities against PARP1 (IC50 = 3.3 nM) and c-Met (IC50 = 32.2 nM), as well as demonstrating good antiproliferative effects on HR-proficient cancer cell lines and those resistant to PARP1 inhibitors. Importantly, compound 16 demonstrates superior antitumor potency compared to the PARP1 inhibitor Olaparib and the c-Met inhibitor Crizotinib, either alone or in combination, in MDA-MB-231 and HCT116OR xenograft models. These findings highlight the potential of PARP1/c-Met dual inhibitors for expanding the indications of PARP1 inhibitors and overcoming tumor cells' resistance to them.

Body Weight Support Treadmill Training Combined With Sciatic Nerve Electrical Stimulation Ameliorating Motor Function by Enhancing PI3K/Akt Proteins Expression via BDNF/TrkB Signaling Pathway in Rats with Spinal Cord Injury.

OBJECTIVE: To investigate the effects of body weight support treadmill training (BWSTT) and sciatic nerve electrical stimulation (SNES) on motor function recovery in spinal cord injury (SCI) rats and its possible mechanism. METHODS: Modified Allen's method was utilized for T10 incomplete SCI. The Basso-Beattie-Bresnahan (BBB) score and modified Tarlov score were applied to assess motor function. Pathologic alterations of the spinal cord and muscles were observed by hematoxylin and eosin (HE) staining. The positive staining region of collagen fibers was assessed with Masson staining. Immunofluorescence was applied to count the positive cells of brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B (TrkB). BDNF, TrkB, phosphatidylinositol-3-kinase (PI3K), and protein kinase B (Akt) relative mRNA and protein expressions were evaluated by reverse transcription polymerase chain reaction (RT-PCR) and Western blotting. RESULTS: On the 21st day of the intervention, the motor scores in SNES and BWSTT + SNES groups were higher than that in SCI group (P < 0.05). Compared with SCI group, mRNA and protein expressions of BDNF/TrkB and PI3K/Akt were more significant on the 21st day of the intervention in SNES and BWSTT + SNES groups (P < 0.05), but there was no difference in BWSTT group (P > 0.05). CONCLUSIONS: This experiment demonstrated that BWSTT combined with SNES contributed to alleviating spinal cord tissue injury, delaying muscle atrophy and improving locomotion. One of the possible mechanisms may be related to the regulation of the BDNF/TrkB signaling pathway, which changes the expression of PI3K/Akt protein. Furthermore, it was discovered that the ultra-early BWSTT may not be conducive to recovery.

A method for analyzing programmed cell death in xylem development by flow cytometry.

Programmed cell death (PCD) is a genetically regulated developmental process leading to the death of specific types of plant cells, which plays important roles in plant development and growth such as wood formation. However, an efficient method needs to be established to study PCD in woody plants. Flow cytometry is widely utilized to evaluate apoptosis in mammalian cells, while it is rarely used to detect PCD in plants, especially in woody plants. Here, we reported that the xylem cell protoplasts from poplar stem were stained with a combination of fluorescein annexin V-FITC and propidium iodide (PI) and then sorted by flow cytometry. As expected, living cells (annexin V-FITC negative/PI negative), early PCD cells (annexin V-FITC positive/PI negative), and late PCD cells (annexin V-FITC positive/PI positive) could be finely distinguished through this method and then subjected for quantitative analysis. The expression of cell-type- and developmental stages-specific marker genes was consistent with the cell morphological observation. Therefore, the newly developed fluorescence-activated cell sorting (FACS) method can be used to study PCD in woody plants, which will be beneficial for studying the molecular mechanisms of wood formation.

PagERF81 regulates lignin biosynthesis and xylem cell differentiation in poplar.

Lignin is a major component of plant cell walls and is essential for plant growth and development. Lignin biosynthesis is controlled by a hierarchical regulatory network involving multiple transcription factors. In this study, we showed that the gene encoding an APETALA 2/ethylene-responsive element binding factor (AP2/ERF) transcription factor, PagERF81, from poplar 84 K (Populus alba × P. glandulosa) is highly expressed in expanding secondary xylem cells. Two independent homozygous Pagerf81 mutant lines created by gene editing, produced significantly more but smaller vessel cells and longer fiber cells with more lignin in cell walls, while PagERF81 overexpression lines had less lignin, compared to non-transgenic controls. Transcriptome and reverse transcription quantitative PCR data revealed that multiple lignin biosynthesis genes including Cinnamoyl CoA reductase 1 (PagCCR1), Cinnamyl alcohol dehydrogenase 6 (PagCAD6), and 4-Coumarate-CoA ligase-like 9 (Pag4CLL9) were up-regulated in Pagerf81 mutants, but down-regulated in PagERF81 overexpression lines. In addition, a transient transactivation assay revealed that PagERF81 repressed the transcription of these three genes. Furthermore, yeast one hybrid and electrophoretic mobility shift assays showed that PagERF81 directly bound to a GCC sequence in the PagCCR1 promoter. No known vessel or fiber cell differentiation related genes were differentially expressed, so the smaller vessel cells and longer fiber cells observed in the Pagerf81 lines might be caused by abnormal lignin deposition in the secondary cell walls. This study provides insight into the regulation of lignin biosynthesis, and a molecular tool to engineer wood with high lignin content, which would contribute to the lignin-related chemical industry and carbon sequestration.

Design, synthesis and biological evaluation of novel 4-aminopiperidine derivatives as SMO/ERK dual inhibitors.

The hedgehog (Hh) pathway is tightly related with the formation, metastasis and recurrence of various cancers, which makes it a perfect anticancer target. Smoothened (SMO) is one of its key members. Three drugs targeting the Hh pathway have been successfully used in clinic, and they are all known as SMO inhibitors. However, serious drug resistant problem has limited their clinical application. The interaction of oncogenic ERK pathway with the Hh pathway in multiple ways has been proved as one of the main factors that result in drug resistance. Dual inhibition of the Hh and ERK pathways has displayed synergistic suppression to cancer cells overexpressing both pathways. Herein, we designed and synthesized a series of novel 4-aminopiperidine derivatives as SMO/ERK dual inhibitors, and evaluated their biological activities. The results showed that compounds I-13 displayed strong inhibitory activities towards both SMO and ERK, and it also exhibited significant cytotoxicity against human cholangiocarcinoma RBE cells which overexpress both the Hh and ERK pathways. All the results indicate that compound I-13 is a promising anticancer candidate as a SMO/ERK dual inhibitor.

Inhibiting Mercury Re-emission and Enhancing Magnesia Recovery by Cobalt-Loaded Carbon Nanotubes in a Novel Magnesia Desulfurization Process.

Mercury re-emission, because of the reduction of Hg2+ to form Hg0 by sulfite, has become a great concern in the desulfurization process. Lowering the concentrations of Hg2+ and sulfite in the desulfurization slurry can retard the Hg0 formation and, thus, mitigate mercury re-emission. To that end, cobalt-based carbon nanotubes (Co-CNTs) were developed for the simultaneous Hg2+ removal and sulfite oxidation in this work. Furthermore, the thermodynamics and kinetics of the Hg2+ adsorption and effect of Hg2+ adsorption on catalytic activity of Co-CNTs were investigated. Experimental results revealed that the Co-CNTs not only accelerated sulfite oxidation to enable the recovery of desulfurization by-products but also acted as an effective adsorbent of Hg2+ removal. The Hg2+ adsorption rate mainly depended on the structure of the adsorption material regardless of the cobalt loading and morphological distribution. The catalytic activity of the Co-CNTs for sulfite oxidation was not significantly affected due to the Hg2+ adsorption. Additionally, the isothermal adsorption behavior was well-fitted to the Langmuir model with an adsorption capacity of 166.7 mg/g. The mercury mass balance analysis revealed that the Hg0 re-emission was decreased by 156% by adding 2.0 g/L of Co-CNTs. These results can be used as a reference for the simultaneous removal of multiple pollutants in the wet-desulfurization process.

[Adsorption of methylene blue from aqueous solution onto magnetic Fe3O4/ graphene oxide nanoparticles].

A simple ultrasound-assisted co-precipitation method was developed to prepare magnetic Fe3O4/graphene oxide (Fe3O4/ GO) nanoparticles. The characterization with transmission electron microscope (TEM) indicated that the products possessed small particle size. The hysteresis loop of the dried Fe3O4/GO nanoparticles demonstrated that the sample had typical features of superparamagnetic material. Batch adsorption studies were carried out to investigate the effects of the initial pH of the solution, the dosage of adsorbent, the contact time and temperature on the adsorption of methylene blue. The results indicated that the composites prepared could be used over a broad pH range (pH 6-9). The adsorption process was very fast within the first 25 min and the equilibrium was reached at 180 min. The adsorption equilibrium and kinetics data fitted well with the Langmuir isotherm model and the pseudo-second-order kinetic model. The adsorption process was a spontaneous and endothermic process in nature. The composite exhibited fairly high adsorption capacity (196.5 mg.g-1) of methylene blue at 313 K. In addition, the magnetic composite could be effectively and simply separated by using an external magnetic field, and then regenerated by hydrogen peroxide and recycled for further use. The results indicated that the adsorbent had a potential in the application of the dye wastewater treatment.