Involvement of cysteinyl leukotriene receptor 1 in Aβ1–42-induced neurotoxicity in vitro and in vivo

Accumulation of amyloid-β (Aβ) is thought to be associated with the progressive neuronal death observed in Alzheimer's disease, but the mechanisms underlying neurotoxicity triggered by Aβ remain elusive. In the current study, we investigated the roles of cysteinyl leukotriene receptor 1 (CysLT₁R) in Aβ_1–42-induced neurotoxicity in vitro or in vivo. In vitro exposure of mouse primary neurons to Aβ_1–42 caused a gradual increases in CysLT₁R expression. In vivo bilateral intrahippocampal injection of Aβ_1–42 also elicited time-dependent increases of CysLT₁R expression in the hippocampus and cortex of mice. The CysLT₁R antagonist pranlukast not only reversed Aβ_1–42-induced upregulation of CysLT₁R, but also suppressed Aβ_1–42-triggered neurotoxicity evidenced by enhanced nuclear factor-kappa B p65, activated caspase-3, decreased B-cell lymphoma-2 and cell viability and impaired memory. Furthermore, chronic treatment with pranlukast produced similar beneficial effects on memory behavior and hippocampal long-term potentiation to memantine or donepezil in intrahippocampal Aβ_1–42-injected mice. Our data indicate that CysLT₁R is involved in Aβ_1–42-induced neurotoxicity, and that blockade of CysLT₁R, such as application of CysLT₁R antagonist, could be a novel and promising strategy for the treatment of Alzheimer's disease.     

Dual-mode US/MRI nanoparticles delivering siRNA and Pt(iv) for ovarian cancer treatment

As known to all, ovarian cancer ranks the most lethal of the gynecological malignancies. The antitumor drugs based on platinum are first-line chemotherapy drugs for ovarian cancer. However, their therapeutic efficiency is severely limited owing to dose-limiting toxicities of platinum. New theranostic strategies to overcome chemotherapy toxicity is highly desirable. Meanwhile, the real-time treating effect is not visible for doctors. Herein, we constructed PFH/siRNA/Fe₃O₄@Pt(iv) NPs-cRGD (NPs-cRGD) for precise theranostics against ovarian tumors with real-time imaging. The NPs-cRGD had a good storage stability and resisted the serum-induced aggregation, which was beneficial for drug delivery. Additionally, gel-retardation assay demonstrated that the NPs-cRGD exhibited great protection to siRNA to resist nuclease degradation. In vitro, the NPs-cRGD showed good dual-mode US/MRI imaging and the relative imaging research was also discussed. Moreover, the in vitro experiments indicated that the NPs-cRGD with US exhibited excellent antitumor therapeutic efficiency, resulting from the cRGD ligands and US exposure enhanced the cellular uptake efficiency. Thus, the dual-mode nanoparticles in this work may provide precious insight into the development of various multi-mode nanoplatforms delivering drugs or genes for precise theranostics against various cancer.

Phase-shifted dual-mode US/MRI nanoparticles (PFH/siRNA/Fe₃O₄@Pt(iv) NPs-cRGD) delivering si-survivin and Pt(iv) prodrug for enhancing ovarian cancer treatment and realizing real-time monitoring.     

New spirobisnaphthalenes from an endolichenic fungus strain CGMCC 3.15192 and their anticancer effects through the P53–P21 pathway

Natural products from fungi have remained a rich resource for drug discovery. Here we report the isolation of three new spirobisnaphthalenes, namely sacrosomycin A-C (1–3), and three known analogues (4–6), from the ethyl acetate extract of a nonsporulating endolichenic fungus derived from Peltigera elisabethae var. mauritzii. The structures of these compounds were elucidated by IR, UV, MS, and NMR. Biological functions of these compounds were evaluated using cultured human cancer cell lines. Short-term cell growth and long-term cell survival assays show that compound 5 demonstrated the strongest cancer cell growth inhibition effect. We reveal that compound 5 induced both cell cycle arrest at the G2/M phase and cell death. Using western blotting, luciferase reporter assay and quantitative PCR (qPCR), we show that compound 5 induced up-regulation of the P53–P21 pathway, supporting the cell cycle arrest and growth inhibition effect of this compound. In contrast, these compounds did not induce cell death in a normal cell line. These results demonstrate a potential anticancer effect of this rare family of spirobisnaphthalene compounds isolated from endolichenic fungi.

New spirobisnaphthalenes from an endolichenic fungus strain and their anticancer effects mediated by the P53–P21 pathway.     

Ciliated muconodular papillary tumor of the lung: A newly defined peripheral pulmonary tumor with conspicuous mucin pool mimicking colloid adenocarcinoma: A case report and review of literature

We report the case of a 68‐year‐old man with a newly defined rare entity of a peripheral pulmonary tumor, consisting of a nodular papillary lesion with papillary structures containing ciliated columnar and goblet cells, as well as floating tumor cells in the mucin pool. The conspicuous mucin pool was observed to be mimicking colloid adenocarcinoma in a low‐power view, particularly in a frozen section slide. We originally reported it as an adenocarcinoma during intraoperative consultation. Immunohistochemically, the tumor cells exhibited a similar immunophenotype to pulmonary adenocarcinoma, except for the presence of focal ciliated and basaloid cells, which we found using CK5/6 and P63 immunostaining. No KRAS or EGFR mutation was found. We revised the diagnosis to that of a ciliated muconodular papillary tumor (CMPT). Four years after a wedge resection, the patient remained free of tumors. Although the malignant potential of CMPT cannot be ignored, a wedge resection with a safe margin might be a treatment option for CMPT patients.     

The direct electrochemistry and bioelectrocatalysis of nitrate reductase at a gold nanoparticles/aminated graphene sheets modified glassy carbon electrode

It is rather difficult to achieve the direct electrochemistry of nitrate reductase (NR) as it is a complex homodimeric enzyme. However, in this study, the direct electron transfer between NR''s redox centers and the electrode surface was achieved with the aid of aminated graphene sheets (am-GSs) which could immobilize NR stably and control the orientation of the enzyme molecules on the surface of the modified electrode through electrostatic attractions. Moreover, when the gold nanoparticles (AuNPs) which could act as electronic wire were introduced to the modified electrode, the NR-based enzymatic reduction of nitrate was promoted and a sensitive electrochemical response regarding the electrochemical reduction of nitrate could be obtained at the NR/AuNPs/am-GSs/GC electrode. Under optimized conditions, a wide linear range from 1.0 × 10⁻⁶ mol L⁻¹ to 2.0 × 10⁻³ mol L⁻¹ was acquired with a low detection limit of 7 × 10⁻⁷ mol L⁻¹ (S/N = 3). The biosensor was successfully employed to determine the total nitrogen in environmental water samples and the results were in good accordance with those obtained by ultraviolet-visible spectrophotometry.

The aminated graphene sheets could immobilize nitrate reductase stably and control its orientation through electrostatic attractions, achieving its direct electrochemistry.     

The use of bisphosphonates in children: review of the literature and guidelines for dental management

Bisphosphonates are inhibitors of osteoclastic bone resorption with therapeutic benefit in a variety of bone disorders in both adults and children. While these agents have been routinely used in adults for the past three decades, their more recent introduction into paediatric medicine means there is a paucity of data on long‐term safety and effects on dental development. There is uncertainty regarding the dental management of children treated with bisphosphonates, particularly when invasive dental procedures, such as extractions and oral surgical procedures, are required. There are limited data with which to make recommendations about the dental management of patients treated with bisphosphonates, and there are no published recommendations that specifically address paediatric patients. This paper aims to outline paediatric uses and adverse effects of bisphosphonates and present recommendations on the dental management of children receiving bisphosphonates.     

Angiotensin II induces mitochondrial dysfunction and promotes apoptosis via JNK signalling pathway in primary mouse calvaria osteoblast

Objectives

This present study was designed to investigate the effects of Angiotensin II on mitochondrial functions, ROS generation and c-jun N-terminal kinases (JNK) signalling pathway-mediated cell apoptosis in mouse calvaria osteoblasts.

Methods

Calvaria osteoblast were isolated and cultured. The cells were separated into two groups—control and treated groups—where the latter was stimulated with angiotensin II (Ang II). Mitochondrial reactive oxygen species (ROS) and superoxide production were measured. Intracellular ATP levels were also detected. The cell proliferation rate was determined for the two groups. Protein production such as Anti-Bax, Bcl-2, COX IV and activation of c-jun N-terminal kinases signal (JNK) pathway was measured by enzyme-linked immunosorbent assay (ELISA) methods and Western blotting in this study.

Results

Ang II treated cells showed significantly higher levels of superoxide production compared to the control group (p < 0.05). Conversely, Ang II induced inhibitory effects on mitochondrial respiratory enzyme complexes, cause membrane potential dissipation, ATP loss and promote ROS generation, cell apoptosis in cultured osteoblasts. In addition, JNK phosphorylations were involved in activating the mitochondria-dependent apoptotic pathway following Ang II stimulation, as pre-treatment of JNK-specific inhibitor SP600125 could rescue osteoblast cells from apoptosis by enhancing the anti-apoptotic protein Bcl-2 expressions, suppressing the translocation of Bax from cytosol into mitochondria, blocking cytochrome C release and caspase-3 activation.

Conclusions

Ang II stimulates osteoblast apoptosis via suppression of the mitochondrial respiratory enzymes, membrane potential and cellular ATP productions. Clinical application with Ang II-stimulated osteoblast could be used for modelling or bone resorption in the oral region.     

Composite pullulan–dextran polysaccharide scaffold with interfacial polyelectrolyte complexation fibers: A platform with enhanced cell interaction and spatial distribution

Hydrogels are highly preferred in soft tissue engineering because they recapitulate the hydrated extracellular matrix. Naturally derived polysaccharides, like pullulan and dextran, are attractive materials with which to form hydrophilic polymeric networks due to their non-immunogenic and non-antigenic properties. However, their inherent hydrophilicity prevents adherent cell growth. In this study, we modified pullulan–dextran scaffolds with interfacial polyelectrolyte complexation (IPC) fibers to improve their ability to support adherent cell growth. We showed that the pullulan–dextran–IPC fiber composite scaffold laden with extracellular matrix protein has improved cell adhesion and proliferation compared to the plain polysaccharide scaffold. We also demonstrated the zero-order release kinetics of the biologics bovine serum albumin and vascular endothelial growth factor (VEGF) incorporated in the composite scaffold. Lastly, we showed that the VEGF released from the composite scaffold retained its capacity to stimulate endothelial cell growth. The incorporation of IPC fibers in the pullulan–dextran hydrogel scaffold improved its functionality and biological activity, thus enhancing its potential in tissue engineering applications.     

A facile fabrication of sepiolite mineral nanofibers with excellent adsorption performance for Cd2+ ions

In this work, sepiolite mineral nanofibers are facilely prepared by a microwave-hydrogen peroxide method, and the bulk densities of the samples are adopted to evaluate the defibering effect. The samples are systematically characterized through X-ray diffraction, scanning electron microscopy, specific surface area measurement and zeta potential determination, and the adsorptive performance for heavy metal ions in aqueous solution is studied using cadmium ions as the representative. It is found that the specific surface area and cumulative pore volume increase respectively up to 109.21 m² g⁻¹ and 0.234 cm³ g⁻¹ under the microwave power of 400 W, while the zeta potential reaches a maximum when the pH is 5.0. The adsorption efficiency of sepiolite mineral nanofibers for cadmium ions can reach 68.6% as the optimal value. The as-fabricated sepiolite nanofibers can be regarded as a low-cost and environmentally friendly material which is a promising candidate for heavy metal ion removal from industrial wastewater.

In this work, sepiolite mineral nanofibers are facilely prepared by a microwave-hydrogen peroxide method, and the bulk densities of the samples are adopted to evaluate the defibering effect.     

Exercise preconditioning-induced late phase of cardioprotection against exhaustive exercise: possible role of protein kinase C delta

The objective of this study was to investigate the late cardiac effect of exercise preconditioning (EP) on the exhaustive exercise-induced myocardial injury in rats and the role of protein kinase C (PKC) in EP. Rats were subjected to a run on the treadmill for four periods of 10 min each at 30 m/min with intervening periods of rest of 10 min as an EP protocol. The exhaustive exercise was performed 24 h after EP. PKC inhibitor chelerythrine (CHE) was injected before EP. The results showed that EP increased the running ability of rats, and alleviated the exhaustive exercise-induced injury in cardiomyocytes, but pretreatment with PKC inhibitor CHE did not abolish the late phase cardioprotection of EP. A significant increase of PKCδ, both at the protein level and the mRNA level in the left ventricular myocardium of rats, accompanied by its activated form (phosphorylated on Thr507, p-PKCδ^Thr507) translocated to intercalated disks and was found in the late phase of EP. This circumstance was not attenuated by CHE. These results suggested that a high level of PKCδ might be involved in cardioprotection against myocardial damage, but if activated PKCδ at reperfusion took on a key role in cardioprotection was still an outstanding question.