BackgroundBone morphogenic proteins (BMPs) play a key role in bone formation. Consequently, it was expected that topical application of recombinant human (rh)BMP-2 and rhBMP-7 would improve the healing of complex fractures. However, up to 36% of fracture patients do not respond to this therapy. There are hints that a systemic increase in transforming growth factor β1 (TGFβ1) interferes with beneficial BMP effects. Therefore, in the present work we investigated the influence of rhTGFβ1 on rhBMP signaling in primary human osteoblasts, with the aim of more specifically delineating the underlying regulatory mechanisms.MethodsBMP signaling was detected by adenoviral Smad-binding-element-reporter assays. Gene expression was determined by reverse transcription polymerase chain reaction (RT-PCR) and confirmed at the protein level by western blot. Histone deacetylase (HDAC) activity was determined using a test kit. Data sets were compared by one-way analysis of variance.ResultsOur findings showed that Smad1/5/8-mediated rhBMP-2 and rhBMP-7 signaling is completely blocked by rhTGFβ1. We then investigated expression levels of genes involved in BMP signaling and regulation (for example, Smad1/5/8, TGFβ receptors type I and II, noggin, sclerostin, BMP and activin receptor membrane bound inhibitor (BAMBI), v-ski sarcoma viral oncogene homolog (Ski), Ski-related novel protein N (SnoN) and Smad ubiquitination regulatory factors (Smurfs)) and confirmed the expression of regulated genes at the protein level. Smad7 and SnoN were significantly induced by rhTGFβ1 treatment while expression of Smad1, Smad6, TGFβRII and activin receptor-like kinase 1 (Alk1) was reduced. Elevated SnoN expression was accompanied by increased HDAC activity. Addition of an HDAC inhibitor, namely valproic acid, fully abolished the inhibitory effect of rhTGFβ1 on rhBMP-2 and rhBMP-7 signaling.ConclusionsrhTGFβ1 effectively blocks rhBMP signaling in osteoblasts. As possible mechanism, we postulate an induction of SnoN that increases HDAC activity and thereby reduces the expression of factors required for efficient BMP signaling. Thus, inhibition of HDAC activity may support bone healing during rhBMP therapy in patients with elevated TGFβ serum levels.

Iridium(III) complexes are an important group of photosensitizers for photodynamic therapy (PDT). This work constructs a donor–acceptor–donor structure‐based iridium(III) complex (IrDAD) with high reactive oxygen species (ROS) generation efficiency, negligible dark toxicity, and synergistic PDT and photothermal therapy (PTT) effect under near‐infrared (NIR) stimulation. This complex self‐assembles into metallosupramolecular aggregates with a unique aggregation‐induced PDT behavior. Compared with conventional iridium(III) photosensitizers, IrDAD not only achieves NIR light deep tissue penetration but also shows highly efficient ROS and heat generation with ROS quantum yield of 14.6% and photothermal conversion efficiency of 27.5%. After conjugation with polyethylene glycol (PEG), IrDAD is formulated to a nanoparticulate system (IrDAD‐NPs) with good solubility. In cancer phototherapy, IrDAD‐NPs preferentially accumulate in tumor area and display a significant tumor inhibition in vivo, with 96% reduction in tumor volume, and even tumor elimination.

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hERG-G572S and -G584S are 2 pore domain mutations that involve the same change in sidechain but have very different in vitro phenotypes; G572S causes a dominant negative trafficking defect, whereas G584S is the first hERG missense mutation where the cause of disease can be exclusively attributed to enhanced inactivation. The G572S mutation is intrinsically more severe than the G584S mutation, consistent with the overall clinical presentation in the 2 small kindreds studied here. Further investigation, involving a larger number of cohorts, to test the hypothesis that in vitro phenotyping of the intrinsic severity of a given mutation will assist with risk stratification is therefore warranted.

In this paper, we have synthesized ZnCdSeS quantum dots (QDs)-gold nanoparticle (Au NPs) hybrids in aqueous solution via bi-functional linker mercaptoacetic acid (MPA). The absorption peaks of ZnCdSeS QDs and Au are both located at 520 nm. It is investigated that PL intensity of QD-Au hybrid can be affected by the amounts of Au and pH value of hybrid solution. The located surface plasmon resonance (LSPR) effect of QD-Au NPs has been demonstrated by increased fluorescence intensity. The phenomenon of fluorescence enhancement can be maximized under the optimized pH value of 8.5. LSPR-enhanced photoluminescence property of QD-Au hybrid will be beneficial for the potential applications in the area of biological imaging and detection.

Effective photosensitizers are of particular importance for the widespread clinical utilization of phototherapy. However, conventional photosensitizers are usually plagued by short-wavelength absorption, inadequate photostability, low reactive oxygen species (ROS) quantum yields, and aggregation-caused ROS quenching. Here, we report a near-infrared (NIR)-supramolecular photosensitizer (RuDA) via self-assembly of an organometallic Ru(II)-arene complex in aqueous solution. RuDA can generate singlet oxygen (1O2) only in aggregate state, showing distinct aggregation-induced 1O2 generation behavior due to the greatly increased singlet-triplet intersystem crossing process. Upon 808 nm laser irradiation, RuDA with excellent photostability displays efficient 1O2 and heat generation in a 1O2 quantum yield of 16.4% (FDA-approved indocyanine green: ΦΔ = 0.2%) together with high photothermal conversion efficiency of 24.2% (commercial gold nanorods: 21.0%, gold nanoshells: 13.0%). In addition, RuDA-NPs with good biocompatibility can be preferably accumulated at tumor sites, inducing significant tumor regression with a 95.2% tumor volume reduction in vivo during photodynamic therapy. This aggregation enhanced photodynamic therapy provides a strategy for the design of photosensitizers with promising photophysical and photochemical characteristics.

The ORCID identification number(s) for the author(s) of this article can be found under https://doi.org/10.1002/smll.202000363. Iridium(III) complexes are potent candidates for photodynamic therapy. However, their clinical usage is impeded by their poor water solubility, high dark toxicity, and negligible absorption in near-infrared region (NIR region). Here, it is proposed to solve these challenges by developing an iridium(III) complexe-based polymeric micelle system. This system is self-assembled using an iridium(III) complex-containing amphiphilic block polymer. The upconversion nanoparticles are included in the polymeric micelles to permit NIR excitation. Compared with the nonformulated iridium(III) complexes, under NIR stimulation, this polymeric micelle system exhibits higher 1 O 2 generation efficiency, negligible dark toxicity, excellent tumor-targeting ability, and synergistic phototherapy-chemotherapy effect both in vitro and in vivo. www.advancedsciencenews.com

Subtle ligand modifications on ruthenium arene complexes can lead to different mechanisms of action and result in significant changes in the anticancer efficacy. Herein, four novel dinuclear ruthenium(II) arene complexes were designed and prepared. In vitro tests indicated that complexes 1−3 displayed moderate antiproliferative activity against the tested cancer cells, while the cytotoxicity of complex 4 is superior or comparable to that of cisplatin. Further studies indicated that complexes 1−4 induce cell death through DNA interaction and a reactiveoxygen-species-mediated endoplasmic reticulum (ER) stress pathway, which is the first example of an organometallic ruthenium(II) arene complex to induce ER stress as well as DNA interaction. This kind of dinuclear ruthenium(II) arene complex has unique biological characteristics and is a promising model for new anticancer drug development.