Sprayable chitosan nanogel with nitric oxide to accelerate diabetic wound healing through bacteria inhibition, biofilm eradication and macrophage polarization.

Bacterial infection and chronic inflammation are two major risks in diabetic wound healing, which increase patient mortality. In this study, a multifunctional sprayable nanogel (Ag-G@CS) based on chitosan has been developed to synergistically inhibit bacterial infection, eradicate biofilm, and relieve inflammation of diabetic wounds. The nanogel is successfully crafted by encapsulating with a nitric oxide (NO) donor and performing in-situ reduction of silver nanoparticles (Ag). The released NO enhances the antibacterial efficacy of Ag, nearly achieving complete eradication of biofilms in vitro. Upon application on both normal or diabetic chronic wounds, the combination effects of released NO and Ag offer a notable antibacterial effect. Furthermore, after bacteria inhibition and biofilm eradication, the NO released by the nanogel orchestrates a transformation of M1 macrophages into M2 macrophages, significantly reducing tumor necrosis factor α (TNF-α) release and relieving inflammation. Remarkably, the released NO also promotes M2a to M2c macrophages, thereby facilitating tissue remodeling in chronic wounds. More importantly, it upregulates the expression of vascular endothelial growth factor (VEGF), further accelerating the wound healing process. Collectively, the formed sprayable nanogel exhibits excellent inhibition of bacterial infections and biofilms, and promotes chronic wound healing via inflammation resolution, which has excellent potential for clinical use in the future.

An unusual case of acquired angioedema associated with monoclonal gammopathies of uncertain significance.

Acquired angioedema (AAE) is a rare disease due to the C1 esterase inhibitor (C1-INH) deficiency. Clinically, its symptoms are similar to hereditary angioedema (HAE) with hereditary C1-INH deficiency. Both conditions have the potential to cause upper airway obstruction, which can be fatal in clinical practice and thus require intense attention. Here, we'd like to discuss the clinical presentation, diagnosis and follow up of a special case of AAE associated with monoclonal gammopathies of unknown significance (MGUS) with recurrent upper airway obstruction. The patient was regularly followed up after being discharged from our ward. Measurements of C3-C4 levels were carried out by a hematological test. Due to the rarity of such a disease, especially in Chinese people, relevant diagnosis methods are missing in this patient, so the patient was only diagnosed with AAE-C1-INH associated with MGUS clinically. The latest follow up showed that he still underwent recurrent upper airway obstruction; thus, he remained in a tracheostomy state due to a lack of proper medication prophylaxis and died eventually. This unusual case reminds emergency physicians to pay attention to such disease during clinical practice, and relevant diagnosis method should be improved.

Outcome of anticoagulation with rivaroxaban in patients with non-retrieved inferior vena cava filters for the prevention of filter thrombosis: a retrospective cohort study.

BACKGROUND: Non-retrieved inferior vena cava filter (IVCF) is associated with some severe complications, such as filter thrombosis. The aim of this retrospective cohort study was to evaluate the outcome of rivaroxaban for the prevention of filter thrombosis in patients with non-retrieved IVCF. METHODS: The study based on the VTE registry databases was limited to patients with non-retrieved IVCF treated at Nanjing Drum Tower Hospital from January 2012 to December 2017. Outcomes included filter thrombosis, total bleeding events, death. RESULTS: A total of 202 patients were enrolled in the study and divided into rivaroxaban group and warfarin group. Mean follow-up period of the two groups was 57.4 ± 20.8 and 62.2 ± 23.0 months, respectively. In risk factors for VTE, transient factors (P = 0.008) and history of VTE (P = 0.028) were statistically different between the two groups. A total of 13 (6.4%) patients developed filter complications, of which 4 (3.5%) and 5 (5.7%) patients in rivaroxaban group and warfarin group developed filter thrombosis, respectively, without significant difference (P = 0.690). The total bleeding events in rivaroxaban group, including major bleeding and clinically relevant and non-major (CRNM) bleeding, were significantly lower than that in warfarin group (P = 0.005). Adjusting for hypertension, transient risk factors, history of VTE and cancer, no differences in the hazard ratio for outcomes were notable. CONCLUSIONS: It is necessary to perform a concomitant anticoagulation in patients with non-retrieved filters. Rivaroxaban can be an alternative anticoagulant option for the prevention of filter thrombosis.

Unfolded protein response-induced expression of long noncoding RNA Ngrl1 supports peripheral axon regeneration by activating the PI3K-Akt pathway.

In mammals, long noncoding RNA (LncRNA) contributes to neuronal development and injury repair mediated by the spatiotemporal regulation of gene expression. However, the pivotal role of lncRNA in intrinsic axon regeneration control following a nerve injury remains unknown. In this article, we report a neurite growth-related lncRNA termed Ngrl1, which supported peripheral axon regeneration post sciatic nerve crush (SNC). A rapid increase in Ngrl1 expression was detected following SNC, and knockdown of Ngrl1 impaired axon regeneration both in vitro and in vivo. The unfolded protein response (i.e., the upstream modulator of Ngrl1 expression) improved the impairment of neurite growth induced by Ngrl1 inhibition in matured dorsal root ganglion neurons. Meanwhile, interference with Ngrl1 impacts the PI3K-Akt pathway, leading to a marked decrease in Akt phosphorylation. Furthermore, the activation of Akt by insulin-like growth factor 1 (IGF-1) or SC79 reversed the reduction of axon regeneration in dorsal root ganglion neuron following inhibition of Ngrl1. In conclusion, unfolded protein response-induced Ngrl1 expression supports the intrinsic control of peripheral axon regeneration by modulating the activation of the PI3K-Akt pathway following SNC.

USP9X controls translation efficiency via deubiquitination of eukaryotic translation initiation factor 4A1.

Controlling translation initiation is an efficient way to regulate gene expression at the post-transcriptional level. However, current knowledge regarding regulatory proteins and their modes of controlling translation initiation is still limited. In this study, we employed tandem affinity purification and mass spectrometry to screen for unknown proteins associated with the translation initiation machinery. Ubiquitin specific peptidase 9, X-linked (USP9X), was identified as a novel binding partner, that interacts with the eukaryotic translation initiation factor 4B (eIF4B) in a mRNA-independent manner. USP9X-deficient cells presented significantly impaired nascent protein synthesis, cap-dependent translation initiation and cellular proliferation. USP9X can selectively alter the translation of pro-oncogenic mRNAs, such as c-Myc and XIAP. Moreover, we found that eIF4A1, which is primarily ubiquitinated at Lys-369, is the substrate of USP9X. USP9X dysfunction increases the ubiquitination of eIF4A1 and enhances its degradation. Our results provide evidence that USP9X is a novel regulator of the translation initiation process via deubiquitination of eIF4A1, which offers new insight in understanding the pivotal role of USP9X in human malignancies and neurodevelopmental disorders.

Perfluorocarbon nanoparticles enhance reactive oxygen levels and tumour growth inhibition in photodynamic therapy.

Photodynamic therapy (PDT) kills cancer cells by converting tumour oxygen into reactive singlet oxygen ((1)O2) using a photosensitizer. However, pre-existing hypoxia in tumours and oxygen consumption during PDT can result in an inadequate oxygen supply, which in turn hampers photodynamic efficacy. Here to overcome this problem, we create oxygen self-enriching photodynamic therapy (Oxy-PDT) by loading a photosensitizer into perfluorocarbon nanodroplets. Because of the higher oxygen capacity and longer (1)O2 lifetime of perfluorocarbon, the photodynamic effect of the loaded photosensitizer is significantly enhanced, as demonstrated by the accelerated generation of (1)O2 and elevated cytotoxicity. Following direct injection into tumours, in vivo studies reveal tumour growth inhibition in the Oxy-PDT-treated mice. In addition, a single-dose intravenous injection of Oxy-PDT into tumour-bearing mice significantly inhibits tumour growth, whereas traditional PDT has no effect. Oxy-PDT may enable the enhancement of existing clinical PDT and future PDT design.

A gating mechanism for Pi release governs the mRNA unwinding by eIF4AI during translation initiation.

Eukaryotic translation initiation factor eIF4AI, the founding member of DEAD-box helicases, undergoes ATP hydrolysis-coupled conformational changes to unwind mRNA secondary structures during translation initiation. However, the mechanism of its coupled enzymatic activities remains unclear. Here we report that a gating mechanism for Pi release controlled by the inter-domain linker of eIF4AI regulates the coupling between ATP hydrolysis and RNA unwinding. Molecular dynamic simulations and experimental results revealed that, through forming a hydrophobic core with the conserved SAT motif of the N-terminal domain and I357 from the C-terminal domain, the linker gated the release of Pi from the hydrolysis site, which avoided futile hydrolysis cycles of eIF4AI. Further mutagenesis studies suggested this linker also plays an auto-inhibitory role in the enzymatic activity of eIF4AI, which may be essential for its function during translation initiation. Overall, our results reveal a novel regulatory mechanism that controls eIF4AI-mediated mRNA unwinding and can guide further mechanistic studies on other DEAD-box helicases.

A new small-molecule Aurora B inhibitor shows antitumor activity in human cancer cell lines.

The Aurora kinase family, as a group of serine/threonine kinases regulating cell cycles, are frequently overexpressed or amplified in human tumors. Here, we showed that the small molecule S4 could inhibit Aurora kinase in both of biochemincal and cell-based levels. The Aurora B inhibition of S4 treatment inhibited the phosphorylation of Histone H3 at serine 10 in HeLa and SMMC7721 cells. Cell proliferation assay showed that inhibition of Aurora kinase led to reduced cancer cell growth. As assessed in colony formation experiment, S4 blocked the capability of the HeLa cells to develop colonies. Subsequently, S4 treatment blocked the mitotic G2/M-G1 phase progression which is characterized by the accumulations of cells with 4 N DNA content, induced a cell cycle arrest in a pseudo G1 phase and resulted in apoptotic cell death in a dose- and time-dependent manners. Taken together, this Aurora kinase inhibitor S4 induces growth inhibition of cancer cell line.

Hydrophobic IR780 encapsulated in biodegradable human serum albumin nanoparticles for photothermal and photodynamic therapy.

It has been reported that IR780 iodide, a near-infrared dye, can be applied for cancer imaging, photodynamic therapy (PDT) and photothermal therapy (PTT). However, the hydrophobicity and toxicity of IR780 severely limit its further clinical applications. In this study, human serum albumin was used to load IR780 to form nanoparticles (HSA-IR780 NPs) by protein self-assembly. Compared to free IR-780, the solubility of HSA-IR780 NPs was greatly increased (1000-fold) while the toxicity was decreased (from 2.5 mg kg(-1) to 25 mg kg(-1)). Moreover, both PTT and PDT could be observed in HSA-IR780 NPs, as determined by increased temperature and enhanced generation of singlet oxygen after laser irradiation at a wavelength of 808 nm. In vivo studies also showed a great tumor inhibition by the injection of HSA-IR780 NPs into tumor-bearing mice. Therefore, HSA-IR780 NPs may serve as a promising substitute for IR780 in further clinical PDT and PTT.

Nucleolin targeting AS1411 modified protein nanoparticle for antitumor drugs delivery.

Over recent years, cell surface nucleolin as an anticancer target has attracted many researchers' attentions. To improve the antitumor efficacy, we developed a nucleolin targeted protein nanoparticle (NTPN) delivery system in which human serum albumin (HSA) was used as drug carrier and a DNA aptamer named AS1411, which had high affinity to nucleolin, was used as a bullet. The HSA nanoparticles (NPs-PTX) were fabricated by a novel self-assembly method and then modified with AS1411 (Apt-NPs-PTX). The resulted Apt-NPs-PTX were spherical. Compared with NPs-PTX, the uptake of Apt-NPs-PTX displayed a significant increase in MCF-7 cells while there was a decrease in nontumor cell lines such as MCF-10A and 3T3 cells. In a cytotoxic study, Apt-NPs-PTX displayed an enhanced cytotoxicity in MCF-7 tumor cells while there was almost no cytotoxicity in MCF-10A cells. Endostatin, a nucleolin inhibitor, could significantly decrease the internalization of Apt-NPs-PTX, suggesting nucleolin mediates the transmembrane process of Apt-NPs-PTX. Therefore, the AS1411 modified NTPN delivery system might be a promising targeted drug delivery system.