Retraction: Astragaloside IV (AS-IV) alleviates the malignant biological behavior of hepatocellular carcinoma via Wnt/ß-catenin signaling pathway.

[This retracts the article DOI: 10.1039/C9RA05933D.].

Preparation of nano-MFI zeolites doped with Al/Ti and their performance in VOC sorption.

Highly crystalline nano-MFI-type zeolites containing different elements were synthesized, and the sorption effects of the elements on volatile organic compounds (VOCs) were investigated. The results showed that the optimal toluene and acetone breakthrough time of the synthesized zeolites was 2.1 and 1.9 times as long as that of the commercial zeolite, respectively. For a weakly polar toluene molecule, MFI zeolites (aluminum-free) showed better adsorption properties than aluminum-containing zeolites. For the highly polar acetone molecule, zeolites with a Si/Al ratio of 87 showed the highest adsorption capacity, which was 7% higher than that of the all-silica zeolite and 1.4 times that of the commercial zeolite. Furthermore, MFI zeolites with Ti replacing part of Al proved to have better performance for highly polar molecules. In the adsorption process of VOCs, in addition to internal diffusion, diffusion on the external surface of the zeolite also played a remarkable role, and the adsorption data of all samples fitted better with the pseudo-first-order model. This study may provide a reliable structure-performance relationship for the synthesis of nanosized zeolite-based adsorbents and their use in the industrial recovery/treatment of VOCs.

Development of a DNA aptamer targeting IDO1 with anti-tumor effects.

Immune checkpoint blockade has become an effective approach to reverse the immune tolerance of tumor cells. Indoleamine 2,3-dioxygenase 1 (IDO1) is frequently upregulated in many types of cancers and contributes to the establishment of an immunosuppressive cancer microenvironment, which has been thought to be a potential target for cancer therapy. However, the development of IDO1 inhibitors for clinical application is still limited. Here, we isolated a DNA aptamer with a strong affinity and inhibitory activity against IDO1, designated as IDO-APT. By conjugating with nanoparticles, in situ injection of IDO-APT to CT26 tumor-bearing mice significantly suppresses the activity of regulatory T cells and promotes the function of CD8+ T cells, leading to tumor suppression and prolonged survival. Therefore, this functional IDO1-specific aptamer with potent anti-tumor effects may serve as a potential therapeutic strategy in cancer immunotherapy. Our data provide an alternative way to target IDO1 in addition to small molecule inhibitors.

Development of a modularized aptamer targeting the nuclear T-cell suppressor PAC1.

Aptamers associated with cancer targeting therapy are commonly focused on cell membrane proteins; however, the study of intracellular, particularly, nuclear proteins is limited. The nuclear phosphatase PAC1 has been reported to be a potential T cell-related immunotherapeutic target. Here, we identified an aptamer, designated as PA5, with high affinity and specificity for PAC1 through the systematic evolution of ligands by exponential enrichment (SELEX) procedure. We then developed a dual-module aptamer PAC1-AS consisting of a cell-internalizing module and a targeting module, which can recognize PAC1 in the nucleus under physiological conditions. This modularized aptamer raises the possibility of manipulating endosomes and provides insights into the exploration and development of an efficient cancer immunotherapy approach.

Acidity-Triggered Transformable Polypeptide Self-Assembly to Initiate Tumor-Specific Biomineralization.

Biomineralization is a normal physiological process that includes nucleation, crystal growth, phase transformation, and orientation evolution. Notably, artificially induced biomineralization in the tumor tissue has emerged as an unconventional yet promising modality for malignancy therapy. However, the modest ion-chelating capabilities of carboxyl-containing biomineralization initiators lead to a deficient blockade, thus compromising antitumor efficacy. Herein, a biomineralization-inducing nanoparticle (BINP) is developed for blockade therapy of osteosarcoma. BINP is composed of dodecylamine-poly((γ-dodecyl-l-glutamate)-co-(l-histidine))-block-poly(l-glutamate-graft-alendronate) and combines a cytomembrane-insertion moiety, a tumor-microenvironment (TME)-responsive component, and an ion-chelating motif. After intravenous injection into osteosarcoma-bearing mice, BINP responds to the acidic TME to expose the dodecyl group on the surface of the expanded nanoparticles, facilitating their cytomembrane insertion. Subsequently, the protruding bisphosphonic acid group triggers continuous ion deposition to construct a mineralized barrier around the tumor, which blocks substance exchange between the tumor and surrounding normal tissues. The BINP-mediated blockade therapy displays tumor inhibition rates of 59.3% and 52.1% for subcutaneous and orthotopic osteosarcomas, respectively, compared with the Control group. In addition, the suppression of osteoclasts by the alendronate moiety alleviates bone dissolution and further inhibits pulmonary metastases. Hence, the BINP-initiated selective biomineralization provides a promising alternative for clinical osteosarcoma therapy.

Acetaldehyde Induces Cytotoxicity via Triggering Mitochondrial Dysfunction and Overactive Mitophagy.

Overconsumption of alcohol damages brain tissue and causes cognitive dysfunction. It has been suggested that the neurotoxicity caused by excessive alcohol consumption is largely mediated by acetaldehyde, the most toxic metabolite of ethanol. Evidence shows that acetaldehyde impairs mitochondrial function and induces cytotoxicity of neuronal cells; however, the exact mechanisms are not fully understood. The aim of this study was to investigate the role of mitophagy in acetaldehyde-induced cytotoxicity. It was found that acetaldehyde treatment induced mitophagic responses and caused cytotoxicity in SH-SY5Y cells. The levels of light chain 3 (LC3)-II, Beclin1, autophagy-related protein (Atg) 5 and Atg16L1, PTEN-induced putative kinase (PINK)1, and Parkin were significantly elevated, while the level of p62 was reduced in acetaldehyde-treated cells. Acetaldehyde also promoted the accumulation of PINK1 and Parkin on mitochondria and caused a remarkable decrease of mitochondrial mass. Treatment with autophagy inhibitors prevented the decline of mitochondrial mass and alleviated the cytotoxicity induced by acetaldehyde, suggesting that overactive mitophagy might be an important mechanism contributing to acetaldehyde-induced cytotoxicity. Antioxidant N-acetyl-L-cysteine significantly attenuated the mitophagic responses and alleviated the cytotoxicity induced by acetaldehyde, indicating that oxidative stress was a major mediator of the excessive mitophagy induced by acetaldehyde. Taken together, these findings provided new insights into the role of mitophagy and oxidative stress in acetaldehyde-induced cytotoxicity.

Versatile Polymer-Initiating Biomineralization for Tumor Blockade Therapy.

Tumor blockade therapy is a promising penetration-independent antitumor modality, which effectively inhibits the exchange of nutrients, oxygen, and information between the tumor and surrounding microenvironments. However, the current blockade therapy strategies have limited antitumor efficacy due to defects of inadequate tumor obstruction, possible side effects, and short duration. For these reasons, a facilely synthesized versatile polymer 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-poly(ethylene glycol)-alendronate (DSPE-PEG-ALN, DPA) is developed to initiate the formation of biomineral shell around osteosarcoma as a potent physical barrier. The DSPE moiety shares a similar chemical structure with the cytomembrane, allowing the membrane insertion of DPA. The bisphosphonic acid groups in ALN attract ions to realize biomineralization around cells. After injection in the invasive osteosarcoma tissue, DPA inserts into the cytomembrane, induces continuous mineral deposition, and ultimately builds a physical barrier around the tumor. Meanwhile, ALN in DPA alleviates bone destruction by suppressing the activity of osteoclasts. Through hindering the exchange of necessary substances, the biomineralization coating inhibits the growth of primary osteosarcoma and pulmonary metastasis simultaneously. Therefore, the multifunctional polymer-initiating blockade therapy provides a promising modality for tumor inhibition in clinics with high efficacy and negligible side effects.

miR-133b inhibits cell proliferation, migration, and invasion of lung adenocarcinoma by targeting CDCA8.

OBJECTIVE: Lung adenocarcinoma (LUAD) is the most common type of lung cancer. This study aims to explore the mechanism by which CDCA8 regulates cell proliferation, invasion, and migration of LUAD, and to generate novel insights into targeted therapy of LUAD. METHODS: Expression profiles of mature microRNAs (miRNAs) and mRNAs, along with clinical data of LUAD were downloaded from TCGA database for differential analysis and survival analysis to mine differentially expressed mRNAs. qRT-PCR was used to detect the expression of CDCA8 and miR-133b in LUAD cell lines, and western blot was used to detect protein expression. The effects of CDCA8 on the proliferation, migration, and invasion of LUAD cells were detected by CCK-8 assay, scratch healing assay, and Transwell assay. Bioinformatics predicted the target miRNA of CDCA8, and dual-luciferase reporter gene assay was used to verify the binding relationship between miR-133b and CDCA8. RESULTS: Data from TCGA-LUAD showed that CDCA8 was significantly overexpressed in LUAD tissue, while its upstream miRNA (miR-133b) was significantly lowly expressed. The result of dual-luciferase test showed that miR-133b targeted CDCA8. The results of in vitro functional experiments showed that overexpression of CDCA8 could promote the proliferation, invasion, and migration of LUAD cells, and miR-133b could reverse this promotion by targeting CDCA8. CONCLUSION: This study found that CDCA8 was a carcinogenic factor in LUAD cells and it was regulated by upstream miR-133b. miR-133b could inhibit proliferation, invasion, and migration of LUAD cells by targeting CDCA8.

A Multichannel Ca2+ Nanomodulator for Multilevel Mitochondrial Destruction-Mediated Cancer Therapy.

Subcellular organelle-targeted nanoformulations for cancer theranostics are receiving increasing attention owing to their benefits of precise drug delivery, maximized therapeutic index, and reduced off-target side effects. Herein, a multichannel calcium ion (Ca2+ ) nanomodulator (CaNMCUR+CDDP ), i.e., a cisplatin (CDDP) and curcumin (CUR) co-incorporating calcium carbonate (CaCO3 ) nanoparticle, is prepared by a facile one-pot strategy in a sealed container with in situ synthesized polydopamine (PDA) as a template to enhance Ca2+ -overload-induced mitochondrial dysfunction in cancer therapy. After systemic administration, the PEGylated CaNMCUR+CDDP (PEG CaNMCUR+CDDP ) selectively accumulates in tumor tissues, enters tumor cells, and induces multilevel destruction of mitochondria by the combined effects of burst Ca2+ release, Ca2+ efflux inhibition by CUR, and chemotherapeutic CDDP, thereby observably boosting mitochondria-targeted tumor inhibition. Fluorescence imaging of CUR combined with photoacoustic imaging of PDA facilitates the visualization of the nanomodulator. The facile and practical design of this multichannel Ca2+ nanomodulator will contribute to the development of multimodal bioimaging-guided organelle-targeted cancer therapy in the future.

Poly(l-glutamic acid)-cisplatin nanoformulations with detachable PEGylation for prolonged circulation half-life and enhanced cell internalization.

PEGylation has been widely applied to prolong the circulation times of nanomedicines via the steric shielding effect, which consequently improves the intratumoral accumulation. However, cell uptake of PEGylated nanoformulations is always blocked by the steric repulsion of PEG, which limits their therapeutic effect. To this end, we designed and prepared two kinds of poly(l-glutamic acid)-cisplatin (PLG-CDDP) nanoformulations with detachable PEG, which is responsive to specific tumor tissue microenvironments for prolonged circulation time and enhanced cell internalization. The extracellular pH (pHe)-responsive cleavage 2-propionic-3-methylmaleic anhydride (CDM)-derived amide bond and matrix metalloproteinases-2/9 (MMP-2/9)-sensitive degradable peptide PLGLAG were utilized to link PLG and PEG, yielding pHe-responsive PEG-pH e-PLG and MMP-sensitive PEG-MMP-PLG. The corresponding smart nanoformulations PEG-pH e-PLG-Pt and PEG-MMP-PLG-Pt were then prepared by the complexation of polypeptides and cisplatin (CDDP). The circulation half-lives of PEG-pH e-PLG-Pt and PEG-MMP-PLG-Pt were about 4.6 and 4.2 times higher than that of the control PLG-Pt, respectively. Upon reaching tumor tissue, PEG on the surface of nanomedicines was detached as triggered by pHe or MMP, which increased intratumoral CDDP retention, enhanced cell uptake, and improved antitumor efficacy toward a fatal high-grade serous ovarian cancer (HGSOC) mouse model, indicating the promising prospects for clinical application of detachable PEGylated nanoformulations.

The mechanism for brassinosteroids suppressing climacteric fruit ripening.

The plant hormone ethylene is important for the ripening of climacteric fruit, such as pear (Pyrus ussuriensis), and the brassinosteroid (BR) class of phytohormones affects ethylene biosynthesis during ripening via an unknown molecular mechanism. Here, we observed that exogenous BR treatment suppressed ethylene production and delayed fruit ripening, whereas treatment with a BR biosynthesis inhibitor promoted ethylene production and accelerated fruit ripening in pear, suggesting BR is a ripening suppressor. The expression of the transcription factor BRASSINAZOLE-RESISTANT 1PuBZR1 was enhanced by BR treatment during pear fruit ripening. PuBZR1 interacted with PuACO1, which converts 1-aminocyclopropane-1-carboxylic acid (ACC) to ethylene, and suppressed its activity. BR-activated PuBZR1 bound to the promoters of PuACO1 and of PuACS1a, which encodes ACC synthase, and directly suppressed their transcription. Moreover, PuBZR1 suppressed the expression of transcription factor PuERF2 by binding its promoter, and PuERF2 bound to the promoters of PuACO1 and PuACS1a. We concluded that PuBZR1 indirectly suppresses the transcription of PuACO1 and PuACS1a through its regulation of PuERF2. Ethylene production and expression profiles of corresponding apple (Malus domestica) homologs showed similar changes following epibrassinolide treatment. Together, these results suggest that BR-activated BZR1 suppresses ACO1 activity and the expression of ACO1 and ACS1, thereby reducing ethylene production and suppressing fruit ripening. This likely represents a conserved mechanism by which BR suppresses ethylene biosynthesis during climacteric fruit ripening.

Ultrasound-Augmented Mitochondrial Calcium Ion Overload by Calcium Nanomodulator to Induce Immunogenic Cell Death.

Immunogenic cell death (ICD), a manner of tumor cell death that can trigger antitumor immune responses, has received extensive attention as a potential synergistic modality for cancer immunotherapy. Although many calcium ion (Ca2+) nanomodulators have been developed for cancer therapy through mitochondrial Ca2+ overload, their ICD-inducing properties have not been explored. Herein, an acid-sensitive PEG-decorated calcium carbonate (CaCO3) nanoparticle incorporating curcumin (CUR; a Ca2+ enhancer) (PEGCaCUR) was prepared using a simple one-pot strategy. PEGCaCUR served as not only a Ca2+ nanomodulator inducing efficient mitochondrial Ca2+ overload but also an ICD inducer during improved synergistic cancer therapy. Combination of PEGCaCUR with ultrasound (US), PEGCaCUR+US, led to an enhanced ICD effect attributable to the enhanced mitochondrial Ca2+ overload, along with subsequent upregulation of reactive oxygen species levels. PEGCaCUR also facilitates photoacoustic/fluorescence dual-mode imaging, as well as effectively suppressing tumor growth and metastasis, indicating promising theranostic properties.

Spatiotemporally Targeted Nanomedicine Overcomes Hypoxia-Induced Drug Resistance of Tumor Cells after Disrupting Neovasculature.

Vascular disrupting agents (VDAs) are emerging anticancer agents, which show rising demand for combination with cytostatic drugs (CSDs), owing to inadequate tumor inhibition when applied singly. Nevertheless, the combination remains a challenge due to the different working sites of VDAs and CSDs and hypoxia-induced drug resistance after disrupting neovasculature by VDAs. Herein, we developed a shell-stacked nanoparticle (SNP) for coencapsulation of a VDA combretastatin A-4 phosphate (CA4P) and a proteasome inhibitor bortezomib (BTZ). The SNP could spatiotemporally deliver CA4P to tumor neovasculature and BTZ to tumor cells mediated by the site-specific stimuli-activated drug release. Moreover, the SNP also reversed the drug resistance caused by the overexpressed ABCG2 under CA4P-induced hypoxic conditions. The spatiotemporally targeted combination therapy significantly inhibited the growth of both the human A549 pulmonary adenocarcinoma xenograft model and patient-derived xenograft (PDX) model of colon cancer in mice, providing a promising strategy for treating advanced cancers.

Polymer-Mediated Penetration-Independent Cancer Therapy.

The development of polymer-based drug delivery systems provides efficient modalities for cancer therapy. Most of the polymer pharmaceuticals target cancer cells directly, but the insufficient penetration always results in unsatisfactory anticancer efficacy. To break the above bottleneck, strategies of penetration-independent cancer therapy have been developed as advanced treatments for various cancers in the past decade. In this Perspective, we discussed the pros and cons of polymer-mediated biological and physical penetration-independent approaches for cancer therapy and highlighted their further prospects from bench to bedsides.

PEGylated Polyurea Bearing Hindered Urea Bond for Drug Delivery.

In recent years, polyureas with dynamic hindered urea bonds (HUBs), a class of promising biomedical polymers, have attracted wide attention as a result of their controlled hydrolytic properties. The effect of the chemical structures on the properties of polyureas and their assemblies has rarely been reported. In this study, four kinds of polyureas with different chemical groups have been synthesized, and the polyureas from cyclohexyl diisocyanate and tert-butyl diamine showed the fastest hydrolytic rate. The amphiphilic polyurea composed of hydrophobic cyclohexyl-tert-butyl polyurea and hydrophilic poly(ethylene glycol) (PEG) was synthesized for the controlled delivery of the antitumor drug paclitaxel (PTX). The PTX-loaded PEGylated polyurea micelle more effectively entered into the murine breast cancer 4T1 cells and inhibited the corresponding tumor growth in vitro and in vivo. Therefore, the PEGylated polyurea with adjustable degradation might be a promising polymer matrix for drug delivery.

Chiral Polypeptide Thermogels Induce Controlled Inflammatory Response as Potential Immunoadjuvants.

The in vivo implanted biomaterials are known to induce inflammatory response and recruit immune cells, which could be used as robust adjuvants for immunotherapy. However, the degree of inflammatory response induced by the implanted biomaterials is hard to control. In this work, we reported the application of three kinds of thermogels from the polypeptide methoxy poly(ethylene glycol)-polyalanine (mPEG-PAla) with various chiralities to regulate the levels of inflammatory responses in vivo. The mPEG-PLAla (EG45LA28) and mPEG-PDAal (EG45DA27) thermogels exhibited comparable storage modulus ( G') and loss modulus ( G″), both of which were about two times higher than the values of the racemic mPEG-PAla (EG45RA) thermogel. The component d-alanine in the polypeptide thermogels led to controlled tissue inflammation after subcutaneous injection, and the content of d-alanine could adjust the level of inflammation. The expression of tumor necrosis factor (TNF-α), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6) in subcutaneous tissue around the injected thermogel EG45DA27 were 3.62, 1.52, and 4.55 times the levels of those after EG45RA thermogel injection and 4.52, 7.38, and 7.96 times the levels of those after EG45LA28 injection, respectively. The results indicated that the chiral polypeptide thermogels could induce a controllable inflammatory response in vivo and exhibit great potential as an efficient adjuvant for immunotherapy.

Astragaloside IV (AS-IV) alleviates the malignant biological behavior of hepatocellular carcinoma via Wnt/ß-catenin signaling pathway.

Astragaloside IV (AS-IV) is an active substance isolated from Astragalus membranaceus (Fisch.) Bungede, which has been shown to have pharmacological effects in a variety of cancers. However, the effects of AS-IV in hepatocellular carcinoma (HCC) and its related mechanisms have been poorly understood. In this study, we explored the roles of AS-IV on HCC and the underlying signaling pathway. We reported that the appropriate concentrations of AS-IV (25, 50, 100 nmol l-1) significantly suppressed the proliferation and cell cycle of HepG2 and Hep3B cell lines whilst promoting apoptosis. Besides, a trans-well and wound healing assay showed that AS-IV could markedly inhibit the migration and invasion of HepG2 and Hep3B cells, the expression of E-cadherin was up-regulation but the expression of N-cadherin and vimentin was down-regulation, and the protein levels of cleaved-caspase-3, 9 were increased markedly compared with the corresponding control. Furthermore, animal model treatment revealed that AS-IV could effectively reduce tumor formation. Moreover, AS-IV also significantly weakened the expression of Wnt, ß-catenin and TCF-4 in vitro and in vivo. Taken together, these results suggested that AS-IV inhibited the biological processes of HCC via regulating of the Wnt/ß-catenin pathway.

ctDNA assessment of EGFR mutation status in Chinese patients with advanced non-small cell lung cancer in real-world setting.

BACKGROUND: The prevalence of EGFR mutations in circulating free tumor-derived DNA (ctDNA) was still unknown in China. This large-scale study (NCT02623257) aimed to explore the prevalence of epidermal growth factor receptor (EGFR) mutations and determine the correlation of EGFR mutation status with clinical characteristics. METHODS: Plasma DNA samples from 1,001 patients with stage III/IV NSCLC who received ≤1st line chemotherapy were collected from 65 hospitals. EGFR mutations were tested by amplification refractory mutation system (ARMS) method. The EGFR mutation rate was calculated and the associations between EGFR status and patients' demographic data, disease status as well as treatment pattern were explored. RESULTS: EGFR mutations were detected in 251 of 1,001 (25.1%) patients, 26.8% in adenocarcinoma and 11.7% in squamous carcinoma. A total of 189 harbored sensitizing mutations alone, 28 had resistance mutations alone, 3 had a combination of activating mutations, and 31 had a combination of activating and resistance mutations. Higher detection rate was observed in chemotherapy-naïve patients than those received 1st line chemotherapy (27.0% vs. 18.0%; P=0.006). Of which, the mutation rate of exon 19 deletion was 9.31% for naïve patients and 7.37% for the 1st chemotherapy patients; while the mutation rate of L858R decreased obviously from 10.20% (naïve) to 3.69% (1st line). We also noticed the mutation rate was 37.1% in patients with ≥2 organ metastases. Multivariate analysis showed female, chemotherapy-naïve, or ≥2 metastatic organs patients had higher EGFR mutation rate. CONCLUSIONS: ctDNA based EGFR mutation test is feasible and could be a surrogate when tissue biopsy is not available.

Depth Super-resolution from RGB-D Pairs with Transform and Spatial Domain Regularization.

This paper proposes a depth super-resolution method with both transform and spatial domain regularization. In the transform domain regularization, nonlocal correlations are exploited via an auto-regressive model, where each patch is further sparsified with a locally-trained transform to consider intra-patch correlations. In the spatial domain regularization, we propose a multi-directional total variation (MTV) prior to characterize the geometrical structures spatially orientated at arbitrary directions in depth maps. To achieve adaptive regularization, the MTV is weighted for each directional finite difference considering local characteristics of RGB-D data. We develop an accelerated proximal gradient algorithm to solve the proposed model. Quantitative and qualitative evaluations compared with state-of-the-art methods demonstrate that the proposed method achieves superior depth super-resolution performance for various configurations of magnification factors and datasets.

PEGylated stereocomplex polylactide coating of stent for upregulated biocompatibility and drug storage.

Treatment of coronary heart disease by percutaneous coronary intervention (PCT) is usually limited to the high restenosis rate after implantation of bare-metal stent. To solve the problem, the coating of PEGylated stereocomplex poly(l-lactide) (PEG-cPLA) was utilized on the surface modification of stainless steel (SS) sheet. Specifically, the 3-aminopropyltriethoxysilane (APTES)-modified methoxy-poly(ethylene glycol)-poly(d-lactide) (mPEG-PDLA) was grafted onto the surface of hydroxylated SS sheet through coupling reaction, and poly(l-lactide)-poly(ethylene glycol)-poly(l-lactide) (PLLA-PEG-PLLA) was coated onto the surface through stereocomplex interaction between DLA and LLA units. The increase of contact angle firstly confirmed the changes of surface composition and hydrophilicity for the PEG-scPLA-modified SS sheet. The decreased fibrinogen adsorption, down-regulated platelet activation, and improved adhesion of human umbilical vein endothelial cells (HUVECs) indicated the excellent biocompatibility of PEG-scPLA-modified SS sheet. In addition, the drug loading capability of SS sheet was greatly upregulated through the formation of scPLA coating on the surface, where fluorescein (FLU) was chosen as a model molecule. Overall, the surface modification of SS sheet with PEG-scPLA could enhance the comprehensive performances, such as biocompatibility and drug loading capability, demonstrating that PEG-scPLA is a promising coating of coronary stent for PCT.