Cyclodextrin-Confined Supramolecular Lanthanide Photoswitch.

The utilization of azobenzene-based photoisomerization cannot only control the morphology of supramolecular assemblies, but can also regulate many biological processes. However, the design of azobenzene-involved nanoconstructs with switchable photoluminescence remains challenging because of the light-quenching ability of azobenzene. Herein, an azobenzene-derived multicomponent nanosystem is reported and its function as a supramolecular lanthanide photoswitch is explored. The metal chelation between lanthanide ions (Ln3+  = Eu3+ and Tb3+ ) and 2,6-pyridinedicarboxylic acid is utilized as the light-emitting center but its inherent fluorescence emission is completely suppressed via the disordered motion of the adjoining azophenyl unit. Interestingly, the hydrophobic cavity of α-cyclodextrin can provide a confined microenvironment to immobilize the molecular conformation of trans-azobenzene, thus leading to the recovery of characteristic lanthanide luminescence both in aqueous solution and the hydrogel state. Also, the luminescence can be reversibly turned off when the cis-azobenzene is expelled from the cavity of α-cyclodextrin upon alternating light irradiation. This mutual cooperation arising from host-guest complexation and metal-ligand coordination confers the desired photoswitchable luminescence abilities on the commonly used azobenzenes, which may hold great promise in the creation of more advanced light-responsive smart materials.

Photooxidation-Driven Purely Organic Room-Temperature Phosphorescent Lysosome-Targeted Imaging.

The construction of host-guest-binding-induced phosphorescent supramolecular assemblies has become one of increasingly significant topics in biomaterial research. Herein, we demonstrate that the cucurbit[8]uril host can induce the anthracene-conjugated bromophenylpyridinium guest to form a linear supramolecular assembly, thus facilitating the enhancement of red fluorescence emission by the host-stabilized charge-transfer interactions. When the anthryl group is photo-oxidized to anthraquinone, the obtained linear nanoconstructs can be readily converted into the homoternary inclusion complex, accompanied by the emergence of strong green phosphorescence in aqueous solution. More intriguingly, dual organelle-targeted imaging abilities have been also distinctively achieved in nuclei and lysosomes after undergoing photochemical reaction upon UV irradiation. This photooxidation-driven purely organic room-temperature phosphorescence provides a convenient and feasible strategy for supramolecular organelle identification to track specific biospecies and physiological events in the living cells.

Supramolecular Assembly with Near-Infrared Emission for Two-Photon Mitochondrial Targeted Imaging.

Two-photon supramolecular assembly with near-infrared (NIR) fluorescence emission is constructed from tetraphenylethene derivative possessing methoxyl and vinyl pyridine salt (TPE-2SP), cucurbit[8]uril (CB[8]), and ß-cyclodextrin modified hyaluronic acid (HA-CD). The obtained experimental results indicate that the TPE-2SP exhibits a very weak fluorescence emission at 650 nm, and then complexes with cucurbit[7]uril (CB[7]) to form 1:2 supramolecular pseudorotaxane with an enhanced NIR fluorescence emission at 660 nm. Compared with CB[7], CB[8] can assemble with TPE-2SP to be two-axial netlike pseudopolyrotaxane, resulting in close packing to increase TPE-2SP fluorescence emission with a redshift of 30 nm. Interestingly, TPE-2SP/CB[8] continues to assemble with cancer cell targeting agent HA-CD into nanoparticles, leading to assembling-induced further enhancement of NIR emission. Surprisingly, supramolecular nanoparticles have the two-photon character, and are successfully applied to mitochondrial targeting imaging. This supramolecular assembly system, with two-photon absorption and assembly-induced enhanced NIR luminescence properties, opens new way for biological targeted imaging.

Mediating K+/H+ Transport on Organelle Membranes to Selectively Eradicate Cancer Stem Cells with a Small Molecule.

Molecules that are capable of disrupting cellular ion homeostasis offer unique opportunities to treat cancer. However, previously reported synthetic ion transporters showed limited value, as promiscuous ionic disruption caused toxicity to both healthy cells and cancer cells indiscriminately. Here we report a simple yet efficient synthetic K+ transporter that takes advantage of the endogenous subcellular pH gradient and membrane potential to site-selectively mediate K+/H+ transport on the mitochondrial and lysosomal membranes in living cells. Consequent mitochondrial and lysosomal damages enhanced cytotoxicity to chemo-resistant ovarian cancer stem cells (CSCs) via apoptosis induction and autophagy suppression with remarkable selectivity (up to 47-fold). The eradication of CSCs blunted tumor formation in mice. We believe this strategy can be exploited in the structural design and applications of next-generation synthetic cation transporters for the treatment of cancer and other diseases related to dysfunctional K+ channels.

Prox1 induces new lymphatic vessel formation and promotes nerve reconstruction in a mouse model of sciatic nerve crush injury.

The peripheral nervous system lacks lymphatic vessels and is protected by the blood-nerve barrier, which prevents lymphocytes and antibodies from entering the neural parenchyma. Peripheral nerve injury results in degeneration of the distal nerve and myelin degeneration causes macrophage aggregation, T lymphocyte infiltration, major histocompatibility complex class II antigen expression, and immunoglobulin G deposition in the nerve membrane, which together result in nerve edema and therefore affect nerve regeneration. In the present paper, we show myelin expression was absent from the sciatic nerve at 7 days after injury, and the expression levels of lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1) and Prospero Homeobox 1 (Prox1) were significantly increased in the sciatic nerve at 7 days after injury. The lymphatic vessels were distributed around the myelin sheath and co-localized with lymphatic endothelial cells. Prox1 induces the formation of new lymphatic vessels, which play important roles in the elimination of tissue edema as well as in morphological and functional restoration of the damaged nerve. This study provides evidence of the involvement of new lymphatic vessels in nerve repair after sciatic nerve injury.

Alkyl-Substituted Cucurbit[6]uril Bridged ß-Cyclodextrin Dimer Mediated Intramolecular FRET Behavior.

A novel triazolyl bridged cucurbituril (CB)-cyclodextrin (CD) dimer was synthesized via click reaction of monopropargyl modified octamethylcucurbit[6]uril and mono-6-azido-ß-cyclodextrin. Moreover, it could form stable supramolecular inclusion complexes possessing efficient fluorescence resonance energy transfer, which benefited from the fact that CD and CB can bind amantadine- and pyridinium-containing fluorophores simultaneously. The supramolecular inclusion complex behaviors were investigated by NMR spectroscopy, UV-vis absorption, and fluorescence spectroscopy.

A New Member of the Inverted Cucurbit[n]uril Family.

A new inverted cucurbituril, namely inverted hexamethylcucurbit[3,3]uril (iMe6 Q[3,3]), has been isolated and characterized. It incorporates a single inverted un-substituted glycoluril unit oriented towards the interior of the cavity, shows good solubility in water and organic solvents (DMSO), and exhibits different selectivity for guests to those of iQ[6] and other known Q[6]s.

Catalytic asymmetric 1,2-addition of α-isothiocyanato phosphonates: synthesis of chiral ß-hydroxy- or ß-amino-substituted α-amino phosphonic acid derivatives.

α-Amino phosphonic acid derivatives are considered to be the most important structural analogues of α-amino acids and have a very wide range of applications. However, approaches for the catalytic asymmetric synthesis of such useful compounds are very limited. In this work, simple, efficient, and versatile organocatalytic asymmetric 1,2-addition reactions of α-isothiocyanato phosphonate were developed. Through these processes, derivatives of ß-hydroxy-α-amino phosphonic acid and α,ß-diamino phosphonic acid, as well as highly functionalized phosphonate-substituted spirooxindole, can be efficiently constructed (up to 99 % yield, d.r. >20:1, and >99 % ee). This novel method provides a new route for the enantioselective functionalization of α-phosphonic acid derivatives.

Rice husk hydrochar prepared by hydrochloric acid assisted hydrothermal carbonization for levofloxacin removal in bioretention columns.

Hydrochars are promising adsorbents in pollutant removal for water treatment. Herein, hydrochloric acid (HCl) co-hydrothermally treated hydrochars were prepared from rice husk biomass at 180 °C via a one-step hydrothermal method. Adsorption behaviors of levofloxacin (LVX) on hydrochars were evaluated. The specific surface area and pore volume of the hydrochar synthesized in 5 mol/L HCl (5H-HC) were almost 17 and 8 times of untreated hydrochar, respectively. The 5H-HC sample exhibited the highest LVX adsorption capability at room temperature (107 mg/g). Thermodynamic experimental results revealed that adsorption was a spontaneous endothermic process. Yan model provided the best description of the breakthrough behavior of LVX in bioretention column, indicating that the adsorption on the samples involved several rate-limiting factors including diffusion and mass transfer. The results show that facile HCl co-hydrothermal carbonization of waste biomass can produce novel hydrochars with high LVX adsorption ability.

Association between CYP1A1 polymorphisms and esophageal cancer: a meta-analysis.

Cytochrome P4501A1 (CYP1A1) enzyme is a member of the CYP superfamily of enzymes. CYP1A1 A2455G and T3801C are two most commonly studied polymorphisms loci. Previous studies have reported that CYP1A1 polymorphisms increase esophageal cancer (EC) risk. However, the results remain controversial and ambiguous. To further investigate the association between CYP1A1 polymorphisms (A2455G and T3801C) and EC risk. A meta-analysis was performed to investigate the association between CYP1A1 polymorphisms and EC risk. A total of 13 articles (A2455G and T3801C: 2 papers, A2455G: 8 papers, T3801C: 3 papers) from the PubMed containing information on the CYP1A1 polymorphisms and EC were included in this meta-analysis, with summational sample size of 1,881 EC cases and 3,786 controls. Stratified analysis was performed to evaluate the ethnicity (Caucasians and Asian) and histopathology type (esophageal squamous cell carcinoma and esophageal adenocarcinoma) effect. No obvious publication bias in the two polymorphisms was observed. Our meta-analysis revealed a significant association between the A2455G polymorphism and EC (OR = 1.55 per A allele, 95 % CI 1.29-1.85, P < 0.001). Stratification analysis by ethnicity and histopathology type showed significant association in the population of Asian origin (OR = 1.55, 95 % CI 1.28-1.89, P < 0.001) and in histopathology type of ESCC (OR = 1.40, 95 % CI 1.19-1.65, P < 0.001). We didn't observe the significant association between CYP1A1 T3801C polymorphism and EC. We observed a difference of allele frequencies between Caucasian and Asian population in the meta-analysis. The allele frequencies in our meta-analysis were consistent with the allele frequencies in 1000 Genome Project. Our meta-analysis demonstrated distinct evidence that CYP1A1 A2455G polymorphism was associated with the risk of EC.

Pd-Catalyzed Intermolecular Carbonylative Dearomatization of Arylamines with Propargylic Acetates for Synthesis of Bridged Polycyclic Lactams.

A new palladium-catalyzed multicomponent dearomatization of arylamines with CO and propargylic acetates for the synthesis of bridged polycyclic lactams is described. This method allows double annulation at the ipso and para positions of the amino group to form four new bonds, three C-C bonds and one C-N bond. DFT calculations and experimental studies indicate that the efficient formation of the allenecarboxanilide intermediate is the key step to achieve the dearomative transformation.

Aryldiazonium Salt-Triggered [2 + 2 + 1] Heteroannulation of Indoles by an Arylhydrazone Radical-Relayed 1,5-Hydrogen Atom Transfer.

An unprecedented three-component [2 + 2 + 1] annulation cascade of indoles with aryldiazonium salts and polyhalomethanes or acetone is presented by dual hydrogen atom transfer (HAT) and C-H functionalization. By employing readily accessible aryldiazonium salts as the radical initiators and electrophiles and polyhalomethanes and acetone as the C1 units, this method unprecedentedly constructs a pyrazole ring on an indole ring skeleton through the formation of two C-N bonds and a C-C bond in a single reaction.

Two-Photon Excited Near-Infrared Phosphorescence Based on Secondary Supramolecular Confinement.

Organic phosphorescence materials have received wide attention in bioimaging for bio-low toxicity and large Stokes. Herein, a design strategy to achieve near-infrared (NIR) excitation and emission of organic room-temperature phosphorescence through two-stage confinement supramolecular assembly is presented. Via supramolecular macrocyclic confinement, the host-guest complexes exhibit phosphorescence with two-photon absorption (excitation wavelength up to 890 nm) and NIR emission (emission wavelength up to 800 nm) in aqueous solution, and further nano-confinement assembly significantly strengthens phosphorescence. Moreover, the nano-assemblies possess color-tunable luminescence spanning from the visible to NIR regions under different excitation wavelengths. Intriguingly, the prepared water-soluble assemblies maintain two-photon absorption and multicolor luminescence in cells or vivo.

A tunable full-color lanthanide noncovalent polymer based on cucurbituril-mediated supramolecular dimerization.

The construction of lanthanide multicolor luminescent materials with tunable photoluminescence properties has been developed as one of the increasingly significant topics and shown inventive applications in miscellaneous fields. However, fabricating such materials based on synergistically assembly-induced emission rather than simple blending of different fluorescent dyes together still remains a challenge. Herein, we report a europium-based noncovalent polymer with tunable full-color emission, which is constructed from the 2,6-pyridinedicarboxylic acid-bearing bromophenylpyridinium salt. This rationally designed bifunctional component can concurrently serve as a guest molecule and a chelating ligand to associate with cucurbit[8]uril and europium ions, thus leading to the formation of a trichromatic (red-green-blue, RGB) photoluminescent polypseudorotaxane-type noncovalent polymer in aqueous solution. Meanwhile, the full-color emission enclosed within the RGB color triangle could be readily produced by simply tuning the molar ratio of cucurbit[8]uril and europium ions. The lanthanide supramolecular polymer featuring tricolor emission, long lifetime, high photoluminescence efficiency and low cytotoxicity could be further applied in multicolor imaging in a cellular environment. These results provide a new and feasible strategy for the construction of full-color single lanthanide self-assembled nanoconstructs.

PIWI-interacting RNAs: Mitochondria-based biogenesis and functions in cancer.

PIWI-interacting RNA (piRNAs), once thought to be mainly functioning in germlines, are now known to play an essential role in somatic and cancerous tissues. Ping-pong cycle initiation and mitochondria-based phased production constitute the core of the piRNA biogenesis and these two processes are well conserved in mammals, including humans. By being involved in DNA methylation, histone marker deposition, mRNA degradation, and protein modification, piRNAs also contribute to carcinogenesis partly due to oncogenic stress-induced piRNA dysregulation. Also, piRNAs play important roles in cancer stemness, drug resistance, and tumor immunology. Results from liquid biopsy analysis of piRNA can be used in both cancer diagnoses and cancer prognoses. A combination of targeting piRNA with other therapeutic strategies could be groundbreaking cancer treatment.

Purely organic light-harvesting phosphorescence energy transfer by ß-cyclodextrin pseudorotaxane for mitochondria targeted imaging.

A new type of purely organic light-harvesting phosphorescence energy transfer (PET) supramolecular assembly is constructed from 4-(4-bromophenyl)-pyridine modified ß-cyclodextrin (CD-PY) as a donor, cucurbit[8]uril (CB[8]) as a mediator, rhodamine B (RhB) as an acceptor, and adamantane modified hyaluronic acid (HA-ADA) as a cancer cell targeting agent. Interestingly, the complexation of free CD-PY, which has no RTP emission in aqueous solution, with CB[8] results in the formation of CD-PY@CB[8] pseudorotaxane with an RTP emission at 510 nm. Then the addition of RhB leads to an efficient light-harvesting PET process with highly efficient energy transfer and an ultrahigh antenna effect (36.42) between CD-PY@CB[8] pseudorotaxane and RhB. Importantly, CD-PY@CB[8]@RhB assembles with HA-ADA into nanoparticles with further enhanced delayed emission at 590 nm. The nanoparticles could be successfully used for mitochondria targeted imaging in A549 cancer cells. This aqueous-state PET based on a supramolecular assembly strategy has potential application in delayed fluorescence cell imaging.

Long-term survival with targeted therapy in an advanced non-small cell lung cancer patient based on genetic profiling.

Non-small cell lung cancer (NSCLC) is a profoundly devastating disease that is the leading cause of cancer-related death worldwide. With the rapid development of next-generation sequencing (NGS), which has supplied the ability to decode tumors at the DNA level, so that targeted therapy plays a crucial role in improving NSCLC survival. We first reported a 32-year-old Chinese female patient received the ninth-line treatment, who was initially diagnosed with advanced NSCLC with EGFR 19 deletion. The patient had a satisfactory clinical response to initial gefitinib treatment. Subsequently, an EGFR T790M mutation was detected from plasma-derived circulating tumor DNA (ctDNA) by ddPCR after disease progression, while NGS did not. Osimertinib was still tried but had no therapeutic effect. Then the disease even progressed on the administration of chemotherapy and gefitinib in succession. Rebiopsy for NGS detection was performed, and gefitinib plus anlotinib/vemurafenib were tried. And then, gefitinib plus crizotinib were administrated for MET amplification after the third biopsy. Furthermore, chemotherapy combined with immunotherapy was performed due to the PD-L1 positive expression. Up to now, osimertinib treatment was undertaken to base on an EGFR exon 20 T790M mutation using NGS-based genotyping in cerebrospinal fluid (CSF) ctDNA. Tumor genome dynamic monitoring can identify tumor driving genes and drug resistance mechanisms to guide tumor treatment. This study found that the total survival time of advanced NSCLC patients was more than four years after chemoradiotherapy and targeted therapy, indicating the significance of dynamic monitoring of gene alterations for cancer treatment.

ADAMTS9-AS2 and CADM2 expression and association with the prognosis in esophageal squamous cell carcinoma.

Background: We investigated whether ADAMTS9-AS2 and CADM2 were related to esophageal squamous cell carcinoma (ESCC). Methodology: ESCC microarray datasets and reverse transcriptase qualitative PCR were used to analyze ADAMTS9-AS2 and CADM2 expression. Results: The GSE120356 and GSE33810 datasets identified ADAMTS9-AS2 and CADM2 as the candidates and ADAMTS9-AS2 and CADM2 expression was downregulated in ESCC. ADAMTS9-AS2 and CADM2 were positively correlated with ESCC. ADAMTS9-AS2 and CADM2 expression could discriminate ESCC from normal tissue. Five-year overall survival was shorter in underexpressed ADAMTS9-AS2 patients, and CADM2 expression level was related to 5-year overall survival. ADAMTS9-AS2 and CADM2 expression were independent prognosis indicators in ESCC patients. Conclusion: Our findings shed new light on the clinical significance of ADAMTS9-AS2 and CADM2 in ESCC carcinogenesis.

piR-823 demonstrates tumor oncogenic activity in esophageal squamous cell carcinoma through DNA methylation induction via DNA methyltransferase 3B.

Piwi-interacting RNAs (piRNAs) dysregulation occurs frequently in extensive cancers. However, there was no report about piRNA expression in esophageal cancer (EC). In this study, the expression levels of piR-823 and DNMT1, DNMT3A, DNMT3B were detected in 54 pairs of ESCC tissues and adjacent normal tissues using the quantitative real-time polymerase chain reaction method. Pearson's chi-squared test and receiver operating characteristic curves were established to evaluate the diagnostic and prognostic value of piR-823 in ESCC. Spearman's correlation analysis was used to evaluate the association between piR-823 and DNMTs. We found that piR-823 was significantly upregulated in ESCC tissues compared with matched normal tissues (P = 0.0213), the level of piR-823 was significantly associated with lymph node metastasis (P = 0.042). The ROC curve analysis of piR-823 expression level yielded an area under the ROC curve value of 0.713 (P = 0.0001). DNMT3B was upregulated in ESCC tissues compared with matched normal tissues (P = 0.0286). There was an obvious positive correlation between piR-823 and DNMT3B expression (r = 0.6420, P < 0.0001). In conclusion, for the first time, we provided evidence about piRNA expression in EC. piRNA-823 and DNMT3B were both upregulated in ESCC and positively correlated with each other, suggesting the tumor oncogenic role of piR-823 in ESCC to epigenetically induce aberrant DNA methylation through DNMT3B. In addition, piRNA-823 showed high specificity in detecting ESCC and higher piRNA-823 level indicated higher risk of lymph node metastasis, suggesting its diagnostic and prognostic biomarker potential.

The abnormalities of coagulation and fibrinolysis in acute lung injury caused by gas explosion.

Acute lung injury (ALI) caused by gas explosion is common, and warrants research on the underlying mechanisms. Specifically, the role of abnormalities of coagulation and fibrinolysis in this process has not been defined. It was hypothesized that the abnormal coagulation and fibrinolysis promoted ALI caused by gas explosion. Based on the presence of ALI, 74 cases of gas explosion injury were divided into the ALI and non-ALI groups. The results of prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB), and platelet count (PLT) were collected within 24 hours and compared between the groups. ALI models caused by gas explosion were established in Sprague Dawley rats, and injuries were evaluated using hematoxylin and eosin (HE) staining and histopathological scoring. Moreover, the bronchoalveolar lavage fluid (BALF) was collected to examine thrombin-antithrombin complex (TAT), tissue factor (TF), tissue factor pathway inhibitor (TFPI), and plasminogen activator inhibitor-1 (PAI-1) levels by enzyme-linked immunosorbent assay (ELISA). The patients in ALI group had shorter PT and longer APTT, raised concentration of FIB and decreased number of PLT, as compared to the non-ALI group. In ALI rats, the HE staining revealed red blood cells in alveoli and interstitial thickening within 2 hours which peaked at 72 hours. The levels of TAT/TF in the BALF increased continually until the seventh day, while the PAI-1 was raised after 24 hours and 7 days. The TFPI was elevated after 2 hours and 24 hours, and then decreased after 72 hours. Abnormalities in coagulation and fibrinolysis in lung tissues play a role in ALI caused by gas explosion.