Near-Infrared Phosphorescent Switch of Diarylethene Phenylpyridinium Derivative and Cucurbit[8]uril for Cell Imaging.

Near-infrared (NIR) pure organic room-temperature phosphorescence (RTP) materials have received growing research interest due to their wide application in the fields of high-resolution bioimaging and luminescent materials. In this work, the authors report a macrocycle-confined pure organic RTP supramolecular assembly, which is constructed by diarylethene phenylpyridinium derivative (DTE-TP) and cucurbit[8]uril (CB[8]). Compared with CB[6] and CB[7], the larger cavity of CB[8] induces molecular folding and enhances the intramolecular charge transfer interactions, which leads to the obtained assembly emitting efficient NIR phosphorescence at 700 nm. Due to the photochromism of the diarylethene core, the NIR phosphorescence is reversibly regulated by light irradiation at wavelengths of 365 and >600 nm. Furthermore, cell-based experiments show that this supramolecular assembly is located in the lysosomes and displays a NIR phosphorescence at 650-750 nm. In addition, by means of phosphorescence resonance energy transfer, the obtained assembly exhibits a red-shifted NIR emission at 817 nm. This supramolecular phosphorescent switch provides a convenient path for the modular design of water-soluble pure organic room-temperature NIR phosphorescent materials.

Dual-responsive drug release and fluorescence imaging based on disulfide-pillar[4]arene aggregate in cancer cells.

The construction of multistimuli-responsive nanoaggregate has become one of the increasingly significant research topics in supramolecular chemistry. We herein reported the pH- and glutathione dual-responsive supramolecular assemblies fabricated by the disulfide-containing pillar[4]arene and tetraphenylethylene derivatives possessing different alkyl chains in length. Morphological characterization experiments showed the binary supramolecular assemblies formed well-defined nanoparticles, which could facilitate their endocytosis in cells. More remarkably, due to the compact nanostructures and the existence of acidifiable carboxyl group and bioreducible disulfide linkage in pillar[4]arene, the obtained nanoaggregates presented high drug-loading efficiency and sustained drug release behaviors, as well as the targeted fluorescence imaging ability in cancer cells. Thus, it can be envisioned that such microenvironment-adaptable supramolecular nanoassemblies featuring dual stimuli-responsiveness and fluorescence-imaging abilities may be developed as more appealing nanosystems for the therapy of refractory disease.

Habitual Tea Consumption and Risk of Cataracts: A Longitudinal Study.

We aimed to investigate the association between habitual tea consumption and the risk of developing cataracts in a large community-based cohort study. We prospectively collected volunteers from 29 recruitment centers that were ≧ 55 years old with no history of cataracts at the beginning of the study. There were 12,080 participants with available information in our study and were divided into two groups according to habitual tea consumption; non-tea-drinking and tea-drinking groups. The mean age was 59 years. Compared to the non-tea-drinking group, the tea-drinking group had a significantly lower incidence of developing cataracts (15.5% vs 12.1%) during follow-up of 46 months. In multivariate Cox proportional hazards regression analysis, the relative risk (RR) of incident cataracts was lower in the tea-drinking group than the non-tea-drinking group (RR = 0.848; 95% confidence interval [CI] = 0.751 to 0.957). Participants with ≧ 2 cups per day were associated with almost 16% reduction in the risk of developing cataracts compared with the non-tea-drinking group (RR = 0.844; 95% CI = 0.741 to 0.961). Our study suggests that habitual tea consumption can reduce the incidence of cataracts and raises the possibility that the tea content may slow the progression of cataracts.

Cucurbituril-Based Biomacromolecular Assemblies.

The construction of controlled biomacromolecular assemblies has become a thriving area of supramolecular chemistry. In this context, cucurbiturils (CBs), a class of macrocyclic receptors having robust skeletons, hydrophobic cavities, and carbonyl-laced portals, have been drawn into the limelight because of their advantageous molecular recognition characteristics with a variety of biomacromolecules, including peptides, nucleic acids, and proteins. In this minireview, we focus on the impressive advances in CB-based biomacromolecular assemblies, such as in biosensors and assays, the regulation of biochemical reactions, and the treatment of serious diseases. CB-promoted subcellular bioimaging has also been demonstrated in different organelles. The case studies presented herein demonstrate the numerous applications, from fundamental research to translational applications, of diverse CB-based supra/biomacromolecular architectures.

Serum neutrophil gelatinase-associated lipocalin and resistin are associated with dengue infection in adults.

BACKGROUND: Dengue is a major health problem in tropical areas, including Taiwan. Dengue virus infection affects various types of cells and results in elevation of serum inflammatory molecules. Because these molecules may be associated with dengue virus infection, the aim of this study was to identify novel molecules in febrile patients with dengue infection. In addition, we determined whether these molecules were correlated with the count of leukocytes and platelets. METHODS: Febrile adults (Age >18 years old) who presented to the emergency department and were confirmed dengue virus infection were enrolled in this study. Serum from dengue patients and healthy controls was collected and serum level of sepsis-associated inflammatory molecules was measured by Luminex assay. RESULTS: Elevated level of macrophage migration inhibitory factor, soluble vascular cell adhesion molecule-1, sFasL, resistin and interferon-γ were detected in patients' serum. Higher levels of neutrophil gelatinase-associated lipocalin (NGAL) and resistin were detected in dengue patients with normal leukocyte count and all dengue patients, respectively. Furthermore, the serum level of NGAL, but not resistin, was correlated with cell count in dengue patients. CONCLUSION: Our results revealed that resistin and NGAL are novel dengue-associated molecules. These results may help elucidate the regulatory mechanisms of anti-dengue immune responses.

Serum Galectin-9 and Galectin-3-Binding Protein in Acute Dengue Virus Infection.

Dengue fever is a serious threat for public health and induces various inflammatory cytokines and mediators, including galectins and glycoproteins. Diverse immune responses and immunological pathways are induced in different phases of dengue fever progression. However, the status of serum galectins and glycoproteins is not fully determined. The aim of this study was to investigate the serum concentration and potential interaction of soluble galectin-1, galectin-3, galectin-9, galectin-3 binding protein (galectin-3BP), glycoprotein 130 (gp130), and E-, L-, and P-selectin in patients with dengue fever in acute febrile phase. In this study, 317 febrile patients (187 dengue patients, 150 non-dengue patients that included 48 patients with bacterial infection and 102 patients with other febrile illness) who presented to the emergency department and 20 healthy controls were enrolled. Our results showed the levels of galectin-9 and galectin-3BP were significantly higher in dengue patients than those in healthy controls. Lower serum levels of galectin-1, galectin-3, and E-, L-, and P-selectin in dengue patients were detected compared to bacteria-infected patients, but not to healthy controls. In addition, strong correlation between galectin-9 and galectin-3BP was observed in dengue patients. In summary, our study suggested galectin-9 and galectin-3BP might be critical inflammatory mediators in acute dengue virus infection.

Diagnostic Accuracies of the TUNEL, SCD, and Comet Based Sperm DNA Fragmentation Assays for Male Infertility: a Meta-analysis Study.

BACKGROUND: Recent studies have provided new insights into the diagnostic value of sperm DNA fragmentation (SDF) for male factor sterility. This study aimed to systematically evaluate the diagnostic accuracy of the SDF test for male infertility. METHODS: Eligible studies were retrieved by searching electronic databases. The quality of the studies was assessed on the basis of quality assessment for studies of diagnostic accuracy (QUADAS) criteria tool. The bivariate metaanalysis model was employed to summarize the diagnostic indices and plot the summary receiver operator characteristic (SROC) curve by using Meta-disc 1.4 software. Influence analysis, meta-regression, and publication bias assay were all conducted through Stata 12.0 software. RESULTS: Our bivariate random effect meta-analysis yielded an AUC (area under curve) value of 0.9211 with a sensitivity (95% confidence interval) of 0.80 (0.78 - 0.82) and specificity of 0.83 (0.80 - 0.86) for the use of the SDF test in differentiating infertile males from normal fertile controls. Moreover, our subgroup analysis suggested that SDF analysis with a single TUNEL test resulted in an AUC value of 0.9506, with a pooled sensitivity of 0.77 (0.74 - 0.80) and specificity of 0.91 (0.87 - 0.94), while SCD and Comet assays displayed a combined sensitivity of 0.77 (0.67 - 0.81) or 0.91 (0.88 - 0.94), and specificity of 0.84 (0.75 - 0.91) or 0.63 (0.54 - 0.70), accompanied by an AUC value of 0.8408 or 0.9473. CONCLUSIONS: The SDF assay confers a relatively high diagnostic accuracy for infertility detection, among which the TUNEL based methodology seems to achieve higher accuracy than the SCD and Comet assays.

Increased expression of ABCB6 enhances protoporphyrin IX accumulation and photodynamic effect in human glioma.

BACKGROUND: Glioma recurrence usually occurs close to the tumor resection margins as a result of residual infiltrating glioma cells. 5-aminolevulinic acid (ALA) fluorescence-guided resection of gliomas has been demonstrated to enhance discrimination of tumor tissue and to improve survival. ALA-based photodynamic therapy is an effective albeit still experimental adjuvant treatment option for gliomas. However, insufficient protoporphyrin IX (PpIX) accumulation may limit the benefits of fluorescence-guided resection and photodynamic therapy. METHODS: We investigated the expression of the ATP-binding cassette transporter ABCB6, which regulates porphyrin synthesis, in surgical specimens from human gliomas and manipulated ABCB6 in human glioma cell lines. RESULTS: Our findings demonstrated that expression levels of ABCB6 were greatly elevated in human gliomas compared with normal brain tissues and correlated with World Health Organization histologic grade. A previously undescribed finding was that ABCB6 mRNA expression in solidly fluorescing tumor tissues was higher than that in vaguely fluorescing tumors, suggesting that ABCB6 may be at least in part responsible for PpIX accumulation in glioma cells. Accordingly, ABCB6 overexpression in glioma cell lines caused a marked increase in intracellular levels of PpIX, and was more sensitive to ALA-induced photodynamic therapy-events that could be prevented by silencing ABCB6 via siRNA treatment. CONCLUSIONS: Our findings indicate a crucial role of ABCB6 in ALA metabolism and accumulation of PpIX in glioma. ABCB6 overexpression is a potential approach to enhance accumulation of PpIX for optimizing the subjective discrimination of vague fluorescence and improving the efficacy of ALA-based photodynamic therapy.

Solvothermal synthesis of bifunctional carbon dots for tartrazine and Fe(III) detection from chamomile residue by ternary DES pretreatment.

A ternary deep eutectic solvent (DES) consisting of choline chloride, lactic acid, and urea in a molar ratio of 1:2:2 was used to pretreat chamomile residue, followed by carbon dots (CDs) preparation using a one-pot solvothermal method. The CDs prepared under the suitable conditions had a high quantum yield of 47.34% and could be used as a bifunctional fluorescent probe for the detection of tartrazine and Fe(III). The concentration of tartrazine or Fe(III) had a good linear relationship with the fluorescence intensity of CDs that the determination coefficient (R2) was 0.9957 and 0.9943, and the limit of detection (LOD) was 40 nM and 119 nM, respectively. After verifying the different fluorescence quenching mechanisms of CDs by these two substances, a quantitative analysis was performed on real samples with recoveries of 90.70%∼104.29%. Overall, this study provided a promising technology for chemical conversion from low-cost chamomile residue to attractive bifunctional fluorescent probe.

Morpholine-modified permethyl ß-cyclodextrin supramolecular nanoparticles for precise dual-targeted imaging.

Possessing dual-targeted agents toward the lysosome and cancer cells, a ternary supramolecular assembly was constructed by a morpholine-modified permethyl ß-cyclodextrin, sulfonated porphyrin, and folic acid-modified chitosan via multivalent interactions. As compared with free porphyrin, the obtained ternary supramolecular assembly showed promoted photodynamic effect and achieved dual-targeted precise imaging in cancer cells.

Highly effective gene delivery based on cyclodextrin multivalent assembly in target cancer cells.

Nucleic acid condensation and controlled release remain significant challenges of gene therapy in the fields of chemical biology and nanotechnology. In this work, we have reported a polysaccharide supramolecular assembly constructed using upconversion nanoparticles encapsulated by ß-cyclodextrin-grafted hyaluronic acid (HACD-UCNPs) and spermine modified with arylazopyrazoles (AAPS). Through UV-Vis spectroscopy, transmission electron microscopy (TEM), dynamic light scattering (DLS), gel electrophoresis, confocal laser imaging and combination experiments, such an assembly can achieve not only nucleic acid condensation but also targeted cells delivery and controlled release. Furthermore, we investigated the ability of the system to deliver siRNA under hypoxic conditions, and the subsequent NIR irradiation regulation achieved the two-step release of RNA, obtaining the best effect. This strategy provides a new approach for nucleic acid condensation and targeted delivery, which may bring broad potential in gene therapy.

Highly efficient discrimination of cancer cells based on in situ-activated phosphorescence energy transfer for targeted cell imaging.

Highly efficient discrimination between cancer cells and normal cells is full of challenges for precise diagnosis. Herein, we report an effective in situ-activated phosphorescence energy transfer supramolecular assembly constructed by a bromophenyl pyridine derivative (BPPY), cucurbit[8]uril (CB[8]), and rhodamine B-grafted hyaluronic acid (HAR) through noncovalent interaction. As compared with BPPY, CB[8] encapsulated two BPPY molecules, resulting in a biaxial pseudorotaxane supramolecular assembly showing purely organic room-temperature phosphorescence induced by macrocyclic confinement, which when further co-assembled with HAR, formed a multivalent supramolecular assembly with phosphorescence energy transfer. Benefitting from the targeting of hyaluronic acid and the cyclolactam ring ON-OFF reaction of HAR, such supramolecular assembly with an open ring presents red delayed fluorescence through phosphorescence energy transfer in cancer cells, while the assembly showed only green phosphorescence in normal cells, realizing highly efficient discrimination between cancer and normal cells. This supramolecular assembly is responsive to the physiological environment and provides a supramolecular platform for precise diagnosis.

Highly Reversible Supramolecular Light Switch for NIR Phosphorescence Resonance Energy Transfer.

Although purely organic room-temperature phosphorescence (RTP) has drawn widespread attention in recent years, regulatable phosphorescence resonance energy transfer (PRET) supramolecular switch is still rare. Herein, single molecular dual-fold supramolecular light switches, which are constructed by phenylpyridinium salts modified diarylethene derivatives (DTE-Cn, n = 3, 5) and cucurbit[8]uril (CB[8]) are reported. Significantly, biaxial [3]pseudorotaxane displayed efficiently reversible RTP after binding with CB[8] and the phosphorescence quenching efficiency is calculated up to be 99%. Furthermore, the binary supramolecular assembly can coassemble with Cy5 to form ternary supramolecular assembly showing efficiently PRET, which is successfully applied in switchable near infrared (NIR) mitochondria-targeted cell imaging and photocontrolled data encryption. This supramolecular strategy involving energy transfer provides a convenient approach for phosphorescent application in biology and material fields.

Supramolecular Dual Polypeptides Induced Tubulin Aggregation for Synergistic Cancer Theranostics.

The advent of macrocycle-based supramolecular chemistry can offer powerful strategies for regulating vital bioactivities in living systems and bring about emerging technology in biomedical science. Herein, we construct a supra-biomacromolecular nanosystem involving microtubules, cell-permeable porphyrins, and antimitotic peptide-decorated permethyl-ß-cyclodextrins for promoting cell apoptosis in a cooperative manner. Through specific polypeptide-tubulin recognition, cyclodextrin moieties are capable of anchoring to the tubulin surface and providing abundant hydrophobic microenvironments to accommodate the photosensitive porphyrins. Consequently, spherical tubulin aggregates are formed, and reactive oxygen species can be efficiently generated via the host-guest complexation. The combined usage of complexation-promoted photodynamic efficacy and tubulin aggregation gives more serious cell apoptosis under light irradiation in vitro and in vivo. To be envisioned, this supramolecularly enhanced photodynamic performance together with controlled aggregation of natural biomacromolecules may be developed as an innovative approach to improve the therapeutic potency against many diseases.

Chronic kidney disease and its association with cataracts-A cross-sectional and longitudinal study.

Introduction: We aim to explore the association between chronic kidney disease (CKD) and cataracts. Methods: A total of 121,380 participants with adequate information collected from 29 community-based recruitment centers since 2008 were analyzed. The association between CKD and self-reported diagnosed cataracts was examined in a cross-sectional cohort and was validated in a longitudinal cohort of 25,263 participants without cataracts at baseline. Results and discussion: Of all participants, cataracts occurred in 503/1,947 (26%) and 10,464/119,433 (9%) subjects in the CKD and non-CKD groups, respectively. Multivariate logistic regression showed that CKD was significantly associated with a higher prevalence of self-reported diagnosed cataracts. In the validation cohort, a higher incidence of cataracts was also noted in the CKD group (65/317, 21%) compared to the non-CKD group (1,964/24,252, 8%) during a mean 47-month follow-up. After adjusting for confounders, subjects with CKD had a 1.498-fold higher risk of incident cataracts than those without CKD (95% confidence interval = 1.114 to 2.013, p value = 0.007). We found that CKD was associated with a higher prevalence of cataracts as well as incident cataracts, which suggests CKD patients and their primary physicians should be aware of this disease and can provide a clue for further exploration of the possible mechanisms and treatments.

Cyclodextrin-Based Multistimuli-Responsive Supramolecular Assemblies and Their Biological Functions.

Cyclodextrins (CDs), which are a class of cyclic oligosaccharides extracted from the enzymatic degradation of starch, are often utilized in molecular recognition and assembly constructs, primarily via host-guest interactions in water. In this review, recent progress in CD-based supramolecular nanoassemblies that are sensitive to chemical, biological, and physical stimuli is updated and reviewed, and intriguing examples of the biological functions of these nanoassemblies are presented, including pH- and redox-responsive drug and gene delivery, enzyme-activated specific cargo release, photoswitchable morphological interconversion, microtubular aggregation, and cell-cell communication, as well as a geomagnetism-controlled nanosystem for the suppression of tumor invasion and metastasis. Moreover, future perspectives and challenges in the fabrication of intelligent CD-based biofunctional materials are also discussed at the end of this review, which is expected to promote the translational development of these nanomaterials in the biomedical field.

Actin Cytoskeleton-Disrupting and Magnetic Field-Responsive Multivalent Supramolecular Assemblies for Efficient Cancer Therapy.

Actin cytoskeleton disruption is a promising and intriguing anticancer strategy, but their efficiency is frequently compromised by severe side effects of the actin cytoskeleton-disrupting agents. In this study, we constructed the biocompatible actin cytoskeleton-targeting multivalent supramolecular assemblies that specifically target and disrupt the tumor actin cytoskeleton for cancer therapy. The assemblies were composed of ß-cyclodextrin-grafted hyaluronic acid (HACD) and iron oxide magnetic nanoparticles (MNPs) grafted by an actin-binding peptide (ABP) and adamantane (Ada)-modified polylysine. Owing to the multivalent binding between cyclodextrin and Ada, HACD, and peptide-grafted MNPs (MNP-ABP-Ada) could self-assemble to form MNP-ABP-Ada⊂HACD nanofibers in a geomagnetism-dependent manner. Furthermore, the presence of ABP rendered the assemblies to efficiently target the actin cytoskeleton. Interestingly, with the acid of a low-frequency alternating magnetic field (200 Hz), the actin cytoskeleton-targeting nanofibers could induce severe actin disruption, leading to a remarkable cell cycle arrest and drastic cell death of tumor cells both in vitro and in vivo, but showed no obvious toxicity to normal cells. The actin cytoskeleton-targeting/disrupting supramolecular assembly implies an excellent strategy for realizing efficient cancer therapy.

Identification of the Potential Prognostic Markers from the miRNA-lncRNA-mRNA Interactions for Metastatic Renal Cancer via Next-Generation Sequencing and Bioinformatics.

The survival rate in patients with metastatic renal cell carcinoma (RCC) is low. In addition, metastatic RCC resists traditional treatment. Therefore, identification of novel biomarkers, signaling pathways, and therapeutic targets is an important issue. The aim of the present study is to identify novel prognostic markers from the miRNA-mediated network for the regulation of metastasis of RCC. To address this issue, the RNA of human RCC cell lines, 786-O and ACHN, derived from primary and metastatic sites, respectively, were collected and subjected to RNA sequencing and small RNA sequencing. The bioinformatic analysis revealed that the pathways of the genes with different expressions were related to tumor progression, and identified miRNA and miRNA-long non-coding RNA (lncRNA) interactions, and mRNA. The results revealed that the expressions of seven miRNAs were associated with the overall survival rate of patients with RCC. Furthermore, the expressions of two lncRNA and three protein-coding genes (mRNA) were significantly associated with the increased or decreased disease-free survival rate. Although the detailed regulatory mechanism between miRNAs and targeted genes was not fully understood, our findings present novel prognostic markers and novel insight on miRNA-mediated pathways for metastatic RCC.

Highly efficient photocontrolled targeted delivery of siRNA by a cyclodextrin-based supramolecular nanoassembly.

In this study, we have constructed a binary supramolecular nanoassembly composed of α-cyclodextrin-modified hyaluronic acid and an azobenzene-modified diphenylalanine derivative with a positively charged imidazole group. This nanoassembly can bind with siRNA through electrostatic interactions and efficiently delivered them into cancer cells and inhibited their growth.

Comparison of Clinical Characteristics Between Febrile and Afebrile Seizures Associated With Acute Gastroenteritis in Childhood.

Background: Acute gastroenteritis (AGE) accompanied by seizures is not a rare scenario in childhood. We investigated the clinical features of children with febrile or afebrile seizures during AGE and aimed to identify the impact of fever in this situation-related seizure. Methods: We retrospectively reviewed the medical charts of children admitted due to seizures associated with mild AGE between January 2008 and December 2017. These consecutive patients were divided into two groups: an "afebrile group" whose diagnosis was compatible with "benign convulsion with mild gastroenteritis (CwG)" and a "febrile group" who had a fever within 24 h of the onset of an AGE-related seizure. We compared the two groups' clinical and laboratory characteristics, electroencephalograms (EEG), neuroimaging, and outcomes. Results: Of the children suffering from AGE and seizures, 41 were afebrile and 30 were febrile, with a mean age of 32.2 ± 27.6 months. The gender, seizure semiology, frequency, duration of seizures, the time interval between AGE symptoms onset and first seizure, and levels of serum sodium, and hepatic enzymes were significantly different between the two groups. The most frequently identified enteropathogen was rotavirus (33%), especially in the male and febrile subjects. Afebrile patients had more EEG abnormalities initially, but all returned to normal later. All cases had an uneventful outcome. Of note, seizure clusters (≥2 episodes) occurred more frequently in the afebrile patients who had a duration of AGE symptoms lasting 2 days or more, or white blood cell counts ≥ 10,000/µL (p-values: 0.05 and 0.04, respectively). In comparison with seven similar studies, all showed more seizure clusters, partial seizures, and a shorter interval between AGE onset and seizures in afebrile patients than in febrile patients. Contrarily, afebrile patients had longer seizure duration and lower serum hepatic transaminases than febrile patients. Conclusion: Although fever partially influenced the clinical features of AGE-related seizures, febrile CwG might have pathophysiology distinctly different from that of febrile seizures. Comprehensive knowledge in discerning febrile and afebrile CwG can help to avoid unnecessary diagnostics tests, and anticonvulsants use.