A molecular container providing supramolecular protection against acetylcholine hydrolysis.

Alzheimer's disease (AD) is characterized by cognitive decline, often attributed to the deficiency of acetylcholine, which can undergo hydrolysis by acetylcholinesterase (AChE) within the biological milieu. Here, we report a supramolecular strategy that takes advantage of confinement effects to inhibit such a hydrolysis process, shedding some light on AD therapy. A water-soluble and bowl-shaped molecule, hexacarboxylated tribenzotriquinacene (TBTQ-C6), was employed to shield acetylcholine (G1) from enzymatic degradation through host-guest binding interactions. Our study revealed highly efficient host-guest interactions with a binding ratio of 1 : 3, resulting in a significant reduction in acetylcholine hydrolysis from 91.1% to 7.4% in the presence of AChE under otherwise identical conditions. Furthermore, TBTQ-C6 showed potential for attenuating the degradation of butyrylcholine (G2) by butyrylcholinesterase (BChE). The broader implications of this study extend to the potential use of molecular containers in various biochemical and pharmacological applications, opening new avenues for research in the field of neurodegenerative diseases.

Exosomal hsa_circ_000200 as a potential biomarker and metastasis enhancer of gastric cancer via miR-4659a/b-3p/HBEGF axis.

BACKGROUND: Exosome, a component of liquid biopsy, loaded protein, DNA, RNA and lipid gradually emerges as biomarker in tumors. However, exosomal circRNAs as biomarker and function mechanism in gastric cancer (GC) are not well understood. METHODS: Differentially expressed circRNAs in GC and healthy people were screened by database. The identification of hsa_circ_000200 was verified by RNase R and sequencing, and the expression of hsa_circ_000200 was evaluated using qRT-PCR. The biological function of hsa_circ_000200 in GC was verified in vitro. Western blot, RIP, RNA fluorescence in situ hybridization, and double luciferase assay were utilized to explore the potential mechanism of hsa_circ_000200. RESULTS: Hsa_circ_000200 up-regulated in GC tissue, serum and serum exosomes. Hsa_circ_000200 in serum exosomes showed better diagnostic ability than that of tissues and serum. Combined with clinicopathological parameters, its level was related to invasion depth, TNM staging, and distal metastasis. Functionally, knockdown of hsa_circ_000200 inhibited GC cells proliferation, migration and invasion in vitro, while its overexpression played the opposite role. Importantly, exosomes with up-regulated hsa_circ_000200 promoted the proliferation and migration of co-cultured GC cells. Mechanistically, hsa_circ_000200 acted as a "ceRNA" for miR-4659a/b-3p to increase HBEGF and TGF-ß/Smad expression, then promoted the development of GC. CONCLUSIONS: Our findings suggest that hsa_circ_000200 promotes the progression of GC through hsa_circ_000200/miR-4659a/b-3p/HBEGF axis and affecting the expression of TGF-ß/Smad. Serum exosomal hsa_circ_000200 may serve as a potential biomarker for GC.

pH-Responsive fluorescent supramolecular nanoparticles based on tetraphenylethylene-labelled chitosan and a six-fold carboxylated tribenzotriquinacene.

We synthesized a new tetraphenylethylene-modified chitosan bioconjugate, CS-TPE, that shows the aggregation-induced emission effect. It can self-assemble into fluorescent polymeric nanoparticles in an aqueous solution at pH 5.3 either alone or with the water-soluble bowl-shaped six-fold carboxylated tribenzotriquinacene derivative TBTQ-C6 via host-guest binding. The spherical nanoparticles formed by CS-TPE amphiphiles or TBTQ-C6/CS-TPE supra-amphiphiles disintegrated under alkaline stimulation at pH 10.4 and the dispersion of the aggregates after the collapse in the presence of TBTQ-C6 was greatly improved. In addition, the fluorescence of CS-TPE was significantly enhanced by introducing TBTQ-C6, and remained relatively stable with variations in pH for both CS-TPE and TBTQ-C6/CS-TPE. Such pH-responsive supramolecular spherical nanoparticles with stable fluorescence emission based on CS-TPE or TBTQ-C6/CS-TPE may find applications in various fields, including the development of visual oral drug delivery systems.

Synthesis of a new water-soluble hexacarboxylated tribenzotriquinacene derivative and its competitive host-guest interaction for drug delivery.

A new water-soluble hexacarboxylated tribenzotriquinacene derivative (TBTQ-CB6) was synthesized and used as a supramolecular drug carrier to load the model anticancer drugs dimethyl viologen (MV) and doxorubicin (DOX) via host-guest interactions. The drugs could be effectively released by spermine (SM), a molecule overexpressed in cancer cells, through host-guest competitive substitution since TBTQ-CB6 has a stronger binding affinity toward SM than MV and DOX. The host-guest interactions of the complexes of TBTQ-CB6 with MV, DOX and SM were investigated by NMR spectroscopy and fluorescence spectroscopy. The association stoichiometry of the complexes of TBTQ-CB6 with MV, DOX, and SM was found to be 1:1 with association constants of K a = (7.67 ± 0.34) × 104 M-1, K a = (6.81 ± 0.33) × 104 M-1, and K a = (5.09 ± 0.98) × 105 M-1, respectively. The competitive substitution process was visualized by NMR titration. This novel TBTQ-based host-guest drug delivery system may have potential use in supramolecular chemotherapy.

Water-soluble host-guest complexes between fullerenes and a sugar-functionalized tribenzotriquinacene assembling to microspheres.

A sugar-functionalized water-soluble tribenzotriquinacene derivative bearing six glucose residues, TBTQ-(OG) 6 , was synthesized and its interaction with C60 and C70-fullerene in co-organic solvents and aqueous solution was investigated by fluorescence spectroscopy and ultraviolet-visible spectroscopy. The association stoichiometry of the complexes TBTQ-(OG) 6 with C60 and TBTQ-(OG) 6 with C70 was found to be 1:1 with binding constants of K a = (1.50 ± 0.10) × 105 M-1 and K a = (2.20 ± 0.16) × 105 M-1, respectively. The binding affinity between TBTQ-(OG) 6 and C60 was further verified by Raman spectroscopy. The geometry of the complex of TBTQ-(OG) 6 with C60 deduced from DFT calculations indicates that the driving force of the complexation is mainly due to the hydrophobic effect and to host-guest π-π interactions. Hydrophobic surface simulations showed that TBTQ-(OG) 6 and C60 forms an amphiphilic supramolecular host-guest complex, which further assembles to microspheres with diameters of 0.3-3.5 µm, as determined by scanning electron microscopy.

Intragenic hypomethylation of DNMT3A in patients with myelodysplastic syndrome.

BACKGROUND: DNMT3A is a DNA methyltransferase that acts in de novo methylation. Aberrant expression of DNMT3A has been reported in several human diseases, including myelodysplastic syndrome (MDS). However, the pattern of DNMT3A methylation remains unknown in MDS. METHODS: The present study was aimed to investigate the methylation status of DNMT3A intragenic differentially methylated region 2 (DMR2) using real-time quantitative methylation-specific PCR and analyze its clinical significance in MDS. RESULTS: Aberrant hypomethylation of DNMT3A was found in 57% (51/90) MDS cases. There were no significant differences in age, sex, white blood cell counts, platelet counts, hemoglobin counts and World Health Organization, International Prognostic Scoring System and karyotype classifications between DNMT3A hypomethylated and DNMT3A hypermethylated groups. However, the patients with DNMT3A hypomethylation had shorter overall survival time than those without DNMT3A hypomethylation (11 months vs. 36 months, p=0.033). Multivariate analysis confirmed the independent adverse impact of DNMT3A hypomethylation in MDS. CONCLUSIONS: Our data suggest that DNMT3A DMR2 hypomethylation may be a negative prognostic hallmark in MDS.

Gastric cancer tissue-derived mesenchymal stem cells impact peripheral blood mononuclear cells via disruption of Treg/Th17 balance to promote gastric cancer progression.

Gastric cancer tissue-derived mesenchymal stem cells (GC-MSCs) are important resident stromal cells in the tumor microenvironment (TME) and have been shown to play a key role in gastric cancer progression. Whether GC-MSCs exert a tumor-promoting function by affecting anti-tumor immunity is still unclear. In this study, we used GC-MSC conditioned medium (GC-MSC-CM) to pretreat peripheral blood mononuclear cells (PBMCs) from healthy donors. We found that GC-MSC-CM pretreatment markedly reversed the inhibitory effect of PBMCs on gastric cancer growth in vivo, but did not affect functions of PBMCs on gastric cancer cell proliferation, cell cycle and apoptosis in vitro. PBMCs pretreated with GC-MSC-CM significantly promoted gastric cancer migration and epithelial-mesenchymal transition in vitro and liver metastases in vivo. Flow cytometry analysis showed that GC-MSC-CM pretreatment increased the proportion of Treg cells and reduced that of Th17 cells in PBMCs. CFSE labeling and naïve CD4+ T cells differentiation analysis revealed that GC-MSC-CM disrupted the Treg/Th17 balance in PBMCs by suppressing Th17 cell proliferation and inducing differentiation of Treg cells. Overall, our collective results indicate that GC-MSCs impair the anti-tumor immune response of PBMCs through disruption of Treg/Th17 balance, thus providing new evidence that gastric cancer tissue-derived MSCs contribute to the immunosuppressive TME.

Trachoma in Yunnan province of southwestern China: findings from trachoma rapid assessment.

BACKGROUND: To understand the situation of active trachoma among children aged 6 to 8 years old and scarring trachoma among those aged 15 and over in Yunnan Province, South-western China. METHODS: A rapid assessment of trachoma was conducted to determine the presence or absence of trachoma in Yunnan. Through risk assessment, 9 sites in 8 suspected trachoma epidemic counties were selected. Trachoma Rapid Assessment was conducted in these areas afterwards. Within each sites, 50 students from grade one in local primary school and adults aged 15 and above with suspected scarring trachoma were examined by survey teams. RESULTS: A total of 450 children aged 6-8 years and 160 adults aged 15 and above were screened in 9 sites of 8 counties. Only 1 case of active trachoma was found. Detection rate of active trachoma in children was 0.2%(1/450) in all sites and 2% (1/50)in Pingbian County. Out of 150 adults only 1 case of TT and 1 case of CO were found in all the highest at risk communities. People with scarring trachoma were aged over 60 years. CONCLUSIONS: The active trachoma was rarely seen and trachoma is unlikely to be a significant public health problem in Yunnan Province, South-western China.

Crosstalk between mesenchymal stem cells and macrophages in inflammatory bowel disease and associated colorectal cancer.

Mesenchymal stem cells (MSCs) are attractive seed cells for immunotherapy, tissue engineering and regenerative medicine due to their self-renewal and multidirectional differentiation abilities, diverse immunoregulatory functions and ease of isolation from a wide range of tissues. MSCs exert their immunoregulatory effect on immune cells via cell-to-cell contact and paracrine mechanisms. In turn, MSCs can also be modulated by immune cells. Macrophages are constantly present in the mucosa of the intestinal tract of mammals and play an important role in the development and progression of inflammatory bowel disease (IBD), a chronic and recurrent inflammatory disease of the gastrointestinal tract characterized by idiopathic mucosal inflammation. The increased morbidity and mortality of IBD have made it a disease hard to cure in the clinic. MSCs have emerged as an important tool for IBD therapy due to their abilities to differentiate into enterocyte-like cells and regulate inflammatory cells, especially macrophages. In this review, we discuss the recent advances in the interaction between MSCs and macrophages in diseases, with an emphasis on IBD. We propose that an optimized MSC-based therapy would provide a novel strategy for the treatment of IBD and the prevention of IBD-associated colorectal cancer (CRC).

Facile Assembly of Chiral Metallosquares by Using Enantiopure Tribenzotriquinacene Corner Motifs.

Invited for the cover of this issue are Wen-Rong Wu, Guang-Jie Xia, and Hak-Fun Chow of The Chinese University of Hong Kong, Xiao-Ping Cao of Lanzhou University and Dietmar Kuck of Bielefeld University. The image depicts how different routes can lead to the same goal. Read the full text of the article at 10.1002/chem.201501556.

Facile Assembly of Chiral Metallosquares by Using Enantiopure Tribenzotriquinacene Corner Motifs.

A pair of enantiomerically pure metallosquares based on linear platinum-diacetylene edges and tribenzotriquinacene corner units was synthesized. Their structures were characterized by (1) H-, (13) C- and (31) P NMR spectroscopy as well as MALDI-TOF mass spectrometry and circular dichroism. Based on DFT calculation, the optimized geometry possesses a distorted square conformation in which the four edges are not sitting on the same plane. The molecular square further self-assembled in the solid state to afford microspheres with diameter of approximately 300 nm, as determined by scanning electron microscopy.

The role of 15-LOX-1 in colitis and colitis-associated colorectal cancer.

INTRODUCTION: Chronic inflammation is known to be mechanistically linked to the development of cancer. This article reviews and discusses the role of 15-lipoxygenase-1 (15-LOX-1) in the resolution of colitis and prevention of colitis-associated colorectal cancer. DISCUSSION: 15-LOX-1 is an inducible and highly regulated enzyme in cells that play an important role in the production of lipid signaling mediators from linoleic acid and arachidonic acid. Together, these acids and 15-LOX-1 are the driving force for the resolution of acute and chronic inflammation in normal cells. Widespread inflammation can progress from local inflammation to ulcerative colitis, tumorigenesis, and finally invasive, metastatic, or benign colon cancer. Thus, reversing inflammation will halt the proliferation of cancerous cells. Decreased expression of 15-LOX-1 may lead to the development of colitis-associated colorectal cancer and colorectal cancer. CONCLUSION: n-3 Polyunsaturated fatty acids are potent anti-inflammatory and pro-resolution products of 15-LOX-1 that can potentially prevent colitis-associated colorectal cancer and colorectal cancer.

Regiocontrolled synthesis and optical resolution of mono-, di-, and trisubstituted tribenzotriquinacene derivatives: key building blocks for further assembly into molecular squares and cubes.

The regiocontrolled syntheses of four chiral C1- or C3-symmetrical tribenzotriquinacene (TBTQ) derivatives bearing methoxy or hydroxy groups at the peripheral positions [(2,6-(OMe)2, (±)-18 and (±)-20; 2,6-(OH)2, (±)-19; and 2,6,10-(OMe)3, (±)-21] by two different synthesis protocols are reported. Compounds (±)-19, (±)-20, and (±)-21 and two (already-known) monosubstituted C1-symmetrical TBTQ analogues [2-OH (±)-23 and 2-OMe (±)-24] were readily resolved by chiral HPLC, and their absolute configurations were determined by X-ray crystallography and/or circular dichroism (CD) studies. Optical resolution of three closely related TBTQ derivatives [2,6-(OMe)2, (±)-18; 2-OMe, (±)-22; and 2-OH, (±)-25] containing the same peripheral substituents but other bridgehead residues failed. Enantiopure TBTQ derivatives of this sort are considered promising structural motifs toward the construction of molecular squares and cubes.

pH-Responsive supramolecular vesicles for imaging-guided drug delivery: Harnessing aggregation-induced emission.

The water-soluble tribenzotriquinacene-based hexacarboxylic acid ammonium salt, TBTQ-C 6 , acts as the host component (H) forming host-guest complexes with tetraphenylethylene (TPE)-functionalized monotopic and tetratopic quaternary ammonium derivatives, G1 and G2, to yield supra-amphiphiles. These supra-amphiphiles self-assemble to form pH-responsive fluorescent vesicles, which have allowed us to capitalize on the aggregation-induced emission (AIE) effect for imaging-guided drug delivery systems. These systems exhibit efficient drug loading and pH-responsive delivery capabilities. Upon encapsulation of the anticancer drug doxorubicin (DOX), both the TPE and DOX chromophores undergo dual-fluorescence deactivation due to the energy transfer relay (ETR) effect. Under acidic conditions, the release of DOX interrupts the ETR effect, resulting in the fluorescence recovery of TPE fluorogens and DOX, allowing for real-time visual monitoring of the drug release process. Cytotoxicity experiments confirmed the low toxicity of the unloaded vectors to normal cells, while the DOX-loaded vectors were found to significantly enhance the anticancer activity of DOX against cancer cells in vitro. The AIE-featured supramolecular vesicles presented in this research hold great potential for imaging-guided drug delivery systems.

C3-symmetrical tribenzotriquinacene derivatives: optical resolution through cryptophane synthesis and supramolecular self-assembly into nanotubes.

Based on a regioselective tris-formylation of a tribenzotriquinacene (TBTQ) hydrocarbon, the racemic C(3)-symmetrical TBTQ-trialdehyde and the corresponding TBTQ-trimethanol were synthesized along with their C(1)-isomers. Conversion of the C(3)-trialdehyde to three diastereomeric TBTQ-based cryptophanes occurring in high yield enabled the preparation of the optically pure C(3)-symmetrical TBTQ-trialdehydes and the determination of their absolute configuration. The racemic C(3)-symmetrical TBTQ-trimethanol was found to form several stable nanotubular aggregates in the solid state.

Facile production of cellulose nanofibers from raw elephant grass by an aluminum chloride-enhanced acidic deep eutectic solvent.

To develop a greener and more efficient method for producing cellulose nanofibers (CNFs) from raw plants, an AlCl3-enhanced ternary deep eutectic solvent, DES2 (consisting of choline chloride, citric acid, and AlCl3·6H2O in a molar ratio of 1:0.4:0.08), was synthesized. Raw elephant grass (EG) was pretreated with DES2, followed by sodium chlorite (NaClO2) bleaching and ultrasonic disruption to extract high-performance CNFs. The DES2 and NaClO2 treatments effectively removed hemicellulose and lignin, achieving removal rates of 99.23 % and 99.62 %, respectively, while maintaining a cellulose content of 78.3 %. DES2 demonstrated easy recyclability and maintained excellent biomass pretreatment performance even after multiple cycles. Following a brief 30-min intermittent ultrasound treatment, the resulting CNFs demonstrated superior crystallinity, increased carboxyl content, and a narrower width distribution compared to CNFs obtained from AlCl3-free DES1. Optimized conditions at 110 °C yielded CNFs with 85.3 % crystallinity, 0.64 mmol/g carboxyl content, 5.15 nm width distribution, and excellent dispersion in water for at least six months. Additionally, CNFs enhanced the tensile strength of chia seed mucilage (CM) composite films, showing a significant improvement to 26.6 MPa, representing a 231.3 % increase over the control film. This study offers a promising approach for efficiently producing CNFs from raw plants.

IDH1 and IDH2 mutation analysis in Chinese patients with acute myeloid leukemia and myelodysplastic syndrome.

The somatic mutations of isocitrate dehydrogenase genes (IDH1 and IDH2) have been identified in a proportion of hematologic malignancies. We examined IDH1 R132 and IDH2 R140/R172 mutations by high resolution melting analysis and direct sequencing in Chinese patients with different myeloid malignancies including 198 acute myeloid leukemia (AML), 82 myelodysplastic syndrome (MDS), 85 chronic myeloid leukemia, and 57 myeloproliferative neoplasms. IDH1 and IDH2 mutations were found in four (2.0%) and ten (5.0%) AML and in two (2.4%) and three (3.6%) MDS cases, but not in other patients. IDH1 and IDH2 mutations were heterozygous and mutually exclusive. IDH1/2 mutations were significantly more frequently observed in cytogenetically normal AML or MDS compared to those without mutations. There was no difference in overall survival of both AML and MDS patients with or without IDH1/2 mutations (P = 0.177 and 0.407, respectively). In conclusion, IDH1/2 mutations are recurrent but rare molecular aberrations in Chinese AML and MDS.

Facile production of chitin from shrimp shells using a deep eutectic solvent and acetic acid.

High purity chitin was extracted from shrimp shells by a green, sustainable, and efficient one-pot approach using a deep eutectic solvent consisting of choline chloride and glycerol (ChCl-Gl) combined with a small amount of acetic acid. Under the conditions of an acetic acid concentration of 7.5 wt% and reaction temperature of 120 °C, the purity of isolated chitin was up to 96.1%, which was superior to that of 87.7% obtained by conventional chemical method. In addition, the viscosity-average molecular weight and crystallinity of the extracted chitin were revealed to be larger than for the latter. Moreover, the deep eutectic solvent could be recycled at least three times without losing the quality of the extracted chitin. This facile approach combining recyclable DES with a small amount of acetic acid was expected to be used for the green and sustainable production of chitin from shrimp shells.

Development of active packaging films based on liquefied shrimp shell chitin and polyvinyl alcohol containing ß-cyclodextrin/cinnamaldehyde inclusion.

To maintain the freshness of fruits and to meet environmental and consumer needs, a biobased packaging film with long-lasting antimicrobial activity was developed in this article. Liquefied ball-milled shrimp shell chitin/polyvinyl alcohol (LBSC/PVA) blend films containing varying concentrations (0, 1, 2, 3, 4, 5 wt%) of the ß-cyclodextrin/cinnamaldehyde (ß-CD/CA) inclusion were prepared and characterized. The association between ß-CD and CA and the sustained release behavior of CA were explored. The physicochemical property, antimicrobial activity and food preservation performance of the films were investigated. Results showed that CA was successfully encapsulated into the cavity of CD by host-guest interactions, which greatly improved the sustained release of CA. The 3 wt% ß-CD/CA/LBSC/PVA blend film showed optimized mechanical properties with a tensile strength of 41.5 MPa and an elongation at break of 810 %. In addition, the incorporation of ß-CD/CA inclusion significantly enhanced the antimicrobial activity and food preservation performance of the blend films. Moreover, the 3 wt% ß-CD/CA/LBSC/PVA blend film exhibited evidently longer lasting antimicrobial activity and cherry tomato preservation performance than the 3 wt% CA/LBSC/PVA blend film, further demonstrating the critical role of ß-CD in delaying CA release. These novel ß-CD/CA/LBSC/PVA blend films may have a potential use in active food packaging.

Antioxidant and antibacterial properties of essential oils-loaded ß-cyclodextrin-epichlorohydrin oligomer and chitosan composite films.

Chitosan (CS) is becoming increasingly popular in food packaging due to its natural degradability and great film-forming properties. Nevertheless, its poor antibacterial properties and inadequate antioxidant properties prevent it from being used effectively. In this study, ß-cyclodextrin-epichlorohydrin (ß-CD-EP) oligomers were prepared and encapsulated with natural essential oils cinnamaldehyde and thymol, and then the inclusion complexes (IC) were incorporated into chitosan in various contents to afford a series of CS-IC composite films. The impacts of IC on the morphological, mechanical, thermal, and water resistance properties, antioxidant and antibacterial activities of chitosan films, as well as the loading and sustained release behavior of IC, were thoroughly examined. The results turned out that the essential oils were well-loaded with high encapsulation efficiency and showed a significant slow-release effect. It was also found that the tensile strength and the elongation at break decreased with increasing IC contents, while the thermal stability was enhanced. The incorporation of IC dramatically promoted the antioxidant and antibacterial properties of the chitosan films towards Gram-positive bacteria. Based on our findings, chitosan films containing essential oils-loaded ß-CD-EP oligomers may serve as an effective food packaging material.