SUMOylation Fine-Tunes Endothelial HEY1 in the Regulation of Angiogenesis.

BACKGROUND: Angiogenesis, which plays a critical role in embryonic development and tissue repair, is controlled by a set of angiogenic signaling pathways. As a TF (transcription factor) belonging to the basic helix-loop-helix family, HEY (hairy/enhancer of split related with YRPW motif)-1 (YRPW motif, abbreviation of 4 highly conserved amino acids in the motif) has been identified as a key player in developmental angiogenesis. However, the precise mechanisms underlying HEY1's actions in angiogenesis remain largely unknown. Our previous studies have suggested a potential role for posttranslational SUMOylation in the dynamic regulation of vascular development and organization. METHODS: Immunoprecipitation, mass spectrometry, and bioinformatics analysis were used to determine the biochemical characteristics of HEY1 SUMOylation. The promoter-binding capability of HEY1 was determined by chromatin immunoprecipitation, dual luciferase, and electrophoretic mobility shift assays. The dimerization pattern of HEY1 was determined by coimmunoprecipitation. The angiogenic capabilities of endothelial cells were assessed by CCK-8 (cell counting kit-8), 5-ethynyl-2-deoxyuridine staining, wound healing, transwell, and sprouting assays. Embryonic and postnatal vascular growth in mouse tissues, matrigel plug assay, cutaneous wound healing model, oxygen-induced retinopathy model, and tumor angiogenesis model were used to investigate the angiogenesis in vivo. RESULTS: We identified intrinsic endothelial HEY1 SUMOylation at conserved lysines by TRIM28 (tripartite motif containing 28) as the unique E3 ligase. Functionally, SUMOylation facilitated HEY1-mediated suppression of angiogenic RTK (receptor tyrosine kinase) signaling and angiogenesis in primary human endothelial cells and mice with endothelial cell-specific expression of wild-type HEY1 or a SUMOylation-deficient HEY1 mutant. Mechanistically, SUMOylation facilitates HEY1 homodimer formation, which in turn preserves HEY1's DNA-binding capability via recognition of E-box promoter elements. Therefore, SUMOylation maintains HEY1's function as a repressive TF controlling numerous angiogenic genes, including RTKs and Notch pathway components. Proangiogenic stimuli induce HEY1 deSUMOylation, leading to heterodimerization of HEY1 with HES (hairy and enhancer of split)-1, which results in ineffective DNA binding and loss of HEY1's angiogenesis-suppressive activity. CONCLUSIONS: Our findings demonstrate that reversible HEY1 SUMOylation is a molecular mechanism that coordinates endothelial angiogenic signaling and angiogenesis, both in physiological and pathological milieus, by fine-tuning the transcriptional activity of HEY1. Specifically, SUMOylation facilitates the formation of the HEY1 transcriptional complex and enhances its DNA-binding capability in endothelial cells.

Recent Advances in Fluorescent Probes for Zinc Ions Based on Various Response Mechanisms.

Zinc is a vital metal element with extensive applications in various fields such as industry, metallurgy, agriculture, food, and healthcare. For living organisms, zinc ions are indispensable, and their deficiency can lead to physiological and metabolic abnormalities that cause multiple diseases. Hence, there is a significant need for selective recognition and effective detection of free zinc ions. As a probe method with high sensitivity, high selectivity, real-time monitoring, safety, harmlessness and ease of operation, fluorescent probes have been widely used in metal ion identification studies, and many convenient, low-cost and easy-to-operate fluorescent probes for Zn2+ detection have been developed. This article reviews the latest research advances in fluorescent chemosensors for Zn2+ detection from 2019 to 2023. In particular, sensors working through photo-induced electron transfer (PET), excited state intramolecular proton transfer (ESIPT), intramolecular charge transfer (ICT), fluorescence resonance energy transfer (FRET), chelation-enhanced fluorescence (CHEF), and aggregation-induced emission (AIE) mechanisms are described. We discuss the use of various recognition mechanisms in detecting zinc ions through specific cases, some of which have been validated through theoretical calculations.

Theoretical investigation of the Zn2+ detection mechanism based on the quinoline derivative of the Schiff-base receptor.

The sensing mechanism of the quinoline-derived Schiff base HL (concentrated from 8-hydroxyquinoline with 2,4-dihydroxybenzaldehyde) as a highly selective fluorescent probe for Zn2+ was investigated by theoretical calculations with DFT and TDDFT. The conformations of the HL molecule, its ketone form and its Zinc complex structure, were optimized in the ground and excited states. The systems have been studied in depth in terms of structural parameters, frontier molecular orbitals, absorption and fluorescence spectra as well as potential energy curves analysis and approximately density gradient analysis. The present theoretical calculations propose a different detection mechanism from that proposed experimentally. The theoretical results predict that the fluorescence quenching in HL is attributed to the excited state intramolecular proton transfer (ESIPT) rather than the photoinduced electron transfer (PET) of benzene to electrons. When Zn2+ is introduced, Zn2+ takes the place of the H atom, creating a complex that blocks the ESIPT reaction and restores fluorescence.

Analysis of the Influence of Waste Seashell as Modified Materials on Asphalt Pavement Performance.

An increasing amount of waste seashells in China has caused serious environmental pollution and resource waste. This paper aims to solve these problems by using waste seashells as modified materials to prepare high-performance modified asphalt. In this study, seashell powder (SP) and stratum corneum-exfoliated seashell powder (SCESP) were adopted to prepare 10%, 20% and 30% of seashell powder-modified asphalt (SPMA) and stratum corneum-exfoliated seashell powder-modified asphalt (SCESPMA) by the high-speed shear apparatus, respectively. The appearance and composition of two kinds of SPs were observed and determined by the scanning electron microscope (SEM). The types of functional groups, temperature frequency characteristics, low temperature performance and adhesion of SPMA were tested by the Fourier-transform infrared (FTIR) spectrometer, dynamic shear rheometer (DSR), bending beam rheometer (BBR) and contact angle meter. The results show that the SP and SCESP are rough and porous, and their main component is CaCO3, which is physically miscible to asphalt. When the loading frequency ranges from 0.1 Hz to 10 Hz, the complex shear modulus (G*) and phase angle (δ) of SPMA and SCESPMA increase and decrease, respectively. At the same load frequency, SCESPMA has a larger G* and a smaller δ than SPMA. At the same temperature, SCESPMA has a larger rutting factor (G*/sin δ) and better high-temperature deformation resistance than SPMA. SP and SCESP reduce the low-temperature cracking resistance of asphalt, of which SCESP has a more adverse effect on the low-temperature performance of asphalt than SP. When SP and SCESP are mixed with asphalt, the cohesion work (Waa), adhesion work (Was) and comprehensive evaluation parameters of water stability (ER1, ER2 and ER3) of asphalt are improved. It is shown that both SP and SCESP have good water damage resistance, of which SCESP has better water damage resistance than SP. These research results have important reference value for the application of waste biological materials in asphalt pavement.

Design of Fluorescent Hybrid Materials Based on POSS for Sensing Applications.

Polyhedral oligomeric silsesquioxane (POSS) has a nanoscale silicon core and eight organic functional groups on the surface, with sizes from 0.7 to 1.5 nm. The three-dimensional nanostructures of POSS can be used to build all types of hybrid materials with specific performance and controllable nanostructures. The applications of POSS-based fluorescent materials have spread across various fields. In particular, the employment of POSS-based fluorescent materials in sensing application can achieve high sensitivity, selectivity, and stability. As a result, POSS-based fluorescent materials are attracting increasing attention due to their fascinating vistas, including unique structural features, easy fabrication, and tunable optical properties by molecular design. Here, we summarize the current available POSS-based fluorescent materials from design to sensing applications. In the design section, we introduce synthetic strategies and structures of the functionalized POSS-based fluorescent materials, as well as photophysical properties. In the application section, the typical POSS-based fluorescent materials used for the detection of various target objects are summarized with selected examples to elaborate on their wide applications.

A Theoretical Study of the Sensing Mechanism of a Schiff-Based Sensor for Fluoride.

In the current work, we studied the sensing process of the sensor (E)-2-((quinolin-8ylimino) methyl) phenol (QP) for fluoride anion (F-) with a "turn on" fluorescent response by density functional theory (DFT) and time-dependent density functional theory (TDDFT) calculations. The proton transfer process and the twisted intramolecular charge transfer (TICT) process of QP have been explored by using potential energy curves as functions of the distance of N-H and dihedral angle C-N=C-C both in the ground and the excited states. According to the calculated results, the fluorescence quenching mechanism of QP and the fluorescent response for F- have been fully explored. These results indicate that the current calculations completely reproduce the experimental results and provide compelling evidence for the sensing mechanism of QP for F-.

Enantiopure Benzofuran-2-carboxamides of 1-Aryltetrahydro-ß-carbolines Are Potent Antimalarials In Vitro.

The tetrahydro-ß-carboline scaffold has proven fertile ground for the discovery of antimalarial agents (e.g., MMV008138 (1) and cipargamin (2)). Similarity searching of a publicly disclosed collection of antimalarial hits for molecules resembling 1 drew our attention to N2-acyl tetrahydro-ß-carboline GNF-Pf-5009 ((±)-3b). Compound purchase, "analog by catalog", and independent synthesis of hits indicated the benzofuran-2-yl amide portion was required for in vitro efficacy against P. falciparum. Preparation of pure enantiomers demonstrated the pharmacological superiority of (R)-3b. Synthesis and evaluation of D- and F-ring substitution variants and benzofuran isosteres indicated a clear structure-activity relationship. Ultimately (R)-3b was tested in Plasmodium berghei-infected mice; unfavorable physicochemical properties may be responsible for the lack of oral efficacy.

Malaria Box-Inspired Discovery of N-Aminoalkyl-ß-carboline-3-carboxamides, a Novel Orally Active Class of Antimalarials.

Virtual ligand screening of a publicly available database of antimalarial hits using a pharmacophore derived from antimalarial MMV008138 identified TCMDC-140230, a tetrahydro-ß-carboline amide, as worthy of exploration. All four stereoisomers of this structure were synthesized, but none potently inhibited growth of the malaria parasite Plasmodium falciparum. Interestingly, 7e, a minor byproduct of these syntheses, proved to be potent in vitro against P. falciparum and was orally efficacious (40 mg/kg) in an in vivo mouse model of malaria.

[Acupuncture with Tiaochong Shugan method by stages for menstrual headache based on syndrome differentiation: a randomized controlled trial].

OBJECTIVE: To compare the clinical efficacy between acupuncture with Tiaochong Shugan method by stages based on syndrome differentiation and oral administration of ibuprofen sustained-release capsule in patients with menstrual headache. METHODS: A total of 90 cases with menstrual headache were randomly divided into an acupuncture group (45 cases, 1 case excluded, 3 cases dropped off) and a medication group (45 cases, 3 cases dropped off). The patients in the acupuncture group were treated with acupuncture with Tiaochong Shugan method by stages based on syndrome differentiation; during period of pain attacks, Ganshu (BL 18), Qimen (LR 14), Hegu (LI 4), Taichong (LR 3), Sizhukong (TE 23) through Shuaigu (GB 8) were selected, once a day; during period of pain relief, Qichong (ST 30), Dahe (KI 12), Guanyuan (CV 4), Taixi (KI 3) were selected, once every 1-2 days. The patients in the medication group were treated with oral administration of ibuprofen sustained-release capsule during period of pain attacks. Each menstrual cycle was taken as a course of treatment, and both groups were treated for 3 courses. The headache comprehensive score (HCS), visual analogue scale (VAS) socre, dysmenorrhea symptom score (DSS) were compared before treatment, 1, 2 and 3 courses into treatment and 1, 2, 3 menstrual cycles after treatment; the clinical efficacy was also evaluated. RESULTS: The HCS score at each time point after treatment was lower than that before treatment in the two groups (P<0.05); 2 and 3 menstrual cycles after treatment, the HCS socres in the acupuncture group were lower than those in the medication group (P<0.05). Except for the 2 and 3 menstrual cycles after treatment in the medication group, the VAS score at each time point after treatment was lower than that before treatment in the two groups (P<0.05). Except for 1 menstrual cycle into treatment, the DSS scores in the acupuncture group at each time point after treatment was lower than that before treatment (P<0.05); the DSS socres at 2 and 3 menstrual cycles into treatment and 1 menstrual cycle after treatment were lower than those before treatment in the medication group (P<0.05). Except for 1 menstrual cycle into treatment, the VAS score and DSS score in the acupuncture group were lower than those in the medication group at each time point after treatment (P<0.05). The total effective rate was 82.9% (34/41) in the acupuncture group, which was higher than 73.8% (31/42) in the medication group (P<0.05). CONCLUSION: The analgesic effect of acupuncture with Tiaochong Shugan method by stages based on syndrome differentiation is superior to oral administration of ibuprofen sustained-release capsules, which could effectively prevent the recurrence of menstrual headache, and improve irregular menstruation-related symptoms.

Quality of life in patients with endometrial carcinoma: A Longitudinal Study.

AIM: To investigate the quality of life in patients with endometrial carcinoma and provide theoretical basis for nursing care. DESIGN: In this study, 69 patients diagnosed with endometrial carcinoma from 2016-2018 were included in the cohort. METHODS: Sixty-nine patients from our hospital who underwent endometrial cancer surgeries were selected. The SF-36 was used to investigate and analyse the patients' quality of life in the first, second and third months after their operations. Questionnaires were administered to analyse the factors affecting postoperative quality of life. RESULTS: Quality of life for the second and third months was obviously better than that for the first month after the operation (p < .05). Based on multivariate regression analysis, we found that patients with higher family income had better quality of life after surgery(p < .05). These results can provide some guidance for daily nursing work after endometrial cancer operation.

Long-Lived T-Shaped Micropillars with Submicron-Villi on PP/POE Surfaces with Grinding-Enhanced Water Repellency Fabricated via Hot Compression Molding.

Superhydrophobic properties are derived from the roughness of the surface of micro/nanostructures and low-surface-energy materials. However, they are both easy to damage on superhydrophobic surfaces after mechanical abrasion in practical applications, resulting in the transition from the Cassie-Baxter state to the Wenzel state and even the loss of water repellency. In this work, the mechanical properties of polypropylene (PP) toughened with poly(ethylene-co-octene) (POE) were improved for the fabrication of long-lived T-shaped micropillars with submicron-villi on top by a combined method of compression molding and grinding. A universal testing machine was modified as equipment for the precise control of the traveling distance of specimens on sandpaper in precise. The PP/POE blend possessed high tensile strength of up to ∼23.84 MPa as well as elongation at break of ∼533.60%. The abrasive grains on sandpaper reshaped their surface morphologies from micropillars to T-shaped microstructures, on which the submicron-villi as secondary structures formed. The abraded microstructured PP/POE surface exhibited the highest contact angle of 154.4° and the most stable wetting state with a bouncing height of 7.68 mm (3.2 times the diameter of the 7-µL droplet) after a traveling distance of 1000 mm on 3000-grit sandpaper among the abraded and unabraded PP/POE surfaces.

Chemokine CXCL1 in serum mediates the antinociceptive effect of manual acupuncture at ST36.

BACKGROUND: Inflammatory pain is the most common type of pain encountered clinically. The analgesic effect of acupuncture has been well-documented. OBJECTIVE: The aim of this study was to investigate the involvement of chemokine CXCL1 in the serum on manual acupuncture (MA)-induced antinociception. METHODS: Rats with inflammatory pain of the right hind paw were induced by intraplantar (i.pl.) administration of complete Freund's adjuvant (CFA). After wards, the CFA-injected rats were treated daily with MA at ST36 from Day 1 to Day 7, and thermal nociceptive thresholds (paw withdrawal latency; PWL) were analyzed. The concentration of CXCL1 in the serum of the rats was measured by enzyme-linked immunosorbent assay (ELISA) after the first and the last MA treatment. Subsequently, the rats were injected with two doses (5 or 10 µg) of recombinant CXCL1 through the tail vein daily from Day 1 to Day 7 or injected with two doses (6.4 or 16 µg) of anti-CXCL1 antibody using the same methods and course at 30 min before MA, and the PWLs were measured again. Finally, naloxone (500 µg, 0.1 mL) was administered by i.pl. injection into the inflamed paw 5 min before the last MA treatment or last injection of recombinant CXCL1. RESULTS: MA significantly increased the PWLs and upregulated the expression of serum CXCL1 in the CFA-injected rats. Without acupuncture, repeated tail vein injection of recombinant CXCL1 showed an analgesic effect on CFA-induced inflammatory pain. Conversely, the neutralization of serum CXCL1 by anti-CXCL1 antibody decreased MA-induced antinociception in a time-dependent manner. Anti-CXCL1 antibody injected just once before the first MA did not affect MA-induced antinociception. The analgesic effects of MA and recombinant CXCL1 were reversed by an i.pl. injection of naloxone. CONCLUSION: This study indicates MA at ST36 had an analgesic effect on inflammatory pain and found a novel function of CXCL1. Increased serum CXCL1 had an antinociceptive effect on inflammatory pain induced by CFA. CXCL1 in serum appeared to be a key molecule involved in the peripheral mechanism of MA-induced antinociception. The analgesic effect of MA or recombinant CXCL1 on inflammatory pain might be mediated through a peripheral opioid pathway, which needs further investigation.

Sensing mechanism of fluorogenic urea with fluoride in solvent media: A new fluorescence quenching mechanism.

The interaction of 1-Phenyl-3-(pyren-1-yl) urea (LH) and fluoride anion (F-) with a unique ON1-OFF-ON2 fluorescent response has been investigated by the density functional theory (DFT) and time-dependent density functional theory (TDDFT) calculations. The hydrogen-bonding dynamics and photophysical properties of the complex LH-F, as well as its isolated receptor LH and anion form L-H1, have been studied in detail. We demonstrate that the intermolecular hydrogen bond (N-H…F) of the complex LH-F is greatly enhanced in the electronically excited state. The nonradiative deactivation via electron transfer and internal conversion rather than excited-state intramolecular proton transfer (ESIPT) can be facilitated by the excited state hydrogen bond strengthening. The results have been cross-validated by molecular structure, electronic spectra, frontier molecular orbitals, and infrared spectra as well as hydrogen bond binding energy. These results indicate that the current calculations completely reproduce the experimental results and provide compelling evidence for the sensing mechanism of LH for F-.

Substituent effect on ESIPT and hydrogen bond mechanism of N-(8-Quinolyl) salicylaldimine: A detailed theoretical exploration.

The effects of substituent on excited-state intramolecular proton transfer (ESIPT) and hydrogen bonding of N-(8-Quinolyl) salicylaldimine (QS) have been studied by theoretical calculation with DFT and TDDFT. The representative electron-withdrawing nitryl and electron-donating methoxyl were selected to analyze the effects on geometries, intramolecular hydrogen bond interaction, absorption/fluorescence spectra, and the ESIPT process. The configurations of the three molecules (QS, QS-OMe and QS-NO2) were optimized in the ground and excited states. The structure parameters, infrared spectra, hydrogen bond interactions, frontier molecular orbitals, absorption/fluorescence spectra, and potential curves have cross-validated the current results. The results show that the introduction of substituent results in a bathochromic-shift of the absorption and fluorescence spectra with large Stokes shift, and is more beneficial to the ESIPT process. The current work will be beneficial to the improvement of ESIPT properties and deepen understanding of the mechanism of ESIPT process.

Nickel(II)-modified covalent-organic framework film for electrocatalytic oxidation of 5-hydroxymethylfurfural (HMF).

Electrochemical oxidation of 5-hydroxymethylfurfural (HMF) is a promising synthetic route for 2,5-furandicarboxylic acid (FDCA) production. Here, we prepared a nickel(ii)-modified covalent-organic framework (COF) film TpBpy-Ni@FTO for HMF electrooxidation. With a high conversion of HMF (96%), TpBpy-Ni@FTO afforded a 58% FDCA yield. This work underlines the great potential of COF-based materials in electrocatalysis.

Hydration and Microstructure of Steel Slag as Cementitious Material and Fine Aggregate in Mortar.

Due to the low hydration activity and poor volume stability, extensive steel slag utilization is restricted. In this paper, the hydration process and microstructure of alkali-activated materials with steel slag as a cementitious material and fine aggregate were studied. The phase composition and micro-morphology of hydration products were measured using XRD, NMR and SEM. The response relationship between microstructure and mechanical properties during hydration was revealed. The results show that the main hydration products of the alkali-activated steel slag powder-granulated blast furnace slag powder cementitious system are Ca(OH)2 and calcium aluminosilicate hydrate (C-A-S-H) gel. With the progress of hydration, the amount of calcium silicate hydrate (C-S-H) gel and the average molecular chain length increase, Al[4]/Si decreases, while C/S increases first and then decreases, and the structure of cement paste becomes much more compact. The interface between steel slag sand and cement paste is denser than that of river sand, since the hydration occurs on the surface of steel slag sand, which leads to the formation of C-A-S-H gel and Ca(OH)2. As a result, the compressive strength of concrete prepared by steel slag sand is higher than that of river sand with the same mix proportion.

Probing the B- & C-rings of the antimalarial tetrahydro-ß-carboline MMV008138 for steric and conformational constraints.

The antimalarial candidate MMV008138 (1a) is of particular interest because its target enzyme (IspD) is absent in human. To achieve higher potency, and to probe for steric demand, a series of analogs of 1a were prepared that featured methyl-substitution of the B- and C-rings, as well as ring-chain transformations. X-ray crystallography, NMR spectroscopy and calculation were used to study the effects of these modifications on the conformation of the C-ring and orientation of the D-ring. Unfortunately, all the B- and C-ring analogs explored lost in vitro antimalarial activity. The possible role of steric effects and conformational changes on target engagement are discussed.

An Excited State Intramolecular Proton Transfer-Based Fluorescent Probe with a Large Stokes Shift for the Turn-on Detection of Cysteine: A Detailed Theoretical Exploration.

DFT and TDDFT calculations are adopted to study the sensing mechanism of a turn-on-type cysteine fluorescent probe (2-(1-phenyl-imidazo[1,5-α]pyridine-3-yl)phenyl acrylate, denoted as MZC-AC). The photoinduced electron transfer (PET) process of MZC-AC and the excited state intramolecular proton transfer (ESIPT) process of MZC have been investigated in detail. We demonstrate that the fluorescence quenching of MZC-AC is ascribed to the PET mechanism and the large Stokes shift fluorescence emission of MZC is the result of the ESIPT mechanism. The results have been cross-validated by geometries, frontier molecular orbital analysis, and potential energy curve scanning. As a result, our calculations completely reproduce the experimental results and give powerful evidence for the sensing mechanism of MZC-AC for cysteine.

In vitro and in vivo evaluation of the antimalarial MMV665831 and structural analogs.

Antimalarial candidates possessing novel mechanisms of action are needed to control drug resistant Plasmodium falciparum. We were drawn to Malaria Box compound 1 (MMV665831) by virtue of its excellent in vitro potency, and twelve analogs were prepared to probe its structure-activity relationship. Modulation of the diethyl amino group was fruitful, producing compound 25, which was twice as potent as 1 against cultured parasites. Efforts were made to modify the phenolic Mannich base functionality of 1, to prevent formation of a reactive quinone methide. Homologated analog 28 had reduced potency relative to 1, but still inhibited growth with EC50 ≤ 200 nM. Thus, the antimalarial activity of 1 does not derive from quinone methide formation. Chemical stability studies on dimethyl analog 2 showed remarkable hydrolytic stability of both the phenolic Mannich base and ethyl ester moieties, and 1 was evaluated for in vivo efficacy in P. berghei-infected mice (40 mg/kg, oral). Unfortunately, no reduction in parasitemia was seen relative to control. These results are discussed in the context of measured plasma and hepatocyte stabilities, with reference to structurally-related, orally-efficacious antimalarials.

Theoretical study on the sensing mechanism of an ON1-OFF-ON2 type fluoride fluorescent chemosensor.

A density functional theory (DFT) and time-dependent density functional theory (TDDFT) calculations have been used to study the sensing mechanism of an ON1-OFF-ON2 type fluoride anion fluorescent chemosensor (Bis[[7-(diethylamino)-2-oxo-2H-chromene]methyl-ene]­carbonothioic dihydrazide (CTC). The current theoretical calculation presents a different sensing mechanism from the experimentally proposed one (Sensor and Actuators B 2016, 222, 823-828). Instead of the combination of CTC deprotonation and poorly emissive excited state tautomer or ICT mechanism, the theoretical results predict the sensing mechanism based on dissociation reaction and excited-state proton transfer (ESPT). The calculated vertical excitation energies both in the ground states and first excited states of different forms of CTC, as well as the potential-energy curves, have completely reproduced the experimental results, providing powerful evidence for our proposed CTC sensing mechanism for fluoride anion.