Integrated Anchored Stapling and Hierarchical Dynamics: MSICDA-Driven CREBBP Bromodomain Inhibition.

Despite recent success in the computational approaches of cyclic peptide design, current studies face challenges in modeling noncanonical amino acids and nonstandard cyclizations due to limited data. To address this challenge, we developed an integrated framework for the tailored design of stapled peptides (SPs) targeting the bromodomain of CREBBP (CREBBP-BrD). We introduce a powerful combination of anchored stapling and hierarchical molecular dynamics to design and optimize SPs by employing the MultiScale integrative conformational dynamics assessment (MSICDA) strategy, which involves an initial virtual screening of over 1.5 million SPs, followed by comprehensive simulations amounting to 154.54 µs across 5418 of instances. The MSICDA method provides a detailed and holistic stability view of peptide-protein interactions, systematically isolated optimized peptides and identified two leading candidates, DA#430 and DA#99409, characterized by their enhanced stability, optimized binding, and high affinity toward the CREBBP-BrD. In cell-free assays, DA#430 and DA#99409 exhibited 2- to 12-fold greater potency than inhibitor SGC-CBP30. Cell studies revealed higher peptide selectivity for cancerous versus normal cells over small molecules. DA#430 combined with (+)-JQ-1 showed promising synergistic effects. Our approach enables the identification of peptides with optimized binding, high affinity, and enhanced stability, leading to more precise and effective cyclic peptide design, thereby establishing MSICDA as a generalizable and transformative tool for uncovering novel targeted drug development in various therapeutic areas.

A molecularly imprinted polypyrrole electrochemiluminescence sensor based on a novel zinc-based metal-organic framework and chitosan for determination of enrofloxacin.

Nowadays, bacterial resistance caused by the abuse of antibiotics has become a worldwide problem. In this work, a quinolone antibiotic, enrofloxacin (ENR), was rapidly monitored by combining a selective molecular imprinting polymer (MIP) with the electrochemiluminescence (ECL) method. Zn-PTC, a novel zinc-based metal-organic framework (MOF) that has a large specific surface area and ultra-high luminous efficiency, was used as the ECL luminophore. Chitosan (CHIT) was used to contact the specific surface area of molecularly imprinted polymer films and further improved the detection sensitivity. Subsequently, the molecularly imprinted polypyrrole was electropolymerized on the surface of the Zn-PTC and CHIT modified glassy carbon electrode (GCE). The specific sites that could target recombining ENR were shaped on the surface of MIP after extracting the ENR templates. The specific concentrations of ENR could be detected according to the difference in ECL intensity (ΔECL) between the eluting and rebinding of ENR. After optimization, a good linear response of ΔECL and a logarithm of specific ENR concentrations could be obtained in the range of 1.0 × 10-12-1.0 × 10-4 mol L-1, with a detection limit of 9.3 × 10-13 mol L-1 (S/N = 3). Notably, this study provided a rapid, convenient, and cheap method for the detection of ENR in actual samples.

A novel molecularly imprinting polypyrrole electrochemiluminescence sensor based on MIL-101-g-C3N4 for supersensitive determination of ciprofloxacin.

Ciprofloxacin (CIP), a quinolone antibiotic, was rapidly and sensitively detected by integrating the molecularly imprinted polymer (MIP) with an ultra-sensitive electrochemiluminescence (ECL) method. g-C3N4, a typical polymer semiconductor, exhibited outstanding ECL efficiency and excellent ECL stability after combining with an iron-based metal-organic framework (MIL-101). Subsequently, the molecularly imprinted polypyrrole was electropolymerized on the composites of MIL-101-g-C3N4 modified glassy carbon electrode (GCE). The specific sites that could target rebinding the CIP molecules were formed on the surface of MIP after extracting the CIP templates. The determination of specific concentrations of CIP could be realized according to the difference in ECL intensity (△ECL) between the eluting and rebinding of the CIP. Under optimal conditions, a good linear response of △ECL and the logarithm of CIP concentrations was obtained in the range 1.0 × 10-9 ~ 1.0 × 10-5 mol/L, with a detection limit of 4.5 × 10-10 mol/L (S/N = 3) (the working potential was -1.8 ~ 0 V). The RSD of all points in the calibration plot was less than 5.0% and the real samples recovery was between 98.0 and 104%. This paper displays satisfactory selectivity and sensitivity, providing a rapid, convenient, and cheap method for the determination of CIP in real samples.

A novel electrochemical sensor based on gold nanobipyramids and poly-L-cysteine for the sensitive determination of trilobatin.

Trilobatin is a flavonoid that has wide application prospects due to its various pharmacological effects, such as anti-inflammation and anti-oxidation. In this work, a novel electrochemical sensor based on gold nanobipyramids (AuNBs) and L-cysteine (L-cys) was constructed for the sensitive and selective determination of trilobatin. The AuNBs, which were prepared by a seed-mediated growth method, had large specific surface areas and excellent electrical conductivity. A layer of L-cys film, which provided more active sites through the amino and hydroxyl groups, was modified on the surface of the AuNBs by electropolymerization. Significantly, the Au-S bond between the L-cys film and AuNBs could improve the stability of the sensor and it exhibited satisfactory electrocatalytic oxidation activity for trilobatin. Under optimized conditions, the sensor based on poly-L-cys/AuNBs/GCE was used to determine trilobatin by differential pulse voltammetry (DPV). Two wide linear ranges between the current peak and the concentration of trilobatin were obtained in the range from 5 to 100 µM and 100 to 1000 µM, and the low detection limit (LOD) was up to 2.55 µM (S/N = 3). The sensor demonstrated desirable reproducibility, stability, and selectivity and was applied to detect real trilobatin samples extracted from Lithocarpus polystachyus Rehd.'s leaves, showing recoveries of 98.36%-104.96%, with satisfactory results.

Dual-binding domain electrochemiluminescence biosensing platform with self-checking function for sensitive detection of synthetic cathinone in e-cigarettes.

Current single signal electrochemiluminescence (ECL) sensors are susceptible to false positive or false negative phenomena due to experimental conditions. Therefore, sensors with "self-checking" function are attracting democratic attention. In quick succession, a highly sensitive single-cathode dual ECL signal aptasensor with self-checking function to improve the shortcomings mentioned above was designed. This aptasensor used In-based metal-organic framework (MIL-68) as load and stabilizer to effectively attenuate the aggregation-induced quenching (ACQ) effect of porphyrin derivatives (Sn-TCPP) while improve ECL stability. The introduction of cooperative-binding split-aptamers" (CBSAs) aptamers increased the specificity of the aptasensor and its unique double-binding domains detection accelerated the detection efficiency. When analyzing 3,4-methylenedioxypyrovalerone (MDPV), we could calculate two concentrations based on the strength of ECL 1 and ECL 2. If the concentrations are the same, the result would be obtained; if not, it should be retested. Depending on the above operation, the results achieve self-check. It was found that the designed aptasensor could quantify the concentration of MDPV between 1.0 × 10-12 g/L and 1.0 × 10-6 g/L with the limit of detection (LOD) of 1.4 × 10-13 g/L and 2.0 × 10-13 g/L, respectively (3 σ/slope). This study not only improves the detection technology of MDPV, but also explores the dual-signal detection of porphyrin for the first time and enriches the definition of self-checking sensor.

A novel three-dimensional molecularly imprinted polypyrrole electrochemical sensor based on MOF derived porous carbon and nitrogen doped graphene for ultrasensitive determination of dopamine.

Herein, a novel molecular imprinting polypyrrole electrochemical sensor was fabricated based on a zirconia and carbon core-shell structure (ZrO2@C) and a nitrogen-doped graphene (NPG) modified glassy carbon electrode (GCE) for ultrasensitive recognition of dopamine (DA). The NPG was prepared by a sacrificial-template-assisted pyrolysis method and ZrO2@C was synthesized via annealing treatment of a zirconium-based metal-organic framework (UiO-66). A convenient electropolymerization method was used to prepare the pyrrole (Py) conductive molecularly imprinted polymer (MIP) in the presence of DA. The elution process of DA was performed by a simple overoxidation process under alkaline conditions. Differential pulse voltammetry (DPV) was used to assess the electrochemical performance of the sensors. The MIP-based electrochemical sensor with specific binding sites could be used for selective recognition of DA. Under the optimal conditions, the linear range of such a sensor was 5.0 × 10-9-1.0 × 10-4 mol L-1 and the detection limit was 3.3 × 10-10 mol L-1 (S/N = 3). This sensor exhibited suitable selectivity, stability, and reproducibility, which suggested that it could be a promising candidate for rapid diagnostic methods in dopamine investigations.

Melittin Tryptophan Substitution with a Fluorescent Amino Acid Reveals the Structural Basis of Selective Antitumor Effect and Subcellular Localization in Tumor Cells.

Melittin is a membrane-active peptide with strong anticancer activity against various cancers. Despite decades of research, the role of the singular Trp in the anticancer activity and selectivity of melittin remains poorly understood. Here, we propose a theranostic solution based on the substitution of Trp19 with a noncanonical fluorescent amino acid (DapAMCA). The introduction of DapAMCA residue in melittin stabilized the helical structure of the peptide, as evaluated by circular dichroism spectra and molecular dynamics simulations. In vitro hemolytic and anticancer activity assays revealed that introducing DapAMCA residue in melittin changed its mode of action with the cell membrane, resulting in reduced hemolytic toxicity and an improved the selectivity index (SI), with up to a five-fold increase compared to melittin. In vitro fluorescence imaging of DapAMCA-labeled melittin (MELFL) in cancer cells demonstrated high membrane-penetrating activity, with strong nuclear and nucleolar localization ability. These findings provide implications for novel anticancer therapies based on Trp-substituted designs and nuclear/nucleolar targeted therapy.

Polyphenol-based hydrogels: Pyramid evolution from crosslinked structures to biomedical applications and the reverse design.

As a kind of nature-derived bioactive materials, polyphenol-based hydrogels possess many unique and outstanding properties such as adhesion, toughness, and self-healing due to their specific crosslinking structures, which have been widely used in biomedical fields including wound healing, antitumor, treatment of motor system injury, digestive system disease, oculopathy, and bioelectronics. In this review, starting with the classification of common polyphenol-based hydrogels, the pyramid evolution process of polyphenol-based hydrogels from crosslinking structures to derived properties and then to biomedical applications is elaborated, as well as the efficient reverse design considerations of polyphenol-based hydrogel systems are proposed. Finally, the existing problems and development prospects of these hydrogel materials are discussed. It is hoped that the unique perspective of the review can promote further innovation and breakthroughs of polyphenol-based hydrogels in the future.

Ultrasensitive ECL aptasensing of kanamycin based on synergistic promotion strategy using 3,4,9,10-perylenetetracar-boxylic-l-cysteine/Au@HKUST-1.

Herein, a sensitive and selective electrochemiluminescence (ECL) aptasensor was designed using Au@HKUST-1 as accelerator towards the perylene derivative (PTC-Cys)/peroxydisulfate (S2O82-) system for kanamycin (KAN) assay. Firstly, the PTC-Cys was prepared by covalently binding l-cysteine to 3,4,9,10-perylenete-tracarboxylic acid, which was acted as the luminophore. Then Au@HKUST-1could play the part of effective catalyst to accelerate the electrochemical reduction process of S2O82-to produce more sulfate radical anions (SO4•-), thus the ECL signal of the compound was noticeably raised by 2.4 times in comparison with that in which only luminophore and S2O82- are present, achieving signal amplification of the ECL system. In the presence of KAN, aptamer was pulled down from the sensing interface, achieving a considerable enhancement of ECL intensity in S2O82- solution. Upon the optimal condition, our proposed strategy can quantify the concentration of KAN from 1.0 × 10-13 to 1.0 × 10-8 M with low limit of detection of 4.2 × 10-14 M (S/N = 3).Besides, our proposed ECL aptasensor exhibited excellent sensitivity, stability and specificity, and could be successfully applied to detect KAN in practical samples, which proved its potential to detect other antibiotics in food security.

A novel electrochemiluminescence sensor based on resonance energy transfer from MoS2QDs@g-C3N4 to NH2-SiO2@PTCA for glutathione assay.

In this work, a solid-state electrochemiluminescence (ECL) sensor based on resonance energy transfer (RET) was proposed using MoS2QDs@g-C3N4 as a donor and NH2-SiO2@PTCA as an acceptor. Herein, MoS2QDs could significantly facilitate the stability and efficiency of the ECL of g-C3N4. PTCA provided a large platform to anchor NH2-SiO2 nanoparticles. The prepared MoS2QDs@g-C3N4 exhibited good spectral overlap with the UV-vis absorption spectrum of NH2-SiO2@PTCA. Based on this, we designed an "off-on" ECL sensing strategy for sensitive and selective detection of glutathione (GSH). Under the best conditions, the linear range of the sensor for GSH detection was from 0.001 to 100 µM with a detection limit of 0.63 nM (S/N = 3). More importantly, GSH in commercial samples can be detected using the proposed sensor, which indicated its superior detection capabilities and potential application value in commercial medicines.

A novel artificial intelligence protocol for finding potential inhibitors of acute myeloid leukemia.

There is currently no effective treatment for acute myeloid leukemia, and surgery is also ineffective as an important treatment for most tumors. Rapidly developing artificial intelligence technology can be applied to different aspects of drug development, and it plays a key role in drug discovery. Based on network pharmacology and virtual screening, candidates were selected from the molecular database. Nine artificial intelligence algorithm models were used to further verify the candidates' potential. The 350 training results of the deep learning model showed higher credibility, and the R-square of the training set and test set of the optimal model reached 0.89 and 0.84, respectively. The random forest model has an R-square of 0.91 and a mean square error of only 0.003. The R-square of the Adaptive Boosting model and the Bagging model reached 0.92 and 0.88, respectively. Molecular dynamics simulation evaluated the stability of the ligand-protein complex and achieved good results. Artificial intelligence models had unearthed the promising candidates for STAT3 inhibitors, and the good performance of most models showed that they still had practical value on small data sets.

A novel artificial intelligence protocol to investigate potential leads for Parkinson's disease.

Previous studies have shown that small molecule inhibitors of NLRP3 may be a potential treatment for Parkinson's disease (PD). NACHT, LRR and PYD domains-containing protein 3 (NLRP3), heat shock protein HSP 90-beta (HSP90AB1), caspase-1 (CASP1) and cellular tumor antigen p53 (TP53) have significant involvement in the pathogenesis pathway of PD. Molecular docking was used to screen the traditional Chinese medicine database TCM Database@Taiwan. Top traditional Chinese medicine (TCM) compounds with high affinities based on Dock Score were selected to form the drug-target interaction network to investigate potential candidates targeting NLRP3, HSP90AB1, CASP1, and TP53 proteins. Artificial intelligence model, 3D-Quantitative Structure-Activity Relationship (3D-QSAR) were constructed respectively utilizing training sets of inhibitors against the four proteins with known inhibitory activities (pIC50). The results showed that 2007_22057 (an indole derivative), 2007_22325 (a valine anhydride) and 2007_15317 (an indole derivative) might be a potential medicine formula for the treatment of PD. Then there are three candidate compounds identified by the result of molecular dynamics.

Applications of Surface Modification Technologies in Nanomedicine for Deep Tumor Penetration.

The impermeable barrier of solid tumors due to the complexity of their components limits the treatment effect of nanomedicine and hinders its clinical translation. Several methods are available to increase the penetrability of nanomedicine, yet they are too complex to be effective, operational, or practical. Surface modification employs the characteristics of direct contact between multiphase surfaces to achieve the most direct and efficient penetration of solid tumors. Furthermore, their simple operation makes their use feasible. In this review, the latest surface modification strategies for the penetration of nanomedicine into solid tumors are summarized and classified into "bulldozer strategies" and "mouse strategies." Additionally, the evaluation methods, existing problems, and the development prospects of these technologies are discussed.

Structural and antioxidant analysis of Tartary buckwheat (Fagopyrum tartaricum Gaertn.) 13S globulin.

BACKGROUND: The main component of buckwheat seed storage proteins is 13S globulin. In this study, Tartary buckwheat 13S globulin was separated and its structural features were investigated using Edman sequencing and matrix-assisted laser desorption / ionization time of flight mass spectrometry (MALDI-TOF-MS). The protective effect of its enzymatic hydrolysates against oxidative stress induced by H2 O2 was also evaluated to elucidate the antioxidant mechanism. RESULTS: Results showed that the isolated Tartary buckwheat 13S globulin contained one acidic and one basic subunit, which were linked by a disulfide bond. Six Tartary buckwheat active peptides were obtained from the enzymatic hydrolysates of Tartary buckwheat 13S globulin acidic subunit with a molecular weight of 38 kDa, namely Pep-1, Pep-2, Pep-3, Pep-4, Pep-5, and Pep-6. Pre-treatment of cells with Tartary buckwheat active peptides maintained the redox state balance of HepG2 cells and protected the activity of antioxidant enzymes in HepG2 cells. The Tartary buckwheat active peptides improved oxidative stress in HepG2 cells via the PPAR-α/HO-1 pathway. CONCLUSION: These results provide an insight into the antioxidant mechanism of Tartary buckwheat 13S globulin and suggest that Tartary buckwheat active peptides can be used as a functional ingredient in the food industry. © 2019 Society of Chemical Industry.

The Effect of Tartary Buckwheat Flavonoids in Inhibiting the Proliferation of MGC80-3 Cells during Seed Germination.

Tartary buckwheat (Fagopyrum tataricum (L.) Gaertn) is rich in functional compounds such as rutin, quercetin, d-chiro-inositol, dietary fiber, and essential amino acids. Electric field (EF) treatment before sprout germination results in physiological and chemical changes, and some alterations might lead to positive applications in plant seeds. MTT assay showed that the effect of total flavonoids on human gastric cancer cell line MGC80-3 was significantly changed after EF treatment for different germination days (3-7 days). Among them, the total flavonoids of tartary buckwheat (BWTF) on the third day had the most obvious inhibitory effect on MGC80-3 (p < 0.01). In addition, flow cytometry evidenced that different ratios of quercetin and rutin had effects on the proliferation of MGC80-3. The same content of quercetin and rutin had the best effect, reaching 6.18 ± 0.82%. The anti-cancer mechanism was mainly promoted by promoting the expression of apoptotic proteins. The expression of Bax/Bcl-2 and caspase-8 in MGC80-3 cells was mediated by BWTFs. This study has good research value for improving the biological and economic value of tartary buckwheat.

A Solid-state Electrochemiluminescence Sensor for Detecting Glutathione with a Graphite-phase Carbon Nitride/Silica Modified Glassy Carbon Electrode.

A solid-state electrochemiluminescence (ECL) sensor for the detection of reduced glutathione (GSH) based on a g-C3N4/SiO2 modified glass carbon electrode (GCE) has been developed in this research. The g-C3N4, which is employed as a luminophore, is simply prepared and exhibits an excellent ECL response. Mesoporous silica hollow spheres (SiO2) with a large specific surface area are introduced here to increase the loading amount of g-C3N4. Compared to a g-C3N4 modified GCE, the g-C3N4/SiO2 modified GCE displays a much higher ECL intensity. A high enhancement effect on the ECL intensity of g-C3N4/SiO2 modified GCE is obtained in the presence of GSH in the electrolyte. Moreover, the enhanced ECL intensity shows a good linear relationship to the GSH concentration in the range from 1.0 × 10-7 to 5.0 × 10-4 M, with a detection limit of 2.0 × 10-8 M (6.1 ng/mL). Besides, the ECL sensor exhibits a good anti-interference ability and has been successfully applied in the detection of GSH in commercial samples. The proposed sensor provides a promising platform for life science.

Evaluation of Surface Structure of Escherichia coli Using Polypyrrole Matrix.

We propose a method to evaluate the surface structure of Escherichia coli focusing on the doping state of bacterial cells into polypyrrole (PPy) matrix. We found that the orientation of doping states of E. coli O rough was different from those of other serotypes of E. coli cells, which had O-antigen on their outer membrane. The results indicated that more than seventy percent of E. coli cells having O-antigen was horizontally doped into PPy matrix based on the chemical structure and the placement of O-antigen. On the other hand, the percentage for horizontal doping state of E. coli O rough cells was only approximately fifty percent. Moreover, the cells of each E. coli serotypes were specifically bound to their own shape-complementary cavities on the microspheres, but the binding affinity of E. coli O rough was a bit lower than that of other serotypes.

Early-life food nutrition, microbiota maturation and immune development shape life-long health.

The current knowledge about early-life nutrition and environmental factors that affect the interaction between the symbiotic microbiota and the host immune system has demonstrated novel regulatory target for treating allergic diseases, autoimmune disorders and metabolic syndrome. Various kinds of food nutrients (such as dietary fiber, starch, polyphenols and proteins) can provide energy resources for both intestinal microbiota and the host. The indigestible food components are fermented by the indigenous gut microbiota to produce diverse metabolites, including short-chain fatty acids, bile acids and trimethylamine-N-oxide, which can regulate the host metabolized physiology, immunity homeostasis and health state. Therefore it is commonly believed early-life perturbation of the microbial community structure and the dietary nutrition interference on the child mucosal immunity contribute to the whole life susceptibility to chronic diseases. In all, the combined interrelationship between food ingredients nutrition, intestinal microbiota configurations and host system immunity provides new therapeutic targets to treat various kinds of pathogenic inflammations and chronic diseases.

Facile synthesis of core-shell nanostructured hollow carbon nanospheres@nickel cobalt double hydroxides as high-performance electrode materials for supercapacitors.

Core-shell nanostructured hollow carbon nanospheres@nickel cobalt double hydroxides (HCNs@NiCo-LDH) were fabricated using a facile hydrothermal method and investigated as high-performance electrode materials for supercapacitors. HCNs were acquired by a successive polymerization, carbonization and etching process, which was subsequently wrapped by ultrathin NiCo-LDH nanosheets. The HCNs@NiCo-LDH electrode achieved a high specific capacitance (2558 F g-1 at 1 A g-1) and outstanding rate capability with 74.9% capacitance retention after a 20-fold increase in current density. Capacitances of 2405, 2310, 2168, 2006 and 1916 F g-1 can be achieved at rates of 3, 5, 10, 15 and 20 A g-1, respectively, which are much higher than the specific capacitances of most reported carbon loaded NiCo-LDH. Specifically, the assembled HCNs@NiCo-LDH//graphene asymmetric supercapacitor displayed distinguished capacitive behaviors with a prominent specific capacitance of 172.8 F g-1 and eminent cycling stability with 93.5% capacitance retention after 3000 cycles. These remarkable electrochemical properties indicate that the unique HCNs@NiCo-LDH core-shell electrode is highly promising for application in energy storage fields.