Deguelin and Paclitaxel Loaded PEG-PCL Nano-Micelles for Suppressing the Proliferation and Inducing Apoptosis of Breast Cancer Cells.

BACKGROUND: Deguelin (DGL) is a natural flavonoid reported to exhibit antitumor effects in breast cancer (BC). PEG-PCL (Polyethylene Glycol- Polycaprolactone), as polymeric micelles, has biodegradability and biocompatibility. The aim of this study was to investigate whether the nanoparticular delivery system, PEG-PCL could improve the bioavailability of DGL for suppressing proliferation of BC cells. METHODS: PEG-PCL polymers were first prepared by ring-opening polymerization, and DGL and paclitaxel (PTX)-loaded PEG-PCL nano-micelles were formulated via the film dispersion method. The composition and molecular weight of PEG-PCL were analyzed by nuclear magnetic resonance and fourier Transform infrared spectroscopy (FTIR) spectra. Particle size, surface potential and hemolytic activity of micelles were assessed by dynamic light scattering, transmission electron microscopy and hemolysis assay, respectively. Then proliferation and apoptosis of MDA-MB-231 and MDA-MB-468 cells were tested with Edu staining, CCK-8, TUNEL staining, and Flow cytometer. Caspase 3 expression was also assessed by Western blot. RESULTS: Our results first indicated that PEG2000-PCL2000 was successfully synthesized. DGL and PTX-loaded PEG-PCL nano-micelles were rounded in shape with a particle size of 35.78 ± 0.35 nm and a surface potential of 2.84 ± 0.27 mV. The micelles had minimal hemolytic activity. Besides, we proved that DGL and PTX-loaded PEG-PCL nano-micelles could suppress proliferation and induce apoptosis in BC cells. The DGL and PTX-loaded PEG-PCL nano-micelles constructed in this study had a prominent inhibitory role on proliferation and a remarkable promotional role on apoptosis in BC cells. CONCLUSIONS: This study proposes that nano-micelles formed by PEG-PCL can enhance the cytotoxicity of Paclitaxel against breast cancer cells, and concurrently, the loading of Deguelin may further inhibit cell proliferation. This presents a potential for the development of a novel therapeutic strategy.

Enhancing the Physicochemical Attributes of Dough and Noodles through the Incorporation of Bacillus vallismortis Laccase.

This investigation examined how the Bacillus vallismortis laccase (rBVL-MRL522) influenced the physicochemical characteristics, structural attributes, and functional capabilities of both dough and noodles. Incorporating rBVL-MRL522 (1 U/g) did not lead to a substantial change in the water absorption of wheat flour. However, the introduction of rBVL-MRL522 caused a significant elongation in the formation time of wheat flour dough, extending it by 88.9%, and also resulted in a 50% increase in the stabilization duration of wheat flour dough. Furthermore, adding rBVL-MRL522 led to a proportional rise in both the elastic and viscous moduli (G'' of the dough, signifying that r-BVL (rBVL-MRL522) has a beneficial effect on the gluten strength of the dough. Integrating rBVL-MRL522 promoted the consolidation of the gluten-based cross-linked structure within the dough, decreasing the size of starch particles and, more evenly, the dispersion of these starch particles. In the noodle processing, adding rBVL-MRL522 at a rate of 1 U/g raised the L* value of the noodles by 2.34 units compared to the noodles prepared without the inclusion of rBVL-MRL522. Using a greater amount of rBVL-MRL522 (2 U/g) substantially increased the hardness of the noodles by 51.31%. Additionally, rBVL-MRL522 showed a noteworthy enhancement in the elasticity, cohesiveness, and chewiness of the noodles. In conclusion, rBVL-MRL522 promoted the cross-linking gluten, leading to a more extensive and condensed three-dimensional network structure in raw and cooked noodles. As a result, this study offers valuable insights into the environmentally friendly processing of dough and associated products.

LEARN algorithm: a novel option for predicting non-alcoholic steatohepatitis.

Background: There is an unmet need for accurate non-invasive methods to diagnose non-alcoholic steatohepatitis (NASH). Since impedance-based measurements of body composition are simple, repeatable and have a strong association with non-alcoholic fatty liver disease (NAFLD) severity, we aimed to develop a novel and fully automatic machine learning algorithm, consisting of a deep neural network based on impedance-based measurements of body composition to identify NASH [the bioeLectrical impEdance Analysis foR Nash (LEARN) algorithm]. Methods: A total of 1,259 consecutive subjects with suspected NAFLD were screened from six medical centers across China, of which 766 patients with biopsy-proven NAFLD were included in final analysis. These patients were randomly subdivided into the training and validation groups, in a ratio of 4:1. The LEARN algorithm was developed in the training group to identify NASH, and subsequently, tested in the validation group. Results: The LEARN algorithm utilizing impedance-based measurements of body composition along with age, sex, pre-existing hypertension and diabetes, was able to predict the likelihood of having NASH. This algorithm showed good discriminatory ability for identifying NASH in both the training and validation groups [area under the receiver operating characteristics (AUROC): 0.81, 95% CI: 0.77-0.84 and AUROC: 0.80, 95% CI: 0.73-0.87, respectively]. This algorithm also performed better than serum cytokeratin-18 neoepitope M30 (CK-18 M30) level or other non-invasive NASH scores (including HAIR, ION, NICE) for identifying NASH (P value <0.001). Additionally, the LEARN algorithm performed well in identifying NASH in different patient subgroups, as well as in subjects with partial missing body composition data. Conclusions: The LEARN algorithm, utilizing simple easily obtained measures, provides a fully automated, simple, non-invasive method for identifying NASH.

Rationally Designed Enzyme-Resistant Peptidic Assemblies for Plasma Membrane Targeting in Cancer Treatment.

Peptides are being increasingly important for subcellular targeted cancer treatment to improve specificity and reverse multidrug resistance. However, there has been yet any report on targeting plasma membrane (PM) through self-assembling peptides. A simple synthetic peptidic molecule (tF4) is developed. It is revealed that tF4 is carboxyl esterase-resistant and self-assembles into vesical nanostructures. Importantly, tF4 assemblies interact with PM through orthogonal hydrogen bonding and hydrophobic interaction to regulate cancer cellular functions. Mechanistically, tF4 assemblies induce stress fiber formation, cytoskeleton reconstruction, and death receptor 4/5 (DR4/5) expression in cancer cells. DR4/5 triggers extrinsic caspase-8 signaling cascade, resulting in cell death. The results provide a new strategy for developing enzyme-resistant and PM-targeting peptidic molecules against cancer.

Segmentation of thyroid glands and nodules in ultrasound images using the improved U-Net architecture.

BACKGROUND: Identifying thyroid nodules' boundaries is crucial for making an accurate clinical assessment. However, manual segmentation is time-consuming. This paper utilized U-Net and its improved methods to automatically segment thyroid nodules and glands. METHODS: The 5822 ultrasound images used in the experiment came from two centers, 4658 images were used as the training dataset, and 1164 images were used as the independent mixed test dataset finally. Based on U-Net, deformable-pyramid split-attention residual U-Net (DSRU-Net) by introducing ResNeSt block, atrous spatial pyramid pooling, and deformable convolution v3 was proposed. This method combined context information and extracts features of interest better, and had advantages in segmenting nodules and glands of different shapes and sizes. RESULTS: DSRU-Net obtained 85.8% mean Intersection over Union, 92.5% mean dice coefficient and 94.1% nodule dice coefficient, which were increased by 1.8%, 1.3% and 1.9% compared with U-Net. CONCLUSIONS: Our method is more capable of identifying and segmenting glands and nodules than the original method, as shown by the results of correlational studies.

Ti3C2 MXene promoted Fe3+/H2O2 fenton oxidation: Comparison of mechanisms under dark and visible light conditions.

The performance and mechanisms of a titanium carbide (Ti3C2) MXene modified Fe3+/hydrogen peroxide (H2O2) system were compared in detail under dark and visible light conditions, with a new mechanism proposed for the reaction and reduction of MXene by Fe3+. Using Bisphenol A (BPA) as the target pollutant, the degradation of BPA by the Fe3+/H2O2 system was improved after adding MXene in the dark, and the degradation rate of BPA was ≥ 95 % within 12.5 min under visible light, six times higher than that in the dark. Fe2+ was ascertained to be the effective component responsible for H2O2 activation to produce ·OH. SEM, XPS, ICP, XRD, and FTIR spectroscopy, analyses show that MXene and Fe3+ form a complex, and then MXene reacts with Fe3+ by breaking the Ti-C bonding to accelerate the Fe3+/Fe2+ cycle. MXene uses photogenerated electrons to promote this reaction under visible light. In addition, quenching experiments and electron spin resonance spectroscopy results show that ·OH and O2•- are the main reactive oxygen species under visible light, while ·OH is the main active species in the dark. MXene thus effectively uses O2 to form O2•- under visible light and promotes the Fe3+/Fe2+ cycle. This study provides a theoretical basis for the combination of visible light catalysis and the advanced oxidation process of a Ti3C2 MXene.

A Dead Reckoning Calibration Scheme Based on Optimization with an Adaptive Quantum-Inspired Evolutionary Algorithm for Vehicle Self-Localization.

Parameter calibration is critical for self-localization based on dead reckoning in the control of intelligent vehicles such as autonomous driving. Most traditional calibration methods for robotics control based on dead reckoning rely on data collection with specially designed paths. For the calibration of parameters in the control of intelligent vehicles, the design of such paths is considered impossible due to the complexity of road conditions. To solve this problem, an optimization-based dead reckoning calibration scheme is introduced in this research using the differential global positioning system to obtain the actual positions of the intelligent vehicle. In this scheme, the difference between the positions obtained through dead reckoning and the positions obtained through the differential global positioning system is selected as the optimization objective function to be minimized. An adaptive quantum-inspired evolutionary algorithm is developed to improve the quality and efficiency of optimization. Experiments with an intelligent vehicle were also conducted to demonstrate the effectiveness of the developed calibration scheme. In addition, the newly introduced adaptive quantum-inspired evolutionary algorithm is compared with the classic genetic algorithm and the classic quantum-inspired evolutionary algorithm using eight benchmark test functions considering computation quality and efficiency.

Efficacy and Safety of Non-Steroidal Mineralocorticoid Receptor Antagonists in Patients With Chronic Kidney Disease and Type 2 Diabetes: A Systematic Review Incorporating an Indirect Comparisons Meta-Analysis.

Background: The non-steroidal mineralocorticoid receptor antagonists (MRAs) are promising treatments in patients with chronic kidney disease (CKD) and type 2 diabetes (T2D). We conducted a meta-analysis to explore the efficacy and safety of the non-steroidal MRAs (finerenone, apararenone, esaxerenone) and detect the differences among them. Methods: We searched several databases for eligible randomized controlled trials (RCTs) investigating non-steroidal MRAs versus placebo in patients with CKD and T2D. We performed a conventional meta-analysis separately, and then indirect comparisons for efficacy and safety outcomes were conducted among these included drugs. Results: Eight RCTs with 14,450 subjects were enrolled. In patients with CKD and T2D, a greater reduction in urinary albumin-to-creatinine ratio (UACR) (WMD -0.40, 95% CI -0.48 to -0.32, p < 0.001), estimated glomerular filtration rate (eGFR) (WMD -2.69, 95% CI -4.47 to -0.91, p = 0.003), systolic blood pressure (SBP) (WMD -4.84, 95% CI -5.96 to -3.72, p < 0.001) and a higher risk of hyperkalemia (RR 2.07, 95% CI 1.86 to 2.30, p < 0.001) were observed in the non-steroidal MRAs versus placebo; there is no significant difference in the incidence of serious adverse events between two groups (RR 1.32, 95% CI 0.98 to 1.79, p = 0.067). Compared with finerenone, esaxerenone showed no significant difference in UACR reduction (WMD 0.24, 95% CI -0.016 to 0.496, p = 0.869); apararenone and esaxerenone showed greater decreases in SBP (WMD 1.37, 95% CI 0.456 to 2.284, p = 0.010; WMD 3.11, 95% CI 0.544 to 5,676, p = 0.021). Conclusions: Despite the moderate increased risk of hyperkalemia, use of non-steroidal MRAs could reduce proteinuria and SBP in patients with CKD and T2D. In terms of renoprotection, esaxerenone and finerenone may have similar effects. Esaxerenone and apararenone may have better antihypertensive effects than finerenone. The head-to-head RCTs are still needed to compare the differences of the efficacy and safety in these non-steroidal MRAs.

Distribution characteristics of microplastics in urban rivers in Chengdu city: The influence of land-use type and population and related suggestions.

In this study, microplastics (MPs) in urban rivers in the Chengdu eco-zone were systematically studied. Microscopic observations and Fourier-transform infrared spectroscopy were used to determine the microplastic (MP) types. The MPs abundance ranged from 20.92 items/L to 762.95 items/L in water and from 20.92 items/100 g dry weight to 58.57 items/100 g dry weight in sediment. In both the water sample and sediment samples, the dominant MPs morphologies were fibres, lumps, and fragments, and the size of MPs was predominantly distributed in the 50-500 µm rage. The primary polymers were polyethylene (PE), polypropylene (PP), polystyrene (PS), and polyethylene terephthalate (PET). Locations with large populations and large areas of woodland and construction land tended to exhibit higher concentrations of MPs. Additionally, compared to water samples, sediment exhibited a more reliable correlation fitting data, thus indicating that sediment was more stable in reflecting the presence of MPs in rivers. This study supplemented the gap in MPs pollution in urban rivers in Chengdu city and discussed the impact of land use and population on the distribution of MPs. Suggestions were provided to alleviate MPs pollution in urban rivers from the perspective of urban planning.

Recent advances in nanotechnology mediated mitochondria-targeted imaging.

Mitochondria play a critical role in cell growth and metabolism. And mitochondrial dysfunction is closely related to various diseases, such as cancers, and neurodegenerative and cardiovascular diseases. Therefore, it is of vital importance to monitor mitochondrial dynamics and function. One of the most widely used methods is to use nanotechnology-mediated mitochondria targeting and imaging. It has gained increasing attention in the past few years because of the flexibility, versatility and effectiveness of nanotechnology. In the past few years, researchers have implemented various types of design and construction of the mitochondrial structure dependent nanoprobes following assorted nanotechnology pathways. This review presents an overview on the recent development of mitochondrial structure dependent target imaging probes and classifies it into two main sections: mitochondrial membrane targeting and mitochondrial microenvironment targeting. Also, the significant impact of previous research as well as the application and perspectives will be demonstrated.

Lipid-Raft-Targeted Molecular Self-Assembly Inactivates YAP to Treat Ovarian Cancer.

The Yes-associated protein (YAP) is a major oncoprotein responsible for cell proliferation control. YAP's oncogenic activity is regulated by both the Hippo kinase cascade and uniquely by a mechanical-force-induced actin remodeling process. Inspired by reports that ovarian cancer cells specifically accumulate the phosphatase protein ALPP on lipid rafts that physically link to actin cytoskeleton, we developed a molecular self-assembly (MSA) technology that selectively halts cancer cell proliferation by inactivating YAP. We designed a ruthenium-complex-peptide precursor molecule that, upon cleavage of phosphate groups, undergoes self-assembly to form nanostructures specifically on lipid rafts of ovarian cancer cells. The MSAs exert potent, cancer-cell-specific antiproliferative effects in multiple cancer cell lines and in mouse xenograft tumor models. Our work illustrates how basic biochemical insights can be exploited as the basis for a nanobiointerface fabrication technology which links nanoscale protein activities at specific subcellular locations to molecular biological activities to suppress cancer cell proliferation.

Promoting Dual-Targeting Anticancer Effect by Regulating the Dynamic Intracellular Self-Assembly.

Despite the promise of nanomedicine in the fight against complex diseases, the enthusiasm for its pharmaceutical development is backed by the elevated costs associated with the R&D process. Therefore, as a compromise solution, nanotechnology was mainly applied as a drug delivery system to improve bioavailability and controllability of pharmaceutical drugs. Attempting to break the restrictions without elevating potential costs, we multiply the functions of excipients in the nanodelivery system by endowing subcellular-targeting ability. To prove the concept, fluorescent endoplasmic reticulum-targeted short peptides were covalently connected to chemotherapy medication chlorambucil achieving enhanced drug-loading efficiency. Via visualized intracellular dynamic enzyme-catalyzed hydrolysis, the ER-targeting excipient and nucleus-targeting chlorambucil are released simultaneously, achieving a synergistic anticancer effect and elucidating the influence of intracellular self-assembly transition on enzymatic reactions.

Constructing Cross-Linked Nanofibrous Scaffold via Dual-Enzyme-Instructed Hierarchical Assembly.

To explore the potential of step-by-step assembly in the fabrication of biological materials, we designed and synthesized two peptide-based molecules for enzyme-instructed hierarchical assembly. Upon the treatment of alkaline phosphatase, one molecule undergoes enzyme-instructed self-assembly forming uniformed nanofibers. The other one that can self-assemble into vesicles undergoes enzyme-induced transformation of self-assembly converting vesicles into irregular aggregates upon the treatment of carboxylesterase. Coadministration of two enzymes to a mixture of these two molecules in a stage-by-stage fashion leads to a physically knotted nanofibrous scaffold that is applicable as a nanostructured matrix for cell culture.

Integrin and Heparan Sulfate Dual-Targeting Peptide Assembly Suppresses Cancer Metastasis.

Metastasis is one of the ongoing challenges in cancer therapy which most treatments failed to address. Inspired by the upregulated expression of both integrin ß1 and heparan sulfate in metastatic tumors, we developed an integrin/HS dual-targeting peptide assembly that selectively inhibits cancer cell migration and invasion. Particularly, the dual-targeting peptide self-assembles into nanofibrous microdomains specifically on the cancer cell membrane, triggering spatial organization of integrins, which form clusters on the apical membrane. Via the actin cytoskeleton that physically connects to integrin clusters, the oncogene yes-associated protein, which regulates cancer metastasis, is deactivated. We showed that in multiple cancer cell lines, including the highly metastatic pancreatic cancer cells, the dual-targeting peptide exerts potent and dose-dependent antimetastatic effects. Our work illustrates how basic biochemical insights can be exploited as the basis for nano-biointerface fabrication, which is potentially a general design strategy for nanomedicine development.

Mechanoresponsive Alignment of Molecular Self-Assembled Negatively Charged Nanofibrils.

Inspired by the mechanoresponsive orientation of actin filaments in cell, we introduce a design paradigm of synthetic molecular self-assembling fibrils that respond to external mechanical force by transforming from a macroscopically disorder state to a highly ordered uniaxial aligned state. The incorporation of aromatic-containing amino acids and negatively charged amino acids lead to self-assembly motifs that transform into uniform nanofibrils in acidic solution. Adjusting the pH level of aqueous solution introduces optimal negative charge to the surface of self-assembling nanofibrils inducing long-range electrostatic repulsion forming a nematic phase. Upon external mechanical force, nanofibrils align in the force direction. Via evaporation casting in capillary confinement, the solvated synthetic self-assembling nanofibrils transform into scalable lamellar domains. Adjusting capillary geometry and drying procedure offers further parameters for tuning the mesoscale alignment of nanofibrils generating a variety of interference colors. The design paradigm of mechanoresponsive alignment of self-assembled nanofibrils as an addition of nanofabrication techniques is potentially employable for realizing biomimetic optical structures.

Self-delivery of N-hydroxylethyl peptide assemblies to the cytosol inducing endoplasmic reticulum dilation in cancer cells.

Inspired by clinical studies on alcohol abuse induced endoplasmic reticulum disruption, we designed a N-hydroxylethyl peptide assembly to regulate the ER stress response in cancer cells. Upon coupling with a coumarin derivative via an ester linkage, a prodrug was synthesized to promote esterase-facilitated self-delivery of N-hydroxylethyl peptide assemblies around the ER, inducing ER dilation. Following this, ER-specific apoptosis was effectively and efficiently activated in various types of cancer cells including drug resistant and metastatic ones.

Correction: Enzyme-mediated dual-targeted-assembly realizes a synergistic anticancer effect.

Correction for 'Enzyme-mediated dual-targeted-assembly realizes a synergistic anticancer effect' by Dingze Mang et al., Chem. Commun., 2019, 55, 6126-6129.

Enzyme-mediated dual-targeted-assembly realizes a synergistic anticancer effect.

We designed and synthesized homochiral-peptide-based boron diketonate complexes. Co-administration of the two stereoisomers in cancer cells led to molecular assembly targeting both the plasma membrane and the lysosomes mediated via membrane-bonded enzymes. The dual-targeted-assembly generates a synergistic anticancer effect with amplified cancer spheroid toxicity and enhanced inhibition efficacy on cancer cell migration.

Self-Assembly-Directed Cancer Cell Membrane Insertion of Synthetic Analogues for Permeability Alteration.

Inspired by the metamorphosis of pore-forming toxins from soluble inactive monomers to cytolytic transmembrane assemblies, we developed self-assembly-directed membrane insertion of synthetic analogues for permeability alteration. An expanded π-conjugation-based molecular precursor with an extremely high rigidity and a long hydrophobic length that is comparable to the hydrophobic width of plasma membrane was synthesized for membrane-inserted self-assembly. Guided by the cancer biomarker expression in vitro, the soluble precursors transform into hydrophobic monomers  forming assemblies inserted into the fluid phase of the membrane exclusively. Membrane insertion of rigid synthetic analogues destroys the selective permeability of the plasma membrane gradually. It eventually leads to cancer cell death, including drug resistant cancer cells.

Regulating Higher-Order Organization through the Synergy of Two Self-Sorted Assemblies.

The extracellular matrix (ECM) is the natural fibrous scaffold that regulates cell behavior in a hierarchical manner. By mimicking the dynamic and reciprocal interactions between ECM and cells, higher-order molecular self-assembly (SA), mediated through the dynamic growth of scaffold-like nanostructures assembled by different molecular components, was developed. Designed and synthesized were two self-sorted coumarin-based gelators, a peptide molecule and a benzoate molecule, which self-assemble into nanofibers and nanobelts, respectively, with different dynamic profiles. Upon the dynamic growth of the fibrous scaffold assembled from peptide gelators, nanobelts assembled from benzoate gelators transform into a layer-by-layer nanosheet, reaching ninefold increase in height. By using light and an enzyme, the spatial-temporal growth of the scaffold can be modified, leading to in situ height regulation of the higher-order architecture.