Insights into 4-hydroxyphenylpyruvate dioxygenase-inhibitor interactions from comparative structural biology.

4-Hydroxyphenylpyruvate dioxygenase (HPPD) plays a key role in tyrosine metabolism and has been identified as a promising target for herbicide and drug discovery. The structures of HPPD complexed with different types of inhibitors have been determined previously. We summarize the structures of HPPD complexed with structurally diverse molecules, including inhibitors, natural products, substrates, and catalytic intermediates; from these structures, the detailed inhibitory mechanisms of different inhibitors were analyzed and compared, and the key structural factors determining the slow-binding behavior of inhibitors were identified. Further, we propose four subpockets that accommodate different inhibitor substructures. We believe that these analyses will facilitate in-depth understanding of the enzymatic reaction mechanism and enable the design of new inhibitors with higher potency and selectivity.

Glycoursodeoxycholic Acid Alleviates Arterial Thrombosis via Suppressing Diacylglycerol Kinases Activity in Platelet.

BACKGROUND: Glycoursodeoxycholic acid (GUDCA) has been acknowledged for its ability to regulate lipid homeostasis and provide benefits for various metabolic disorders. However, the impact of GUDCA on arterial thrombotic events remains unexplored. The objective of this study is to examine the effects of GUDCA on thrombogenesis and elucidate its underlying mechanisms. METHODS: Plasma samples from patients with arterial thrombotic events and diet-induced obese mice were collected to determine the GUDCA concentrations using mass spectrometry. Multiple in vivo murine thrombosis models and in vitro platelet functional assays were conducted to comprehensively evaluate the antithrombotic effects of GUDCA. Moreover, lipidomic analysis was performed to identify the alterations of intraplatelet lipid components following GUDCA treatment. RESULTS: Plasma GUDCA level was significantly decreased in patients with arterial thrombotic events and negatively correlated with thrombotic propensity in diet-induced obese mice. GUDCA exhibited prominent suppressing effects on platelet reactivity as evidenced by the attenuation of platelet activation, secretion, aggregation, spreading, and retraction (P<0.05). In vivo, GUDCA administration robustly alleviated thrombogenesis (P<0.05) without affecting hemostasis. Mechanistically, GUDCA inhibited DGK (diacylglycerol kinase) activity, leading to the downregulation of the phosphatidic acid-mediated signaling pathway. Conversely, phosphatidic acid supplementation was sufficient to abolish the antithrombotic effects of GUDCA. More importantly, long-term oral administration of GUDCA normalized the enhanced DGK activity, thereby remarkably alleviating the platelet hyperreactivity as well as the heightened thrombotic tendency in diet-induced obese mice (P<0.05). CONCLUSIONS: Our study implicated that GUDCA reduces platelet hyperreactivity and improves thrombotic propensity by inhibiting DGKs activity, which is a potentially effective prophylactic approach and promising therapeutic agent for arterial thrombotic events.

Enhancing the spatial resolution of light-field displays without losing angular resolution by a computational subpixel realignment.

Low spatial resolution is an urgent problem in integral imaging light-field displays (LFDs). This study proposes a computational method to enhance the spatial resolution without losing angular resolution. How rays reconstruct voxels through lenslets is changed so that every ray through a lenslet merely provides a subpixel. The three subpixels of a pixel no longer form one voxel but three independent voxels. We further demonstrate imperfect integration of subpixels, called the sampling error, can be eliminated on specific image depths, including the central depth plane. By realigning subpixels in the above manner under no sampling error, the sampling rate of voxels is three times the conventional pixel-based LFDs. Moreover, the ray number of every voxel is preserved for an unaffected angular resolution. With unavoidable component alignment errors, resolution gains of 2.52 and 2.0 are verified in simulation and experiment by computationally updating the elemental image array. The proposed computational method further reveals that LFDs intrinsically have a higher space-bandwidth product than presumed.

Co-Assembly of Carbon Nanotube Porins into Biomimetic Peptoid Membranes.

Robust and cost-effective membrane-based separations are essential to solving many global crises, such as the lack of clean water. Even though the current polymer-based membranes are widely used for separations, their performance and precision can be enhanced by using a biomimetic membrane architecture that consists of highly permeable and selective channels embedded in a universal membrane matrix. Researchers have shown that artificial water and ion channels, such as carbon nanotube porins (CNTPs), embedded in lipid membranes can deliver strong separation performance. However, their applications are limited by the relative fragility and low stability of the lipid matrix. In this work, we demonstrate that CNTPs can co-assemble into two dimension (2D) peptoid membrane nanosheets, opening up a way to produce highly programmable synthetic membranes with superior crystallinity and robustness. A combination of molecular dynamics (MD) simulations, Raman spectroscopy, X-ray diffraction (XRD), and atomic force microscopy (AFM) measurements to verify the co-assembly of CNTP and peptoids are used and show that it does not disrupt peptoid monomer packing within the membrane. These results provide a new option for designing affordable artificial membranes and highly robust nanoporous solids.

Real-time computer-generated integral imaging light field displays: revisiting the point retracing rendering method from a signal processing perspective.

Integral imaging light field displays (InIm-LFDs) can provide realistic 3D images by showing an elemental image array (EIA) under a lens array. However, it is always challenging to computationally generate an EIA in real-time with entry-level computing hardware because the current practice that projects many viewpoints to the EIA induces heavy computations. This study discards the viewpoint-based strategy, revisits the early point retracing rendering method, and proposes that InIm-LFDs and regular 2D displays share two similar signal processing phases: sampling and reconstructing. An InIm-LFD is demonstrated to create a finite number of static voxels for signal sampling. Each voxel is invariantly formed by homogeneous pixels for signal reconstructing. We obtain the static voxel-pixel mapping through arbitrarily accurate raytracing in advance and store it as a lookup table (LUT). Our EIA rendering method first resamples input 3D data with the pre-defined voxels and then assigns every voxel's value to its homogeneous pixels through the LUT. As a result, the proposed method reduces the computational complexity by several orders of magnitude. The experimental rendering speed is as fast as 7 to 10 ms for a full-HD EIA frame on an entry-level laptop. Finally, considering a voxel may not be perfectly integrated by its homogeneous pixels, called the sampling error, the proposed and conventional viewpoint-based methods are analyzed in the Fourier domain. We prove that even with severe sampling errors, the two methods negligibly differ in the output signal's frequency spectrum. We expect the proposed method to break the long-standing tradeoff between rendering speed, accuracy, and system complexity for computer-generated integral imaging.

Divergent Construction of Thiochromanes and N-Arylbutanamides via Arylthiodifluoromethyl Radical-Triggered Cascade of Alkenes.

A strategy utilizing silver-catalyzed oxidative decarboxylation radical cascade cyclization of arylthiodifluoroacetic acids with alkenes for the simple and efficient preparation of difluoromethylated thiochromanes and 2,2-disubstituted-N-arylbutanamides derivatives has been developed. This approach includes good functional group tolerance, easily accessible starting materials, and operational simplicity.

Hierarchical Nanomaterials Assembled from Peptoids and Other Sequence-Defined Synthetic Polymers.

In nature, the self-assembly of sequence-specific biopolymers into hierarchical structures plays an essential role in the construction of functional biomaterials. To develop synthetic materials that can mimic and surpass the function of these natural counterparts, various sequence-defined bio- and biomimetic polymers have been developed and exploited as building blocks for hierarchical self-assembly. This review summarizes the recent advances in the molecular self-assembly of hierarchical nanomaterials based on peptoids (or poly-N-substituted glycines) and other sequence-defined synthetic polymers. Modern techniques to monitor the assembly mechanisms and characterize the physicochemical properties of these self-assembly systems are highlighted. In addition, discussions about their potential applications in biomedical sciences and renewable energy are also included. This review aims to highlight essential features of sequence-defined synthetic polymers (e.g., high stability and protein-like high-information content) and how these unique features enable the construction of robust biomimetic functional materials with high programmability and predictability, with an emphasis on peptoids and their self-assembled nanomaterials.

Efficacy and safety of immune checkpoint inhibitors combined with anti-VEGF therapy in the treatment of unresectable or advanced liver cancer: a systematic review.

OBJECTIVE: This study aimed to evaluate the clinical effects and safety of immune checkpoint inhibitors (ICIs) combined with anti-VEGF therapy for the treatment of unresectable or advanced liver cancer. METHOD: Related databases were searched from inception to December 2022 to identify randomized controlled studies and clinical trials that evaluated the combination of ICIs and anti-VEGF therapy for the treatment of unresectable liver cancer. The outcome index was extracted and analyzed by RevMan5.4.ResultsA total of 8 clinical trials were included. In terms of efficacy, the intervention group had longer OS and PFS for unresectable or advanced liver cancer than the control group. In terms of safety, (1) Adverse events of all grades showed that the combination treatment led to significantly higher risks of urinary system disorders, cardiovascular system disorder, blood system disorders and liver dysfunction than the control treatment. Compared with monotherapy, the combination treatment led to lower risks of gastrointestinal disorders. (2) Adverse events above grade 3 showed that, compared with the control treatment, the combination treatment led to significantly higher risks of urinary system disorders, blood systeam disorders, cardiovascular system disorders and liver dysfunction. Additionally, compared with monotherapy, the combination treatment led to significantly lower risks of gastrointestinal disorders. CONCLUSIONS: ICIs combined with anti-VEGF therapy exerts significant clinical effects in patients with unresectable or advanced liver cancer, can prolong the survival of these patients and can improve their quality of life. However, clinical attention should be given to the occurrence of adverse reactions.

Antitumor Effect of Poplar Propolis on Human Cutaneous Squamous Cell Carcinoma A431 Cells.

Propolis is a gelatinous substance processed by western worker bees from the resin of plant buds and mixed with the secretions of the maxillary glands and beeswax. Propolis has extensive biological activities and antitumor effects. There have been few reports about the antitumor effect of propolis against human cutaneous squamous cell carcinoma (CSCC) A431 cells and its potential mechanism. CCK-8 assays, label-free proteomics, RT-PCR, and a xenograft tumor model were employed to explore this possibility. The results showed that the inhibition rate of A431 cell proliferation by the ethanol extract of propolis (EEP) was dose-dependent, with an IC50 of 39.17 µg/mL. There were 193 differentially expressed proteins in the EEP group compared with the control group (p < 0.05), of which 103 proteins (53.37%) were upregulated, and 90 proteins (46.63%) were downregulated. The main three activated and suppressed Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were extracellular matrix (ECM)-receptor interaction, amoebiasis, cell adhesion molecules (CAMs), nonalcoholic fatty liver disease (NAFLD), retrograde endocannabinoid signaling, and Alzheimer's disease. The tumor volume of the 100 mg/kg EEP group was significantly different from that of the control group (p < 0.05). These results provide a theoretical basis for the potential treatment of human CSCC A431 cell tumors using propolis.

Photoinduced Photocatalyst-Free Cascade Cyclization of Alkynes with Sodium Sulfinates for the Synthesis of Benzothiophenes and Thioflavones.

The subject of this investigation is a new method for the construction of sulfonylated heterocycles which overcomes the limitations of classical approaches using a cheap feedstock sulfonylating agent, especially under photocatalyst- and metal-free conditions.

Prognostic value and immunological role of PTPN21 in pan-cancer analysis.

Introduction: At present, cancer remains a persistent public health challenge facing the whole world. Studies have found that PTPN21 is associated with the development of cancer. However, the prognostic potential of PTPN21 in pan-cancer remains unclear. In this work, we aimed to analyze the expression and prognostic value of PTPN21 in pan-cancer and to further study the relationship between PTPN21 and immune infiltration. Material and methods: TCGA and GEO data were used for expression and survival analysis. Genetic alterations in PTPN21 from TCGA cancer were studied in cBioPortal. TIMER2 was used to evaluate the correlation between PTPN21 expression and immune infiltration. The R packages "ggplot2" and "clusterProfiler" were used for GO and KEGG analysis. Results: PTPN21 was found to be a valuable diagnostic biomarker in multiple cancers, including bladder urothelial carcinoma (BLCA), kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP), and lung squamous cell carcinoma (LUSC). In addition, we observed that PTPN21 expression was associated with a variety of tumor mutations. Our results indicated a correlation between PTPN21 expression and immune infiltration. Enrichment analysis showed that PTPN21 was mainly involved in the regulation of neuroactive ligand-receptor interaction. Conclusions: Our study showed that PTPN21 expression is associated with clinical prognosis, mutation, and immune infiltration of tumors. PTPN21 may be a potential biomarker for many cancers, especially in KIRC.

Diagnosis of Bacterial Plant Diseases via a Nitroreductase-Activated Fluorescent Sensor.

Plant diseases caused by bacteria have become one of the serious problems that threaten human food security, which led to the remarkable reduction of agricultural yields and economic loss. Nitroreductase (NTR), as an important biomarker, is highly expressed in bacteria, and the level of NTR is closely related to the progression of pathogen infection. Therefore, the design of small-molecule fluorescent sensors targeting NTR is of great significance for the detection and diagnosis of plant pathogenic bacteria. In this study, a new fluorescent sensor targeting NTR was discovered and then successfully applied to the imaging of zebrafish and pathogenic bacteria. Most importantly, the developed sensor achieved the real-time diagnosis of Brassica napus L. infected with bacteria, which provides a promising tool for examining the temporal and spatial infection of plant pathogens in precision agriculture.

Catalyst- and Oxidizing Reagent-Free Electrochemical Benzylic C(sp3)-H Oxidation of Phenol Derivatives.

A site-selective electrochemical approach for the benzylic C(sp3)-H oxidation reaction of phenol derivatives along with hydrogen evolution has been developed. The protocol proceeds in an easily available undivided cell at room temperature under catalyst- and oxidizing reagent-free conditions. The corresponding aryl aldehydes and ketones are obtained in satisfactory yields, and the gram-scale synthesis is easy to be carried out.

Synthesis of polychloromethylated and halogenated spiro[5,5]trienones via dearomative spirocyclization of biaryl ynones.

We disclosed a selective polychloromethylation and halogenation reaction of alkynes via a radical addition/spirocyclization cascade sequence, in which polyhaloalkanes were used as the precursor for polyhalomethyl and halogen radicals. Using this strategy, a series of valuable halogen-, CHCl2- or CCl3-containing spiro[5,5]trienones were synthesized in good yields with good functional group tolerance in one pot under simple and mild conditions. It is noted that an unprecedented halogenation instead of dibromomethylation was achieved when CH2Br2 was used in this work.

Therapeutic potential of 1,2,3-triazole hybrids for leukemia treatment.

Leukemia, a hematological malignancy originating from the bone marrow, is the principal cancer of childhood. In recent decades, improved remission rates and survival of patients with leukemia have been achieved due to significant breakthroughs in the treatment. However, chemoresistance and relapse are common, creating an urgent need for the search for novel pharmaceutical interventions. 1,2,3-Triazole is one of the most fascinating pharmacophores in the discovery of new drugs, and several 1,2,3-triazole derivatives have already been used in clinics or are under clinical evaluation for the treatment of cancers. In particular, 1,2,3-triazole hybrids could suppress tumor proliferation, invasion, and metastasis by inhibiting enzymes, proteins, and receptors in cancer cells, revealing their potential as putative antileukemic agents. This review covers the recent advances regarding the 1,2,3-triazole hybrids with potential antileukemic activity, focusing on the chemical structures, structure-activity relationship, and mechanisms of action, covering articles published from January 2017 to January 2022.

Microstructure, Mechanical and Electrical Properties of Hybrid Copper Matrix Composites with Fe Microspheres and rGO Nanosheets.

Copper matrix composites have a wide application as magnetic conductive materials, electromagnetic materials, electrical discharge machining materials, etc. Such materials are expected to have a good combination of excellent electrical conductivity and good mechanical strength. In this work, micro/nano hybrid reinforcements with Fe microspheres and reduced graphene oxide (rGO) nanosheets were developed for copper matrix composites. The rGO/Fe/Cu powders were firstly wet-mixed and then densified by the vacuum hot-pressing sintering to obtain the bulk compacts. Microstructure, electrical conductivity and mechanical properties of such compacts were investigated. Microstructural result of as-sintered compacts shows that the Fe microspheres could distribute in the matrix uniformly, and rGO nanosheets exhibit both agglomerated and dispersed states. The grain size of Cu matrix decreased with the increase of the rGO content. Hardness, compression and tensile 0.2% yield strength of the as-sintered compacts were improved evidently by the addition of the hybrid Fe/rGO, comparing with pure Cu and single Fe-added composites. However, a lower electrical conductivity appeared in the more rGO-added composites, but still reached more than 33.0% international annealing copper standard (IACS). These performance change could be sought in the spatially geometrical distribution and characteristics of such micro/nano Fe/rGO hybrid addition, and the relevant mechanisms were discussed.

Development of Small-Molecule Fluorescent Probes Targeting Enzymes.

As biological catalysts, enzymes are vital in controlling numerous metabolic reactions. The regulation of enzymes in living cells and the amount present are indicators of the metabolic status of cell, whether in normal condition or disease. The small-molecule fluorescent probes are of interest because of their high sensitivity and selectivity, as well as their potential for automated detection. Fluorescent probes have been useful in targeting particular enzymes of interest such as proteases and caspases. However, it is difficult to develop an ideal fluorescent probe for versatile purposes. In the future, the design and synthesis of enzyme-targeting fluorescent probes will focus more on improving the selectivity, sensitivity, penetration ability and to couple the fluorescent probes with other available imaging molecules/technologies.

Design of a Metallacycle-Based Supramolecular Photosensitizer for In Vivo Image-Guided Photodynamic Inactivation of Bacteria.

Bacterial infection is one of the greatest threats to public health. In vivo real-time monitoring and effective treatment of infected sites through non-invasive techniques, remain a challenge. Herein, we designed a PtII metallacycle-based supramolecular photosensitizer through the host-guest interaction between a pillar[5]arene-modified metallacycle and 1-butyl-4-[4-(diphenylamino)styryl]pyridinium. Leveraging the aggregation-induced emission supramolecular photosensitizer, we improved fluorescence performance and antimicrobial photodynamic inactivation. In vivo studies revealed that it displayed precise fluorescence tracking of S. aureus-infected sites, and in situ performed image-guided efficient PDI of S. aureus without noticeable side effects. These results demonstrated that metallacycle combined with host-guest chemistry could provide a paradigm for the development of powerful photosensitizers for biomedicine.

Rational Redesign of Enzyme via the Combination of Quantum Mechanics/Molecular Mechanics, Molecular Dynamics, and Structural Biology Study.

Increasing demands for efficient and versatile chemical reactions have prompted innovations in enzyme engineering. A major challenge in engineering α-ketoglutarate-dependent oxygenases is to develop a rational strategy which can be widely used for directly evolving the desired mutant to generate new products. Herein, we report a strategy for rational redesign of a model enzyme, 4-hydroxyphenylpyruvate dioxygenase (HPPD), based on quantum mechanics/molecular mechanics (QM/MM) calculation and molecular dynamic simulations. This strategy enriched our understanding of the HPPD catalytic reaction pathway and led to the discovery of a series of HPPD mutants producing hydroxyphenylacetate (HPA) as the alternative product other than the native product homogentisate. The predicted HPPD-Fe(IV)═O-HPA intermediate was further confirmed by the crystal structure of Arabidopsis thaliana HPPD/S267W complexed with HPA. These findings not only provide a good understanding of the structure-function relationship of HPPD but also demonstrate a generally applicable platform for the development of biocatalysts.

Pyroglutamate Aminopeptidase I Promotes Hepatocellular Carcinoma via IL-6/STAT3 Activation as Revealed by a Specific Biosensor.

As a global health challenge, hepatocellular carcinoma (HCC) is strongly associated with chronic inflammation. Targeting inflammation, particularly inflammatory factors, is regarded as an important strategy for HCC diagnosis and treatment. Pyroglutamic aminopeptidase I (PGP-I), a common exopeptidase, was recently identified as a novel inflammatory cytokine in cells. However, whether PGP-I is involved in HCC development and can be regarded as a biomarker remains unclear. To address this issue, endogenous PGP-I was imaged in live cells and in vivo, and the related biochemical and pathological processes were analyzed accordingly with a newly developed fluorogenic PGP-I biosensor. Bioimaging with the specific biosensor demonstrated the aberrant expression of PGP-I in HCC cell lines and tumor-bearing nude mice. Moreover, overexpression of PGP-I in HCC cells promoted tumor progression, whereas knockdown of PGP-I significantly suppressed tumor cell growth and migration. The activity of PGP-I was further identified to be highly related to the phosphorylation of STAT3, which could be impeded by the natural product parthenolide. Collectively, these findings suggest that PGP-I, which can promote hepatocellular tumor progression through the classical inflammation-/tumor-related IL-6/STAT3 pathway, may serve as a potential HCC biomarker and therapeutic target.