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Background: Histamine is a widely distributed biogenic amine with multiple biological functions mediated by specific receptors that determine the local effects of histamine. This review aims to summarize the published findings on the expression and functional roles of histamine receptors in the inner ear and to identify potential research hotspots and gaps. Methods: A search of the electronic databases PubMed, Web of Science, and OVID EMBASE was performed using the keywords histamine, cochlea*, and inner ear. Of the 181 studies identified, 18 eligible publications were included in the full-text analysis. Results: All four types of histamine receptors were identified in the mammalian inner ear. The functional studies of histamine in the inner ear were mainly in vitro. Clinical evidence suggests that histamine and its receptors may play a role in Ménière's disease, but the exact mechanism is not fully understood. The effects of histamine on hearing development remain unclear. Conclusions: Existing studies have successfully determined the expression of all four histamine receptors in the mammalian inner ear. However, further functional studies are needed to explore the potential of histamine receptors as targets for the treatment of hearing and balance disorders. [ABSTRACT FROM AUTHOR]

Radiotherapy could regulate systemic antitumor immunity, while the immune state in the tumor microenvironment (TME) also affects the efficacy of radiotherapy. We have found that higher CD8+ T cell infiltration is associated with longer overall survival of lung adenocarcinoma and melanoma patients receiving radiotherapy. 8-Gray radiation increased the transcriptional levels of chemokines in tumor cells in vitro. However, it was not sufficient to induce significant lymphocyte infiltration in vivo. Dipeptidyl peptidase 4 (DPP4) has been reported to inactivate chemokines via post-translational truncation. Single-cell sequencing revealed that dendritic cells (DCs) had a higher DPP4 expression among other cells in the TME and upregulated DPP4 expression after radiation. Combining a DPP4 inhibitor with radiotherapy could promote chemokines expression and T cell infiltration in the TME, enhancing the antitumor effect of radiotherapy. Moreover, this therapy further enhanced the therapeutic efficacy of anti-PD-1. In this study, we demonstrated the underlying mechanism of why radiotherapy failed to induce sufficient T cell infiltration and proposed an effective strategy to promote T cell infiltration and sensitize radiotherapy. These findings demonstrate the translational value of DPP4 inhibition as a complementary approach to enhance the efficacy of radiotherapy and the combination of radiotherapy with immunotherapy. [ABSTRACT FROM AUTHOR]

Hair cells (HCs) in the mammalian cochleae cannot spontaneously regenerate once damaged, resulting in permanent hearing loss. It has been shown that Atoh1 overexpression induces hair cell-like cells (HCLCs) in the cochlea of newborn rodents, but this is hard to achieve in adult mammals. In this study, we used a three-dimensional cochlear culture system and an adenoviral-mediated delivery vector to overexpress Atoh1 in adult mouse cochleae. HCLCs were successfully induced from 3 days after virus infection (3 DVI) in vitro, and the number increased with time. HCLCs were myosin7a positive and distinguishable from remnant HCs in a culture environment. Meanwhile, patch-clamp results showed that noninactive outward potassium currents (sustained outward potassium currents) could be recorded in HCLCs and that their magnitude increased with time, similar to normal HCs. Furthermore, transient HCN currents were recorded in some HCLCs, indicating that the HCLCs experienced a developmental stage similar to normal HCs. We also compared the electrophysiological features of HCLCs from adult mice with native HCs and found the HCLCs gradually matured, similar to the normal HCs. Meanwhile, HCLCs from adult mice possessed the same bundles as developmental HCs. However, these HCLCs did not express prestin, which is a special marker for outer hair cells (OHCs), even at 13 DVI. These results demonstrate that Atoh1 overexpression induces HCLC formation in the adult mammalian cochlea and that these HCLCs were functional and experienced a developmental process similar to that of normal HCs. [ABSTRACT FROM AUTHOR]

• A rigid-flexible coupling dynamics model of the CFRP in-situ machining system was proposed. • The dynamics characteristics of the CFRP in-situ machining system under different layout was studied by applying the FEMSTMM. • The optimization model of overall layout of the multi-support reconfigurable compliant tooling was established. • The modal test, excitation test and milling test are designed to verify the effectiveness of the proposed method. The multi-support reconfigurable compliant tooling and robotic in-situ processing method provide a new technical direction for CFRP milling edge processing. Aiming at the layout optimization of CFRP in-situ machining system (CFRPIMS), the dynamics characteristics of the whole system were studied. A rigid-flexible coupling dynamics model of the CFRPIMS was proposed by applying transfer matrix method for multibody systems (MSTMM), treating CFRP as a thin-walled flexible plate and supporting fixtures as rigid bodies. And then the natural frequency and dynamics responses under the different support layout are simulated, which are verified by modal tests and excitation tests. To improve the support rigidity of CFRP workpieces, the optimization model of overall layout of the compliant tooling was established combined with genetic algorithm. Based on the milling test results, compared with the original scheme, the optimization method can effectively reduce the vibration response of the workpiece in the y -direction (along the milling edge direction) and the z -direction (perpendicular to milling edge direction) by more than 60 %. [ABSTRACT FROM AUTHOR]

Deep learning provides a great potential for in-loop filtering to improve both coding efficiency and subjective quality in video coding. State-of-the-art work focuses on network structure design and employs a single powerful network to solve all problems. In contrast, this paper proposes a deep learning based systematic approach that includes an effective Convolutional Neural Network (CNN) structure, a hierarchical training strategy, and a video codec oriented switchable mechanism. First, we propose a novel CNN structure, i.e., Squeeze-and-Excitation Filtering CNN (SEFCNN), as an optional in-loop filter. To capture the non-linear interaction between channels, the SEFCNN is comprised of two subnets, i.e., Feature EXtracting (FEX) subnet and Feature ENhancing (FEN) subnet. Then, we develop a hierarchical model training strategy to adapt the two subnets to different coding scenarios. For high-rate videos with small artifacts, we train a single global model using the FEX for all types of frames, whereas for low-rate videos with large artifacts, different models are trained using both FEX and FEN for different types of frames. Finally, we propose an adaptive enhancing mechanism which is switchable between the CNN-based and the conventional methods. We selectively apply the CNN model to some frames or some regions in a frame. Experimental results show that the proposed scheme outperforms state-of-the-art work in coding efficiency, while the computational complexity is acceptable after GPU acceleration. [ABSTRACT FROM AUTHOR]

• An easy-realized phononic crystal pipe design is proposed for vibration suppression. • Sleeve installation generates bandgap with the axial periodic change in cross section. • Bandgap closes up due to asynchronous recovery of edge frequencies to sleeve length. • Equivalent model explains the singular dependence of closure of bandgap on sleeve length. • Vibration suppression within the sleeved phononic crystal pipe is validated by tests. Flexural vibration of pipes is a common problem in many practical engineering applications, which usually influences the operating state of the system or even causes damage of the equipment. In the present work, an easy-realized design of phononic crystal pipe is proposed to implement vibration suppression by directly upgrading the bare pipe with attached sleeves without replacing the original structure. Based on the mechanism of Bragg scattering, flexural wave bandgap could be obtained with the periodical changing in cross section of the sleeved pipe. Sleeve installation generates both added mass and added stiffness simultaneously, which leads to the parabolic variations in edge frequencies of the bandgap against sleeve dimensions. Asynchronous recovery of the two frequency loci makes the bandgap close up when the sleeve covers about half length of the unit cell. This feature is not observed in analyses of binary phononic crystal pipes. Equivalent models are proposed to discuss the predicted variations, and the singular dependence of closure of bandgap on sleeve length is theoretical explained. Experiments are carried out to validate the feasibility of attaching sleeves for flexural vibration suppression of pipes. The proposed design could effectively attenuate the vibration energy with the intended bandgap. [Display omitted] [ABSTRACT FROM AUTHOR]

To meet the booming demands for lithium-ion battery (LIB), it is practically significant to promote its electrochemical performance and safety. In our work, a novel kind of flexible membrane as separator for LIB is prepared via phase inversion method with soluble polyimide (SPI) containing trifluoromethyl substituent, which is synthesized from 1,4-bis(4-amino-2-trifluoromethylphenoxy)benzene (6FAPB) and 4,4′-oxydiphthalic anhydride (ODPA). The SPI separator shows 5% weight loss temperature (Td5%) of 535 °C and maintains intrinsic dimension even after heating at 200 °C. The SPI membrane depicts a sponge-like structure with abundant interconnected pores and delivers a dominant porosity (67%). The SPI membrane displays desired electrolyte wettability, validated by contact angle tests (16.2° and 46.8° for SPI membrane and PE separator, respectively) and electrolyte uptake tests (420 and 132% for SPI membrane and PE separator, respectively). The LIB with SPI membrane as separator exhibits nice ionic conductivity (0.92 mS cm−1) than that with PE separator (0.30 mS cm−1), and therefore affords better electrochemical performance, such as cycling stability and rate capability. [ABSTRACT FROM AUTHOR]

A robust fluorinated polyimide (FPI) nanofibers membrane was prepared by an electrospinning technique and subsequent thermo-crosslinking process. Compared to pristine FPI nanofibers membrane, the thermally cross-linked FPI nanofibers membrane possesses considerable mechanical strength (i.e., 31.7 MPa), small average pore size and narrow pore-size distribution and shows enhanced performance to prevent the growth and penetration of dendritic lithium, which is crucial to safe and reliable lithium-ion batteries. It is demonstrated that the FPI nanofibers membrane possesses admirable thermal stability and flame retardancy. The as-prepared pristine or thermally cross-linked FPI nanofibers membrane as a separator has greater electrolyte wettability, larger ionic conductivity, higher electrochemical oxidation limit, lower interfacial resistance, as compared to its non-fluorinated analogue nanofibers membrane and the commercial polyethylene (PE) separator. Moreover, compared with non-fluorinated PI analogue nanofibers membrane, the battery assembled with FPI nanofibers membrane with FPI binder exhibits enhanced cycle performance and rate capacity. And the electrochemical performances of the FPI-based battery are also better than the commercial battery fabricated by PE separator and polyvinylidene fluoride (PVDF) binder. [ABSTRACT FROM AUTHOR]

[Display omitted] • A computational method of ion mobility near AFm surfaces was developed and applied. • Ions' mobility patterns were analyzed by studying their density profiles. • AFm-related phase models were simulated using the modified ClayFF force field. • Ion migration and adsorption at the AFm surface were simulated. • Interactions between ions and [Ca 2 Al (OH) 6 ]+ layers were explored. Chloride salts can cause severe corrosion damage to reinforcing steel bars in cement-based materials whereas nitrite salts inhibit corrosion. The storage and release of these two anions in cement materials occurs mainly at the interface of monosulfoaluminate (AFm) hydrates. In this paper, molecular dynamics are used to analyze the interaction between anions and AFm phases and clarify the competitive relationships between the anions at adsorption sites on the AFm surface. It was found that the ordered structure of the [Ca 2 Al(OH) 6 ]+ layers of the AFm plays a key role in anion adsorption and that the mobility of ions desorbed from AFm layers decreases linearly with increasing proximity to the AFm surfaces. [ABSTRACT FROM AUTHOR]

[Display omitted] • Single metal atoms on porous BN were studied as catalysts for urea synthesis. • Metal and its adjacent B atoms act as asymmetrical active sites for N 2 activation. • The anchored Fe and Co atoms were screened as ideal catalysts for urea synthesis. • The binding strength of NCON* rationalize the catalytic trend for urea synthesis. Urea electrosynthesis under ambient conditions has been emerging as a sustainable strategy to replace the harsh industrial process, in which the activation of the inert N 2 molecule and the then C N coupling still remain the huge challenge due to the lack of advanced electrocatalysts with multiple active sites. Here, by means of density functional theory (DFT) computations, a new family of electrocatalysts with asymmetrical triple active sites was proposed to boost urea production by anchoring single metal atoms on porous boron nitride nanosheet with divacancy (M/p-BN). Through the high-throughput screening, we found that the anchored Fe and Co atoms exhibit satisfied catalytic activity for urea formation with low limiting potentials, moderate kinetic barriers for C N coupling reaction, and excellent suppressing effect on the side reactions, in which Fe/Co and their adjacent two B atoms perform as collaborative adsorption sites. Furthermore, the high activity of the two promising catalysts can be well rationalized by their optimal binding strength with the NCON* species, which is mainly determined by the intrinsic charge distribution on the active sites. This work suggested that the anchoring of a single metal atom can highly activate BN nanosheet to achieve multiple active sites, which opens a new avenue to develop novel and efficient catalysts for other electrocatalytic reactions. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs), serving as the regulators for gene expression and cellular function, have emerged as the important biomarkers for diagnosis of cancers. In this study, a label-free electrochemical biosensing platform equipped with metal-organic frameworks (MOFs)-based nanoreactors has been developed by coupling three-dimensional (3D) DNA walker for amplification detection of miRNA. The MOF-based nanoreactors are constructed via the encapsulation of GOx in zeolitic imidazolate framework-8 (ZIF-8) driven by the rapid GOx-triggered nucleation of ZIF-8 with high catalytic activity, which also contributes to preserve the biological activity of GOx even in harsh environments. The gold nanoparticles (AuNPs) are further loaded on the surface of ZIF-8 by electrostatic adsorption, which can be used to not only anchor the orbit of 3D DNA walker by Au–S covalent bond but also promote the electron transfer on electrode interface. In the presence of target miRNA-21, the 3D DNA walker is initiated, resulting in the recycling of targets and the immobilization of numerous fuel DNAs with G-quadruplex/hemin complex on the nanoreactors spontaneously. As a result, a cascade catalysis reaction is triggered in the confined space of ZIF-8 nanoreactors, where the H 2 O 2 as an intermediate is generated with the oxidization of glucose catalyzed by GOx and subsequently decomposed by G-quadruplex/hemin HRP-mimicking DNAzyme for the further oxidation of ABTS to obtain a differential pulse voltammetry (DPV) signal. Under the optimal conditions, the proposed electrochemical biosensor exhibits an excellent performance for amplification detection of miRNA-21 in the dynamic working range from 0.1 nM to 10 μM with a detection limit of 29 pM, which opens a new way for clinical analysis of miRNAs and early diagnosis of cancers. • GOx@ZIF-8 nanoreactors are prepared by rapid GOx-triggered nucleation of ZIF-8 with high catalytic activity. • AuNPs loaded on GOx@ZIF-8 are served as the support of 3D DNA orbits and the bridge for electron transport. • 3D DNA walker triggered by target miRNA facilitates dual-enzyme cascade catalysis. • Successful analysis of human serum samples is demonstrated. [ABSTRACT FROM AUTHOR]

Abstract: Gallium oxide (Ga2O3) films were deposited on MgO (100) substrates by metalorganic vapor phase epitaxy. Structure analyses showed that the films deposited at 550–700°C were epitaxial β-Ga2O3 films with an out of plane relationship of β-Ga2O3(100)||MgO(100). The film deposited at 650°C showed the best crystallinity and the microstructure of the film was investigated by high resolution transmission electron microscopy. A theoretical model of the growth mechanism was proposed and the in-plane epitaxial relationship was given to be β-Ga2O3[001]||MgO<011>. A four-domain structure inside the epitaxial film was clarified. The β-Ga2O3 film deposited at 650°C showed an absolute average transmittance of 95.9% in the ultraviolet and visible range, which had an optical band gap of 4.87eV. [Copyright &y& Elsevier]

Abstract: Ga2O3:In films with different indium (In) content x [x=In/(Ga+In) atomic ratio] have been deposited on MgO (100) substrates by metalorganic chemical vapor deposition (MOCVD). Structural analyses revealed that the film deposited with actual In content (x′) of 0.09 was an epitaxial film and the films with x′=0.18 and 0.37 had mixed-phase structures of monoclinic Ga2O3 and bixbyite In2O3. The absolute average transmittance of the obtained films in the visible region exceeded 95%, and the band gap was in the range of 4.74–4.87eV. Photoluminescence (PL) measurements were performed at room temperature, in which the visible luminescences were strong and could be seen by the naked eye. The strong emissions in the visible light region were proposed to originate from the gallium vacancies, oxygen deficiencies and other defects in these films. [Copyright &y& Elsevier]

Abstract: Indium oxide (In2O3) film has been deposited on MgO(100) substrate at 600°C by metalorganic chemical vapor deposition (MOCVD). The crystal structure and epitaxial relationship of the sample were examined by X-ray diffraction (XRD) and high-resolution transmission electron microscopy (HRTEM). The results showed a clear epitaxial relationship of In2O3(111)||MgO(100) with In2O3[011̅]||MgO<072> or In2O3[01]||MgO<011>. A multiple domain structure was found inside the In2O3 film and a theoretical model clarifying the geometrical relationships between each domain and the substrate has been proposed. Scanning electron microscopy (SEM) micrograph showed that the main surface features were triangle-shaped grains on the film. The absolute average transmittance of the obtained film in the visible range was over 93%. [Copyright &y& Elsevier]

Abstract: Epitaxial In2O3 films have been deposited on Y-stabilized ZrO2 (YSZ) (100) substrates by metalorganic chemical vapor deposition (MOCVD). The films were deposited at different substrate temperatures (450–750°C). The film deposited at 650°C has the best crystalline quality, and observation of the interface area shows a clear cube-on-cube epitaxial relationship of In2O3(100)||YSZ(100) with In2O3[001]||YSZ[001]. The Hall mobility of the single-crystalline In2O3 film deposited at 650°C is as high as 66.5cm2 V−1 s−1 with carrier concentration of 1.5×1019 cm−3 and resistivity of 6.3×10−3 Ωcm. The absolute average transmittance of the obtained films in the visible range exceeds 95%. [ABSTRACT FROM AUTHOR]

Abstract: SnO2 films have been deposited on Y-stabilized ZrO2 (YSZ) (100) substrates at different substrate temperatures (500–800°C) by metalorganic chemical vapor deposition (MOCVD). Structural, electrical and optical properties of the films have been investigated. The films deposited at 500 and 600°C are epitaxial SnO2 films with orthorhombic columbite structure, and the HRTEM analysis shows a clear epitaxial relationship of columbite SnO2(100)||YSZ(100). The films deposited at 700 and 800°C have mixed-phase structures of rutile and columbite SnO2. The carrier concentration of the films is in the range from 1.15×1019 to 2.68×1019 cm−3, and the resistivity is from 2.48×10−2 to 1.16×10−2 Ωcm. The absolute average transmittance of the films in the visible range exceeds 90%. The band gap of the obtained SnO2 films is about 3.75–3.87eV. [ABSTRACT FROM AUTHOR]

Abstract: Tin oxide (SnO2) epitaxial film has been deposited on Y-stabilized ZrO2 (YSZ) (100) substrate by metalorganic chemical vapor deposition (MOCVD). Structural and optical properties of the film as well as the epitaxial mechanism have been investigated in detail. The results of structure analyses show that the obtained film is epitaxial SnO2 with orthorhombic columbite structure. A novel epitaxial relationship of orthorhombic SnO2(100)||YSZ(100) with SnO2 [001]||YSZ<001> was clearly observed from the interface area between the film and the substrate. The absolute average transmittance of the orthorhombic SnO2 film in the visible range exceeds 90%, and the optical band gap of the film is about 3.79eV. [Copyright &y& Elsevier]

Abstract: Ga2x In2(1−x)O3 films with different gallium (Ga) content x [x =Ga/(Ga+In) atomic ratio] have been deposited on ZrO2 (100) substrates by metalorganic chemical vapor deposition (MOCVD). The structural, electrical and optical properties of obtained films have been studied. Structure analysis revealed that the films deposited with Ga content x =0.1, 0.3 and 0.5 were polycrystalline structures of bixbyite In2O3 and the samples prepared with x =0.7 and 0.9 exhibited amorphous structures. As Ga content x increased from 0.1 to 0.9, the resistivity of the films increased from 2.20×10−3 to 1.90Ωcm and the optical band gap of the films monotonously broadened from 3.72 to 4.46eV. The average transmittance of the samples in the visible range exceeded 78%. [Copyright &y& Elsevier]

A preparative high-speed countercurrent chromatography (HSCCC) method for isolation and purification of didymin, nairutin, and clinopodiside A from Clinopodium chinensis (Benth) O. Kuntze (Duanxueliu in Chinese) was successfully established. The separation was performed in two steps with two different kinds of solvent systems. In the first step, ethyl acetate-1-butanol-water (5:0.8:5, v/v) was used as the two-phase solvent system; nairutin was purified, and didymin and clinopodiside A were eluted together. In the second step, ethyl acetate-methanol-water (5:1:5, v/v) was used as the two-phase solvent system; didymin and clinopodiside A were separated and purified. After two-step separation, 15.2 mg of nairutin, 39.1 mg of clinopodiside A, and 20.6 mg of didymin were obtained from 100 mg of crude extract with purities of 96.5%, 98.4%, and 99.1%, respectively, as determined by HPLC analysis. The chemical structures of the three components were confirmed by 1H NMR and 13C NMR. [ABSTRACT FROM AUTHOR]

Abstract: Sarsasapogenin M (1) and sarsasapogenin N (2), two new oligospirostanosides with a unique aglycone moiety, (25S)-5β-spirostan-3β, 17α-diol, along with seven known compounds (25S)-5β-spirostan-3β-ol-3-O-β-d-glucopyranosyl-(1,2)-[β-d-xylopyranosyl-(1,4)]-β-d-glucopyranoside (3), (25S)-5β-spirostan-3β-ol-3-O-β-d-glucopyranosyl-(1,2)-β-d-glucopyranoside (4), (25S)-5β-spirostan-3β-ol-3-O-α-l-rhamnopyranosyl-(1,2)-[α-l-rhamnopyranosyl-(1,4)]-β-d-glucopyranoside (5), (25S)26-O-β-d-glucopyranosyl-5β-furost-20 (22)-ene-3β,26-diol-3-O-β-d-glucopyranosyl-(1,2)-β-d-glucopyranoside (6), yamogenin (7), β-sitosterol (8), and sitosterol-β-d-glucoside (9) were isolated from the roots of Asparagus officinalis L. Their structures were determined by spectral analysis, including extensive 1D and 2D NMR experiments. [Copyright &y& Elsevier]

Convolutional Neural Network (CNN) structures have been designed for in-loop filtering to improve video coding performance. These CNN models are usually trained through learning the correlations between the reconstructed and the original frames, which are then applied to every single reconstructed frame to improve the overall video quality. This direct model training and deployment strategy is effective for intra coding since a locally optimal model is sufficient. However, when applied to inter coding, it causes over-filtering because the intertwined reference dependencies across inter frames are not taken into consideration. To address this issue, existing methods usually resort to the Rate–Distortion Optimization (RDO) to selectively apply the CNN model, but fail to address the limitation of using a local CNN model. In this paper, we propose a progressive approach to train and incorporate the CNN-based in-loop filters to work seamlessly with video encoders. First, we develop a progressive training method to obtain the inter model. Using transfer learning, reconstructed frames using the CNN model are progressively involved back into the training of the CNN model itself, to simulate the reference dependencies in inter coding. Next, we design a frame-level model selection strategy for the high-bitrate coding where the over-filtering effect is diluted. Experimental results show that the proposed method outperforms the RDO method that utilizes only local model. Proposed approach also achieves comparable coding performance but with less computational complexity when integrating our progressive model into the RDO scheme. • CNN models from direct training are local optimal and effective for intra coding. • Direct models cause over-filtering in inter coding. • Develop a progressive training method to produce inter in-loop filtering models. • Propose a frame-level model selection strategy for the high-bitrate coding scenario. [ABSTRACT FROM AUTHOR]

A novel approach has been developed for the synthesis of bicyclic β, γ‐fused bicyclic γ‐ureasultams containing two consecutive chiral centers through an intramolecular Mannich and aza‐Michael addition cascade of alkenyl sulfamides. The straightforward practical procedure and readily available starting materials enable the synthesis of variously substituted ureasultams. In addition, bicyclic γ‐ureasultams is a class of potential biotin analogues. [ABSTRACT FROM AUTHOR]

Simple Summary: This review covers the most recent and up-to-date literature on liquid biopsy techniques in head and neck cancer. Head and neck cancer remains a common, difficult to treat and deadly type of disease. Part of the challenge in treating head and neck cancer lies in identifying disease at its early stages, determining responses to treatment and managing any recurrent disease. Liquid biopsies are the sampling of body fluids to determine markers that can indicate the presence of cancer. These technologies have immense potential in helping improve treatment for head and neck cancers. In this review, we discuss the current state of liquid biopsies for head and neck cancer, as well as limitations and challenges the field must overcome to advance our research in this area. Head and neck cancers are the seventh most frequent malignancy worldwide, consisting of a heterogeneous group of cancers that develop in the oral cavity, pharynx, and larynx, with head and neck squamous cell carcinoma (HNSCC) being the most common pathology. Due to limitations with screening and physical examination, HNSCC often presents in advanced disease states and is thus associated with poor survival. In this setting, liquid biopsies, or obtaining patient bodily fluid samples for cancer diagnosis and prognosis, may play a dramatic role in optimizing care for HNSCC patients. In recent years, there have been dramatic advancements in investigations focused on optimizing and implementing liquid biopsies in general, and specifically for HNSCC patients. Moving forward, there remain significant challenges in liquid biopsy technological development, as well as opportunities for the development of HNSCC liquid biopsy clinical trials and treatment paradigms. In this review, we discuss the current state of liquid biopsy technologies via circulating tumor cells, circulating tumor DNA and exosomes, approaches in head and neck cancer, challenges to optimization and application of liquid biopsies for clinical study, and future prospects for this field of research as it applies to head and neck cancer. [ABSTRACT FROM AUTHOR]

Covering: 1925 to July 2023 Among the sesquiterpenoids with rich structural diversity and potential bioactivities, lindenane sesquiterpenoids (LSs) possess a characteristic cis, trans-3,5,6-carbocyclic skeleton and mainly exist as monomers and diverse oligomers in plants from the Lindera genus and Chloranthaceae family. Since the first identification of lindeneol from Lindera strychnifolia in 1925, 354 natural LSs and their oligomers with anti-inflammatory, antitumor, and anti-infective activities have been discovered. Structurally, two-thirds of LSs exist as oligomers with interesting skeletons through diverse polymeric patterns, especially Diels–Alder [4 + 2] cycloaddition. Fascinated by their diverse bioactivities and intriguing polycyclic architectures, synthetic chemists have engaged in the total synthesis of natural LSs in recent decades. In this review, the research achievements related to LSs from 1925 to July of 2023 are systematically and comprehensively summarized, focusing on the classification of their structures, chemical synthesis, and bioactivities, which will be helpful for further research on LSs and their oligomers. [ABSTRACT FROM AUTHOR]

Distiller's grains (DGs) are solid mixtures that remain after the production of alcoholic beverages. A large amount of DGs is produced each year during the brewing process. Currently, they are mostly used as a feedstock or substrate in the feed industry. However, the lack of a comprehensive understanding of the chemical composition of DGs is a major constraint on their further development and application for high-value-added usages. Some studies were published on the bioactive constituents of DGs in several different types of journals. Data were therefore collated to provide a comprehensive overview of these natural products. DGs are rich in phenols, phytosterols, and fatty acids, in addition to general lipid and protein constituents. These compounds and their related extracts possess diverse biological activities, including antioxidant, anti-inflammatory, and anti-hyperglycaemic effects. We hope that this review will provide research incentives for the further development and utilisation of DGs to develop high-value-added products. [ABSTRACT FROM AUTHOR]

The growing number of surveillance cameras imposes great demand on high efficiency video coding. Although modern video coding standards have significantly improved the video coding efficiency, they are designed for general video rather than surveillance video. The special characteristics of surveillance video leave a large space for further performance improvement. In this paper, we leverage a deep learning approach to enhance the quality of compressed surveillance video. More specifically, we formulate the problem of frame enhancement as a regression problem and design a Residual Squeeze-and-Excitation Network (RSE-Net), to address it. RSE-Net extensively exploits the non-linear mapping between the reconstructed frame and the ground truth, with only a small number of parameters. Moreover, By improving You Only Look Once (YOLO) network, we successfully detect the grouped vehicles within a frame. A novel model training scheme is then developed through learning from the grouped vehicles. With the proposed scheme, we train a global model for both foreground and background of surveillance video. Experimental results show that our method achieves average 0.40 dB, 0.22 dB and 0.24 dB PSNR gains over H.265/HEVC anchor in AI, LDP and RA configurations, and produces visually pleasing results when applied to compressed surveillance video. [ABSTRACT FROM AUTHOR]

[Display omitted] • Carrier-free nanoplatforms with self-assembly from natural plants. • Nano self-assembly of pure small molecules for enhanced bioactivity. • Extracellular vesicles containing active substances from fresh plants. • Charcoal nanocomponents with carbon skeleton structure from charred plants. • Nanoaggregate particles with wide curative effects from decoction of plants formulae. Natural plants as well as traditional Chinese medicine have made outstanding contributions to the health and reproduction of human beings and remain the basis and major resource for drug innovation. Carrier-free nanoplatforms completely self-assembled by pure molecules or therapeutic components have attracted increasing attention due to their advantages of improved pharmacodynamics/pharmacokinetics, reduced toxicity, and high drug loading. In recent years, carrier-free nanoplatforms produced by self-assembly from natural plants have contributed to progress in a variety of therapeutic modalities. Notably, these nanoplatforms based on the interactions of components from different natural plants improve efficiency and depress toxicity. In this review, different types of self-assembled nanoplatforms are first summarized, mainly including nanoassemblies of pure small molecules isolated from different plants, extracellular vesicles separated from fresh plants, charcoal nanocomponents obtained from charred plants, and nanoaggregates from plants formulae decoctions. Key Scientific Concepts of Review : We mainly focus on composition, self-assembly mechanisms, biological activity and modes of action. Finally, a future perspective of existing challenges with respect to the clinical application of plant-based carrier-free nanoplatforms is discussed, which may be instructive to further develop effective carrier-free nanoplatforms from natural plants in the future. [ABSTRACT FROM AUTHOR]

Abstract: A new phenolic glucoside ester, 6′-E-(2″-methyl-2″-butenoyl) arbutin (1), was isolated from the leaves of Heliciopsis lobata. Its structure was elucidated by spectral analysis. [Copyright &y& Elsevier]

Abstract: Compounds (I) and (II) exhibit moderate inhibition on NO production on LPS‐activated RAW 264.0 cells. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: Elodexanthones A—J (1—10), two pairs of rearranged isoprenylated xanthone enantiomers with an unprecedent 6/6/5/6 tetracyclic core (1—2) along with seven new isoprenylated xanthones (3—9) and a pair of phenylpropanoid xanthones (10), were purified and enantio‐separated from the whole plant of Hypericum elodeoides. Their structures including absolute configurations were characterized by the comprehensive analysis of NMR, HRESIMS, NMR calculations, and ECD calculations. Through Bayer‐Villiger oxidation, Claisen condensation and electrophilic addition, the rearranged skeletons of elodexanthones A—B (1—2) were generated from isoprenylated xanthone precursors. The bioactivities evaluation exhibited that compounds 3, 5, 8—10 showed anti‐inflammatory activity with the IC50 values in the range of 9.53—34.39 μmol/L, and compounds 3—7, and 9 showed notable α‐glucosidase inhibitory activity (IC50: 6.02—257.11 μmol/L). [ABSTRACT FROM AUTHOR]

Sirtuin1 (SIRT1), an NAD+-dependent histone deacetylase, plays a crucial role in regulating molecular signaling pathways. Recently, inhibition of SIRT1 rather than its activation shows the therapeutic potential for central nervous system disorder, however, the discovered SIRT1 inhibitors remains limited. In this work, a dual recognition-based strategy was developed to screen SIRT1 inhibitors from natural resources in situ. This approach utilized a Ni-modified metal-organic framework (Ni@Tyr@UiO-66-NH 2) along with cell lysate containing an engineered His-tagged SIRT1 protein, eliminating the need for purified proteins, pure compounds, and protein immobilization. The high-performance Ni@Tyr@UiO-66-NH 2 was synthesized by modifying the surface of UiO-66-NH 2 with Ni2+ ions to specifically capture His-tagged SIRT1 while persevering its enzyme activity. By employing dual recognition, in which Ni@Tyr@UiO-66-NH 2 recognized SIRT1 and SIRT1 recognized its ligands, the process of identifying SIRT1 inhibitors from complex matrix was vastly streamlined. The developed method allowed the efficient discovery of 16 natural SIRT1 inhibitors from Chinese herbs. Among them, 6 compounds were fully characterized, and suffruticosol A was found to have an excellent IC 50 value of 0.95 ± 0.12 μM. Overall, an innovative dual recognition-based strategy was proposed to efficiently identify SIRT1 inhibitors in this study, offering scientific clues for the development of drugs targeting CNS disorders. [Display omitted] • A new Ni-modified MOF (Ni@Tyr@UiO-66-NH 2) was synthesized. • The MOF adsorbed His-tagged SIRT1 efficiently while maintaining the enzyme activity. • A dual recognition-based strategy was established based on the new MOF and His-tag. • 16 new natural SIRT1 inhibitors were identified in situ by applying the strategy. [ABSTRACT FROM AUTHOR]

In this study, ten phenylpropionyl phenylethylamines, including five previously undescribed ones (1a / b , 2a / b , and 3), five known analogues (4 – 8), and two established phenylpropanoids precursors (9 , 10) were isolated from the aerial parts of Chloranthus henryi Hemsl. Their structures, including absolute configurations, were determined by high-resolution mass spectrometry, enantio-separation, electronic circular dichroism calculation, and single crystal diffraction. Compounds 1a and 1b were the first examples of natural hetero- [2 + 2] cycloaddition products between phenylpropionyl phenylethylamine and phenylpropene. The plausible hetero- [2 + 2] biosynthesis pathway was confirmed by a photocatalytic biomimetic synthesis in eight steps, which also led to the production of three other potential natural homo -[2 + 2] adducts (1′a / b , 2′ , and 3′). Bioactivity screening indicated that these adducts bear medium inhibitory activity on nitric oxide generation, with IC 50 values of 6–35 μM in RAW 264.7 macrophages. Chorahenramides A and B (1a and 1b), the first example of natural hetero- [2 + 2] cycloaddition product between phenylpropionyl phenylethylamine and phenylpropene were isolated from the aerial parts of Chloranthus henryi Hemsl, which was confirmed by a photocatalytic biomimetic synthesis in eight steps. [Display omitted] • Phenylpropionyl phenylethylamines (PPPAs) were isolated from Chloranthus henryi. • Compound 1 was the first example of natural PPPAs with heter- [2 + 2] skeleton. • Plausible biosynthesis pathway was confirmed by photocatalytic synthesis. • Potential PPPAs were discovered by chemical conversion and identified via GNPS. • Compound 2′ showed significant anti-inflammatory activity (IC 50 : 5.74 ± 1.24 μM). [ABSTRACT FROM AUTHOR]

Identifying medicinally relevant compounds from natural resources generally involves the tedious work of screening plants for the desired activity before capturing the bioactive molecules from them. In this work, we created a paper-based ligand fishing platform to vastly simplify the discovery process. This paper-based method exploits the enzymatic cascade reaction between α -glucosidase (GAA), glucose oxidase (GOx), and horseradish peroxidase (HRP), to simultaneously screen the plants and capture the GAA inhibitors from them. The designed test strip could capture ligands in tandem with screening the plants, and it features a very simply operation based on direct visual assessment. Multiple acylated flavonol glycosides from the leaves of Quercus variabilis Blume were newly found to possess GAA inhibitory activities, and they may be potential leads for new antidiabetic medications. Our study demonstrates the prospect of the newly discovered GAA ligands as potential bioactive ingredients as well as the utility of the paper-based ligand fishing method. [Display omitted] • Test strip (GDTS) built on enzyme cascade reaction and dopamine-paper was newly set. • GDTS can screen bioactive plants and concurrently capture α -glucosidase inhibitors. • Four plants were screened by GDTS as targets from fourteen plants. • Twenty-two inhibitors were acquired from target plants via GDTS. • Acylated flavonol glucosides in Quercus variabilis were new GAA inhibitors. [ABSTRACT FROM AUTHOR]

PD-1/PD-L1 pathway blockade is a promising immunotherapy for the treatment of cancer. In this manuscript, a series of triaryl compounds containing ester chains were designed and synthesized based on the pharmacophore studies of the lead BMS-1. After several SAR iterations, 22 showed the best biochemical activity binding to hPD-L1 with an IC 50 of 1.21 nM in HTRF assay, and a K D value of 5.068 nM in SPR analysis. Cell-based experiments showed that 22 effectively promoted A549 cell death by restoring T-cell immune function. 22 showed significant in vivo antitumor activity in a 4T1 mouse model without obvious toxicity, with a TGI rate of 67.8 % (20 mg/kg, ip). Immunohistochemistry data indicated that 22 activates the immune activity in tumors. These results suggest that 22 is a promising compound for further development of PD-1/PD-L1 inhibitor for cancer therapy. [Display omitted] • Synthesis of a series of novel triaryl derivatives containing ester chains. • 22 Showed the best biochemical activity binding to hPD-L1 with an IC 50 of 1.21 nM. • 22 effectively promoted A549 cell death by restoring T cell immune function. • 22 showed significant in vivo antitumor activity in a 4T1 mouse model. [ABSTRACT FROM AUTHOR]

[Display omitted] • Trisarcglaboids A and B were new family lindenane sesquiterpenoid trimer. • Compound 1 was highly cytotoxic to five human cancer cell lines. • Compound 1 potentially induced apoptosis by blocking Akt phosphorylation. Trisarcglaboids A and B (1 and 2), representing the first example of lindenane sesquiterpenoid trimers repolymerized based on the classical [4 + 2] type dimer, together with known biogenic precursors chlorahololide D (3) and sarcandrolide A (4), were identified as chemical components of the root of Sarcandra glabra. The novel trimeric lindenane sesquiterpenoid skeletons, including their absolute configurations, were characterized using MS, NMR, ECD, and X-ray single crystal diffraction. The proposed Diels-Alder cycloaddition between Δ 2(3) of the tiglic acyl group of the classical [4 + 2] type dimer and Δ 15(4),5(6) of the third lindenane may serve as the key biogenic step. In addition, compound 1 exerted significant cytotoxicity against five human cancer cell lines with IC 50 values ranging from 1 to 7 μM, potentially through blocking Akt phosphorylation and activating the endogenous apoptosis pathway. [ABSTRACT FROM AUTHOR]

Covering: July 2010 to December 2021 Limonoids, a kind of natural tetranortriterpenoids with diverse skeletons and valuable insecticidal and medicinal bioactivities, are the characteristic metabolites of most plants of the Meliaceae family. The chemistry and bioactivities of meliaceous limonoids are a continuing hot area of natural products research; to date, about 2700 meliaceous limonoids have been identified. In particular, more than 1600, including thirty kinds of novel rearranged skeletons, have been isolated and identified in the past decade due to their wide distribution and abundant content in Meliaceae plants and active biosynthetic pathways. In addition to the discovery of new structures, many positive medicinal bioactivities of meliaceous limonoids have been investigated, and extensive achievements regarding the chemical and biological synthesis have been made. This review summarizes the recent research progress in the discovery of new structures, medicinal and agricultural bioactivities, and chem/biosynthesis of limonoids from the plants of the Meliaceae family during the past decade, with an emphasis on the discovery of limonoids with novel skeletons, the medicinal bioactivities and mechanisms, and chemical synthesis. The structures, origins, and bioactivities of other new limonoids were provided as ESI. Studies published from July 2010 to December 2021 are reviewed, and 482 references are cited. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: Spirolindemers A and B, unprecedented lindenane sesquiterpenoid dimer (1) and trimer (2) equipped with oxaspiro[4.5]decane unit, were discovered from the medicinal plant Chloranthus henryi. Their structures including absolute configurations were achieved by HRMS, NMR, ECD, X‐ray diffraction analyses, and quantum chemical calculations. Biogenetically, hetero‐ and homo‐Diels‐Alder additions may dominate the formation of oxaspiro[4.5]decane and spiro[4.5]decane skeletons, respectively. Compound 1 showed anti‐inflammatory activity by inhibiting the expression of iNOS and COX‐2. [ABSTRACT FROM AUTHOR]

Garciyunnanones A–R (1 – 18), eighteen undescribed caged polycyclic polyprenylated acylphloroglucinols, two undescribed biogenetic congeners (19 – 20), and nineteen known analogues (21 – 39), were isolated from the stem barks of Garcinia yunnanensis Hu. All of these isolates are decorated with a C-5 lavandulyl substituent. Their structures and absolute configurations were confirmed by HRESIMS, 1D & 2D NMR spectroscopic analysis, quantum chemical calculations of electronic circular dichroism data, and single-crystal X-ray diffraction analysis. The X-ray crystallographic data of ten isolated caged compounds ascertained the absolute configuration of C-23 in the lavandulyl as S. The cytotoxicity on three cancer cell lines and the anti-nonalcoholic steatohepatitis activity of the isolates were tested. In a free fatty acid-induced L02 cell model, compounds 33 and 39 decreased intracellular lipid accumulation significantly. [Display omitted] • Twenty undescribed polycyclic polyprenylated acylphloroglucinols were isolated from the stem barks of Garcinia yunnanensis Hu. • The absolute configuration of the lavandulyl group at C-23 was determined to be S by using the single crystals data. • A rule for distinguishing between adamantane and homoadamantane skeletons of caged PPAPs by 13C NMR data. [ABSTRACT FROM AUTHOR]

A study of the rhizomes of Polygonatum cyrtonema led to the isolation of three pairs of mixtures of 25 R and 25 S stereoisomeric spirostanol saponins: (25 R, 25 S) spirostan-5-en-12-one-3- O-β-D-glucopyranosyl-(1 → 2)- O-[β-D-glucopyranosyl-(1 → 3)]- O-β-D-glucopyranosyl-(1 → 4)-β-D-galactopyranoside ( 1a, 1b), (25 R, 25 S) spirostan-5-en-12-one-3- O-D-glucopyranosyl-(1 → 2)- O-[β-D-xylopyranosyl(1 → 3)]-O-β-Dglucopyranosyl(1 → 4)-β-D-galactopyranoside( 2a, 2b), and (25 R, 25 S)-3-β-hydroxyspirost-5-en-12-one ( 3a, 3b). Compound 1a is a new spirostanol saponin named cyrtonemoside A. The structures were determined by spectroscopic methods, mainly 1D and 2D NMR. [ABSTRACT FROM AUTHOR]

Glycosides including triterpenoid saponins and flavonoid glycosides are the main constituents of Glycyrrhiza uralensis Fisch (licorice) and exhibit prominent pharmacological activities. However, conventional methods for the separation of glycosides always cause irreversible adsorption and unavoidable loss of sample due to their high hydrophilicities. The present paper describes a convenient method for the simultaneous separation of triterpenoid saponins and flavonoid glycosides from licorice by pH-zone-refining counter-current chromatography. Ethyl acetate/ n-butanol/water (2:3:5, v/v) with 10 mM TFA in the upper organic stationary phase and 10 mM ammonia in the lower aqueous mobile phase was used as the biphasic solvent system. Three triterpenoid saponins and two flavonoid glycosides including licorice-saponin A3 (63.3 mg), glycyrrhizic acid (342.2 mg), 3- O-[ β- d-glucuronopyranosyl-(1 → 2)- β- d-galactopyranosyl]glycyrrhetic acid (56.0 mg), liquiritin apioside (232.6 mg), and liquiritin (386.5 mg) were successfully obtained from licorice ethanol extract (2 g) in one step. This method subtly takes advantage of the common acidic properties of triterpenoid saponins and flavonoid glycosides, and obviously is much more efficient and convenient than the previous methods. It is also the first time that the separation of acidic triterpenoid saponins by using p H-zone-refining counter-current chromatography has been reported. [ABSTRACT FROM AUTHOR]

Highlights: [•] Two triterpenoids, fourteen lignans and three phenolics were obtained from Boschniakia himalaica. [•] Fourteen of these compounds were reported for the first time from B. himalaica. [•] Compound 17 was reported as a natural product for the first time. [•] The presence of lignans and their glycosides will be chemotaxonomically significant for B. himalaica. [ABSTRACT FROM AUTHOR]

• Physalin H treatment suppresses LPS-induced inflammation and oxidative stress. • Physalin H blocks the interaction between NRF2 and KEAP1 to inhibit the ubiquitination of NRF2. • Physalin H-mediated NRF2 nuclear translocation and activation plays a protective role in acute lung injury. Physalin H (PH), a withanolide isolated from Physalis angulata L. has been reported to have anti-inflammatory effect. However, its impact on acute lung injury (ALI) remains unexplored. In this study, we observed that PH significantly alleviated inflammation in LPS-stimulated macrophages by suppressing the release of proinflammatory cytokines (TNF-α, IL-1β, and IL-6) and down-regulating the expression of the inflammation-related genes. RNA sequencing analysis revealed a significant up-regulation of the NRF2 pathway by PH. Further investigation elucidated that PH attenuated the ubiquitination of NRF2 by impeding the interaction between NRF2 and KEAP1, thereby facilitating NRF2 nuclear translocation and up-regulating the expression of target genes. Consequently, it regulated redox system and exerted anti-inflammatory effect. Consistently, PH also significantly alleviated pathological damage and inflammation in LPS-induced ALI mice model, which could be reversed by administration of an NRF2 inhibitor. Collectively, these results suggest that PH ameliorates ALI by activating the KEAP1/NRF2 pathway. These findings provide a foundation for further development of pH as a new anti-inflammatory agent for ALI therapy. [ABSTRACT FROM AUTHOR]

In this work, a novel of dual tubulin/HDAC inhibitors were designed and synthesized based on the structure of natural product millepachine, which has been identified as a tubulin polymerization inhibitor. Biological evaluation revealed that compound 9n exhibited an impressive potency against PC-3 cells with the IC 50 value of 16 nM and effectively inhibited both microtubule polymerization and HDAC activity. Furthermore, compound 9n not only induced cell cycle arrest at G2/M phase, but also induced PC- 3 cells apoptosis. Further study revealed that the induction of cell apoptosis by 9n was accompanied by a decrease in mitochondrial membrane potential and an elevation in reactive oxygen species levels in PC-3 cells. Additionally, 9n exhibited inhibitory effects on tumor cell migration and angiogenesis. In PC-3 xenograft model, 9n achieved a remarkable tumor inhibition rate of 90.07%@20 mg/kg, significantly surpassing to that of CA-4 (55.62%@20 mg/kg). Meanwhile, 9n exhibited the favorable drug metabolism characteristics in vivo. All the results indicate that 9n is a promising dual tubulin/HDAC inhibitor for chemotherapy of prostate cancer, deserving the further investigation. [Display omitted] • A series of microtubule/HDAC inhibitors were designed and synthesized based on the structure of natural product millepachine. • Compound 9n can inhibit microtubule polymerization by binding to colchicine sites and can simultaneously inhibit HDACs. • Compound 9n displayed exhibited potent inhibitory effects on tumor cell migration and angiogenesis. • Compound 9n greatly inhibited tumor growth on PC-3 xenograft BALB/c nude mice at 20 mg/kg by intravenous injection. [ABSTRACT FROM AUTHOR]

Ferritinophagy is a cellular process to release redox-active iron. Excessive activation of ferritinophagy ultimately results in ferroptosis characterized by ROS accumulation which plays important roles in the development and progression of cancer. Sinomenine, a main bioactive alkaloid from the traditional Chinese medicine Sinomenum acutum , inhibits the proliferation of cancer cells by promoting ROS production. Herein, new compounds were designed and synthesized through the stepwise optimization of sinomenine. Among them, D3-3 induced the production of lipid ROS, and significantly promoted colorectal cancer cells to release the ferrous ion in an autophagy-dependent manner. Moreover, D3-3 enhanced the interaction of FTH1-NCOA4, indicating the activation of ferritinophagy. In vivo experiments showed that D3-3 restrained tumor growth and promoted lipid peroxidation in the HCT-116 xenograft model. These findings demonstrated that D3-3 is an inducer of ferritinophagy, eventually triggering ferroptosis. Compound D3-3, as the first molecule to be definitively demonstrated to induce ferritinophagy, is worth further evaluation as a promising drug candidate in the treatment of colorectal cancer. [Display omitted] • Design and synthesis 28 sinomenine derivatives. • Compound D3-3 significantly induced ferroptosis in HCT-116 cells. • Compound D3-3 caused iron overload in an autophagy-dependent manner by enhancing the interaction of NCOA4 and FTH1. • Compound D3-3 was able to promote lipid peroxidation in colon cancer cells in vivo. [ABSTRACT FROM AUTHOR]

Currently available PARP inhibitors are mainly used for the treatment of BRCA-mutated triple-negative breast cancer (TNBC), with a narrow application range of approximately 15% of patients. Recent studies have shown that EZH2 inhibitors have an obvious effect on breast cancer xenograft models and can promote the sensitivity of ovarian cancer cells to PARP inhibitors. Here, a series of new dual-target PARP1/EZH2 inhibitors for wild-BRCA type TNBC were designed and synthesized. SAR studies helped us identify compound 12e , encoded KWLX-12e , with good inhibitory activity against PARP1 (IC 50 = 6.89 nM) and EZH2 (IC 50 = 27.34 nM). Meanwhile, KWLX-12e showed an optimal cytotoxicity against MDA-MB-231 cells (IC 50 = 2.84 μM) and BT-549 cells (IC 50 = 0.91 μM), with no toxicity on normal breast cell lines. KWLX-12e also exhibited good antitumor activity with the TGI value of 75.94%, more effective than Niraparib plus GSK126 (TGI = 57.24%). Mechanistic studies showed that KWLX-12e achieved synthetic lethality indirectly by inhibiting EZH2 to increase the sensitivity to PARP1, and induced cell death by regulating excessive autophagy. KWLX-12e is expected to be a potential candidate for the treatment of TNBC. [Display omitted] • Novel dual-target PARP1/EZH2 inhibitors were designed and synthesized. • KWLX-12e showed potential inhibitory activity on PARP1/EZH2 and had no toxicity. • KWLX-12e increased sensitivity to PARP1 by inhibiting EZH2. • KWLX-12e could significantly inhibit tumor growth and proliferation. [ABSTRACT FROM AUTHOR]

Covalent modification of Keap1 results in reducing ubiquitination and the accumulation of Nrf2, which subsequently initiates the transcription of cellular anti-oxidant and anti-inflammatory genes. Iso- seco -tanapartholide (IST), a sesquiterpene isolated from the traditional Chinese medicine Artemisia argyi , had been reported to possess NF-κB inhibitory activity. However, its deep anti-inflammatory effects and direct target have never been reported. Here we show that IST activated Nrf2 and increased its target gene expression. In particular, LPS-caused inflammation in vitro and in vivo was mitigated by IST-induced Nrf2 activation but aggravated by Nrf2 inhibition. Mechanically, IST targeted Keap1 proteins via alkylating its cysteine residues 151, 273, 288, and so on. Subsequently, the modifying agent IST was displaced by intermolecular sulfhydryl disulfide interchange to lead to a disulfide dimer of Keap1. The resulting conformational change of Keap1 liberated Nrf2 from sequestration and allowed it translocation to the nucleus to activate the transcriptional program. Further studies demonstrated that Keap1 dimer formation contributed to the anti-inflammatory effects of IST. Taken together, our findings reveal a new mechanism for Nrf2 activation and provide a potential lead compound to treat inflammatory diseases through targeting Keap1. [Display omitted] • IST exerts anti-inflammatory effects in vitro and in vivo. • IST activates Nrf2 and its target gene expression. • IST covalently modifies Keap1 and induces its oligomerization. • IST-induced Keap1 dimer is cross-linked by intermolecular disulfide bridges. • Keap1 dimer formation contributes to the anti-inflammatory effects of IST. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: Twenty‐two new limonoids, mufolinoids A—V (1—22), including six rings A, B‐seco limonoids (1—6), twelve ring A‐seco limonoids (7—18), four ring‐intact limonoids (19—22), together with thirteen known compounds (23—35) were isolated from Munronia unifoliolata. Their structures including absolute configurations were elucidated by combination of NMR, HR‐MS, single‐crystal X‐ray diffraction and calculations of ECD and NMR technologies. Compounds 24, 25, 33, 34 could be significantly reversed the multidrug resistance of MCF‐7/doxorubicin (DOX) cells, and the reversal fold (RF) was much higher than that of positive drug Verapamil. Compounds 24, 28, and 29 exhibited significant anti‐inflammatory activity with the IC50 values in the range of 17.7—39.4 μmol/L. Furthermore, compound 29 could markedly inhibit the release of IL‐1β by inhibiting the initiation and assembly of NLRP3 inflammasome, which demonstrates the great potential of limonoids as an anti‐inflammatory agent. [ABSTRACT FROM AUTHOR]

As the most sensitive and direct indicator of global climate change, the freezing and thawing of the Antarctic ice sheet is of great significance for research on surface mass and energy balance. In this study, four representative regions in Antarctica were selected and correlation analysis, Granger causality testing, and cluster analysis were applied to comprehensively analyze the correlation and response of spatiotemporal variation in freeze-thaw and temperature. The conclusions are as follows. (1) In the Antarctic Peninsula, a phenomenon was demonstrated that the summer shifts rearward. Hotter December and colder March temperatures were observed in the Amery Ice Shelf and Queen Maud Land. (2) The Antarctic Peninsula featured the most severe degree of melting among the four regions, with the largest melt area in the past 30 years appearing during the 2015/2016 season. However, the number of melt days in most areas of the Antarctic Peninsula was observed to have decreased. (3) There is a strong correlation between the freeze-thaw state of the Antarctic ice sheet and temperature, as well as spatial differences among regions, but the data were clustered at different time scales. [ABSTRACT FROM AUTHOR]

[Display omitted] Previously, we have reported a withanolide-type steroid, named tubocapsenolide A (TA), which shows potent anti-proliferative activity in several cancer cell lines. However, its inhibitory effect on the Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) pathway and therapeutic potential on osteosarcoma have not been reported. In the present study, we aimed to investigate the effect and molecular mechanism of TA in osteosarcoma. The biological functions of TA in U2OS cells were investigated using colony formation, 5-ethynyl-20-deoxyuridine (EDU) staining, and cell cycle/apoptosis assays. The interaction between TA and Src homology 2 phosphatase 2 (SHP-2) was detected by enzyme activity and validated by target-identification methods such as drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA), and biolayer interferometry (BLI). The in vivo anti-tumor efficacy of TA was analyzed in the xenograft tumor model. Western blotting analysis was performed to detect the protein expression levels. TA exhibited antitumor activity against osteosarcoma both in vitro and in vivo by regulating the JAK/STAT3 signaling pathway. Mechanically, TA interacted with SHP-2 directly and activated its phosphatase activity. Importantly, protein tyrosine phosphatase (PTP) inhibitor, SHP-2 inhibitor, and SHP-2 siRNA could reverse the inhibitory effect of TA on the JAK/STAT3 signaling pathway and restored the TA-induced cell death. TA activated the phosphatase activity of SHP-2, which resulted in the inhibition of the JAK/STAT3 pathway and contributed to the antitumor efficacy of TA. Collectively, these findings suggested that TA could serve as a novel therapeutic agent for the treatment of osteosarcoma. [ABSTRACT FROM AUTHOR]