Berberine-based self-assembly agents with enhanced synergistic antitumor efficacy.

Tumors are still a major threat to people worldwide. Nanodrug delivery and targeting systems can significantly improve the therapeutic efficacy of chemotherapeutic drugs for antitumor purposes. However, many nanocarriers are likely to exhibit drawbacks such as a complex preparation process, limited drug-loading capacity, untargeted drug release, and toxicity associated with nanocarriers. Therefore, new therapeutic alternatives are urgently needed to develop antitumor drugs. Natural products with abundant scaffold diversity and structural complexity, which are derived from medicinal plants, are important sources of new antitumor drugs. Here, two carrier-free berberine (BBR)-based nanoparticles (NPs) were established to increase the synergistic efficacy of tumor treatment. BBR can interact with glycyrrhetinic acid (GA) and artesunate (ART) to self-assemble BBR-GA and BBR-ART NPs without any nanocarriers, respectively, the formation of which is dominated by electrostatic and hydrophobic interactions. Moreover, BBR-GA NPs could lead to mitochondria-mediated cell apoptosis by regulating mitochondrial fission and dysfunction, while BBR-ART NPs induced ferroptosis in tumor cells. BBR-based NPs have been demonstrated to possess significant tumor targeting and enhanced antitumor properties compared with those of simple monomer mixes both in vitro and in vivo. These carrier-free self-assemblies based on natural products provide a strategy for synergistic drug delivery and thus offer broad prospects for developing enhanced antitumor drugs.

Study of Iron Complex Photosensitizer with Hollow Double-Shell Nano Structure Used to Enhance Ferroptosis and Photodynamic Therapy.

Ferroptosis therapy, which uses ferroptosis inducers to produce lethal lipid peroxides and induce tumor cell death, is considered a promising cancer treatment strategy. However, challenges remain regarding how to increase the accumulation of reactive oxygen species (ROS) in the tumor microenvironment (TME) to enhance antitumor efficacy. In this study, a hyaluronic acid (HA) encapsulated hollow mesoporous manganese dioxide (H-MnO2) with double-shell nanostructure is designed to contain iron coordinated cyanine near-infrared dye IR783 (IR783-Fe) for synergistic ferroptosis photodynamic therapy against tumors. The nano photosensitizer IR783-Fe@MnO2-HA, in which HA actively targets the CD44 receptor, subsequently dissociates and releases Fe3+ and IR783 in acidic TME. First, Fe3+ consumes glutathione to produce Fe2+, which promotes the Fenton reaction in cells to produce hydroxyl free radicals (·OH) and induce ferroptosis of tumor cells. In addition, MnO2 catalyzes the production of O2 from H2O2 and enhances the production of singlet oxygen (1O2) by IR783 under laser irradiation, thus increasing the production and accumulation of ROS to provide photodynamic therapy. The highly biocompatible IR783-Fe@MnO2-HA nano-photosensitizers have exhibited tumor-targeting ability and efficient tumor inhibition in vivo due to the synergistic effect of photodynamic and ferroptosis antitumor therapies.

Engineered probiotic overcomes pathogen defences using signal interference and antibiotic production to treat infection in mice.

Probiotic supplements are suggested to promote human health by preventing pathogen colonization. However, the mechanistic bases for their efficacy in vivo are largely uncharacterized. Here using metabolomics and bacterial genetics, we show that the human oral probiotic Streptococcus salivarius K12 (SAL) produces salivabactin, an antibiotic that effectively inhibits pathogenic Streptococcus pyogenes (GAS) in vitro and in mice. However, prophylactic dosing with SAL enhanced GAS colonization in mice and ex vivo in human saliva. We showed that, on co-colonization, GAS responds to a SAL intercellular peptide signal that controls SAL salivabactin production. GAS produces a secreted protease, SpeB, that targets SAL-derived salivaricins and enhances GAS survival. Using this knowledge, we re-engineered probiotic SAL to prevent signal eavesdropping by GAS and potentiate SAL antimicrobials. This engineered probiotic demonstrated superior efficacy in preventing GAS colonization in vivo. Our findings show that knowledge of interspecies interactions can identify antibiotic- and probiotic-based strategies to combat infection.

Neddylation-dependent LSD1 destabilization inhibits the stemness and chemoresistance of gastric cancer.

Histone lysine-specific demethylase 1 (LSD1) expression has been evaluated in multiple tumors, including gastric cancer (GC). However, the mechanisms underlying LSD1 dysregulation in GC remain largely unclear. In this study, neural precursor cell-expressed developmentally down-regulated protein 8 (NEDD8) was identified to be conjugated to LSD1 at K63 by ubiquitin-conjugating enzyme E2 M (UBE2M), and this neddylated LSD1 could promote LSD1 ubiquitination and degradation, leading to a decrease of GC cell stemness and chemoresistance. Herein, our findings revealed a novel mechanism of LSD1 neddylation and its contribution to decreasing GC cell stemness and chemoresistance. Taken together, our findings may whistle about the future application of neddylation inhibitors.

MST-net: A multi-scale swin transformer network for EEG-based cognitive load assessment.

Cognitive load assessment plays a crucial role in monitoring safe production, resource allocation, and subjective initiative in human-computer interaction. Due to its high time resolution and convenient acquisition, Electroencephalography (EEG) is widely applied in brain monitoring and cognitive state assessment. In this study, a multi-scale Swin Transformer network (MST-Net) was proposed for cognitive load assessment, which extracts local features with different sensory fields using a multi-scale parallel convolution model and introduces the attention mechanism of the Swin Transformer to obtain the feature correlations among multi-scale local features. The performance of the proposed network was validated using the EEG signals collected during cognitive tasks and N-back tasks with three different load levels. Results show that the MST-Net network achieved the best classification accuracy on both local and public datasets, and was higher than the mainstream Swin Transformer and CNN. Furthermore, results of ablation experiments and feature visualization revealed that the proposed MST-Net could well characterize different cognitive loads, which not only provided novel and powerful tools for cognitive load assessment but also showed potential for broad application in brain-computer interface (BCI) systems.

Curettage combined with bone cavity opening reduces recurrence of the mandibular conventional ameloblastoma and effectively preserves the mandible: a retrospective study.

BACKGROUND: Patients with mandibular conventional ameloblastoma undergoing radical surgical treatment experience greater trauma and often find it challenging to accept, whereas conservative therapy is associated with a higher recurrence rate. In this study, we have improved traditional conservative treatment for mandibular conventional ameloblastoma by curettage combined with bone cavity opening (Cur/BCO). This retrospective study aimed to evaluate the effectiveness of the Cur/BCO treatment by comparing its recurrence rate and bone mineral density (BMD) growth rate with the traditional conservative treatment approach. METHODS: A total of 40 patients, meeting the study's inclusion and exclusion criteria from 2012 to 2020, were screened, with 20 in the modified group and 20 in the traditional group. ImageJ (RRID: SCR_003070) software was employed for measuring image indices. All data were analyzed using T-test, Chi-square test and Fisher exact test in SPSS 26.0 (p = 0.05). RESULTS: The incidence of recurrence was significantly lower in the modified group, at only 5%, compared to 35% in the traditional group (p < 0.05). Regarding bone mineral density (BMD) growth rate, the average value in the modified group was 0.0862 ± 0.2302 (/month), significantly higher than the average value of 0.0608 ± 0.2474 (/month) in the traditional group (p < 0.05). CONCLUSIONS: In this study, it was found that the recurrence rate of the modified conservative treatment (Cur/BCO) was lower than that of the traditional conservative treatment for managing mandibular conventional ameloblastoma. Furthermore, the BMD growth rate was quicker in the modified group. Thus, Cur/BCO could be considered as a viable option for the conservative treatment of mandibular conventional ameloblastoma.

Micafungin: A promising inhibitor of UBE2M in cancer cell growth suppression.

Neddylation is a protein modification process similar to ubiquitination, carried out through a series of activating (E1), conjugating (E2), and ligating (E3) enzymes. This process has been found to be overactive in various cancers, leading to increased oncogenic activities. Ubiquitin-conjugating enzyme 2 M (UBE2M) is one of two neddylation enzymes that play a vital role in this pathway. Studies have shown that targeting UBE2M in cancer treatment is crucial, as it regulates many molecular mechanisms like DNA damage, apoptosis, and cell proliferation. However, developing small molecule inhibitors against UBE2M remains challenging due to the lack of suitable druggable pockets. We have discovered that Micafungin, an antifungal agent that inhibits the production of 1,3-ß-D-glucan in fungal cell walls, acts as a neddylation inhibitor that targets UBE2M. Biochemical studies reveal that Micafungin obstructs neddylation and stabilizes UBE2M. In cellular experiments, the drug was found to interact with UBE2M, prevent neddylation, accumulate cullin ring ligases (CRLs) substrates, reduce cell survival and migration, and induce DNA damage in gastric cancer cells. This research uncovers a new anti-cancer mechanism for Micafungin, paving the way for the development of a novel class of neddylation inhibitors that target UBE2M.

Extremely negative emotion interferes with cognition: Evidence from ERPs and time-varying brain network.

In recent years, the relationship between emotion and cognition was a hot topic. However, it remains unclear which specific emotions can significantly interfere with cognition and how they do so. In this study, we designed a novel Affective Stroop experiment paradigm to investigate these issues. The extremely negative (EN), moderately negative (MN), moderately positive (MP), extremely positive (EP) and neutral pictures were displayed before Stroop tasks. The behavioral results revealed that EN emotion significantly interfered with cognitive performance compared to other types of emotions, with a significant increase in reaction time under the EN emotion condition (P < 0.05). Furthermore, the dynamic brain mechanisms were analyzed from both Event-Related Potential (ERP) and time-varying brain network perspectives. Results showed that EN emotion evoked larger N2, P3, and LPP amplitudes in the frontal, parietal, and occipital brain regions. In contrast, the Stroop task under EN condition led to smaller N2, P3, and LPP amplitudes compared to neutral condition. This indicates that EN emotion was prioritized and consumed more cognitive resources relative to neutral emotion. During the P3 and LPP stages, we observed enhanced bottom-up connections between the parietal and frontal regions while the processing of EN emotion. Additionally, there were stronger top-down cognitive control connections from the frontal to the occipital regions while processing the Stroop task under EN condition. These findings consistently suggest that EN emotion interferes with cognition by consuming more cognitive resources, and the brain needs to enhance cognitive control to support Stroop task execution.

Chemical Synthesis of a Keto Sugar Nucleotide.

Keto sugar nucleotides (KSNs) are common and versatile precursors to various deoxy sugar nucleotides, which are substrates for the corresponding glycosyltransferases involved in the biosynthesis of glycoproteins, glycolipids, and natural products. However, there has been no KSN synthesized chemically due to the inherent instability. Herein, the first chemical synthesis of the archetypal KSN TDP-4-keto-6-deoxy-d-glucose (1) is achieved by an efficient and optimized route, providing feasible access to other KSNs and analogues, thereby opening a new avenue for new applications.

PROTAC Nanoplatform with Targeted Degradation of NAD(P)H:Quinone Oxidoreductase 1 to Enhance Reactive Oxygen Species-Mediated Apoptosis.

Apoptosis mediated by reactive oxygen species (ROS) has emerged as a promising therapeutic strategy for tumors. However, the overexpression of NAD(P)H:quinone oxidoreductase 1 (NQO1) protein restricted ROS production through a negative feedback pathway in tumor cells, promoting tumor progression, and weakening the effect of drug therapy. Here, a PROTACs nanodrug delivery system (PN) was constructed to increase ROS generation by degrading the NQO1 protein. Specifically, a PROTAC (proteolytic targeting chimera) molecule DQ was designed and synthesized. Then DQ and withaferin A (WA, an inducer of ROS) were loaded into PNs. DQ degraded the overexpressed NQO1 protein in tumor cells through a protein ubiquitination degradation pathway, thereby weakening the antioxidant capacity of tumor cells. Meanwhile, the reduction of NQO1 could inhibit the negative feedback effect of ROS production, thus increasing ROS generation. It has been demonstrated that PNs can significantly increase ROS production and possess potent antitumor properties in vitro and in vivo. This nanoplatform may offer an alternative approach to treating tumors with NQO1 overexpression.

Carrier-free nanoplatforms from natural plants for enhanced bioactivity.

BACKGROUND: 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. AIM OF REVIEW: 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.

EEG Network Analysis of Depressive Emotion Interference Spatial Cognition Based on a Simulated Robotic Arm Docking Task.

Depressive emotion (DE) refers to clinically relevant depressive symptoms without meeting the diagnostic criteria for depression. Studies have demonstrated that DE can cause spatial cognition impairment. However, the brain network mechanisms underlying DE interference spatial cognition remain unclear. This study aimed to reveal the differences in brain network connections between DE and healthy control (HC) groups during resting state and a spatial cognition task. The longer operation time of the DE group during spatial cognition task indicated DE interference spatial cognition. In the resting state stage, the DE group had weaker network connections in theta and alpha bands than the HC group had. Specifically, the electrodes in parietal regions were hubs of the differential networks, which are related to spatial attention. Moreover, in docking task stages, the left frontoparietal network connections in delta, beta, and gamma bands were stronger in the DE group than those of the HC group. The enhanced left frontoparietal connections in the DE group may be related to brain resource reorganization to compensate for spatial cognition decline and ensure the completion of spatial cognition tasks. Thus, these findings might provide new insights into the neural mechanisms of depressive emotion interference spatial cognition.

EEG Identity Authentication in Multi-Domain Features: A Multi-Scale 3D-CNN Approach.

Electroencephalogram (EEG) authentication has become a research hotspot in the field of information security due to its advantages of living, internal, and anti-stress. However, the performance of identity authentication system is limited by the inherent attributes of EEG, such as low SNR, low stability, and strong randomness. Researchers generally believe that the in-depth fusion of features can improve the performance of identity authentication and have explored among various feature domains. This experiment invited 70 subjects to participate in the EEG identity authentication task, and the experimental materials were visual stimuli of the self and non-self-names. This paper proposes an innovative EEG authentication framework, including efficient three-dimensional representation of EEG signals, multi-scale convolution structure, and the combination of multiple authentication strategies. In this work, individual EEG signals are converted into spatial-temporal-frequency domain three-dimensional forms to provide multi-angle mixed feature representation. Then, the individual identity features are extracted by the various convolution kernel of multi-scale vision, and the strategy of combining multiple convolution kernels is explored. The results show that the small-size and long-shape convolution kernel is suitable for ERP tasks, which can obtain better convergence and accuracy. The experimental results show that the classification performance of the proposed framework is excellent, and the multi-scale convolution method is effective to extract high-quality identity characteristics across feature domains. The results show that the branch number matches the EEG component number can obtain the excellent cost performance. In addition, this paper explores the network training performance for multi-scale module combination strategy and provides reference for deep network construction strategy of EEG signal processing.

ERP-WGAN: A data augmentation method for EEG single-trial detection.

Brain computer interaction based on EEG presents great potential and becomes the research hotspots. However, the insufficient scale of EEG database limits the BCI system performance, especially the positive and negative sample imbalance caused by oddball paradigm. To alleviate the bottleneck problem of scarce EEG sample, we propose a data augmentation method based on generative adversarial network to improve the performance of EEG signal classification. Taking the characteristics of EEG into account in wasserstein generative adversarial networks (WGAN), the problems of model collapse and poor quality of artificial data were solved by using resting noise, smoothing and random amplitude. The quality of artificial data was comprehensively evaluated from verisimilitude, diversity and accuracy. Compared with the three artificial data methods and two data sampling methods, the proposed ERP-WGAN framework significantly improve the performance of both subject and general classifiers, especially the accuracy of general classifiers trained by less than 5 dimensional features is improved by 20-25%. Moreover, we evaluate the training sets performance with different mixing ratios of artificial and real samples. ERP-WGAN can reduced at least 73% of the real subject data and acquisition cost, which greatly saves the test cycle and research cost.

Theranostic nanosystem with supramolecular self-assembly for enhanced reactive oxygen species-mediated apoptosis guided by dual-modality tumor imaging.

With the development of precision medicine, visual and traceable treatments are highly desirable for cancer therapy. However, researchers and clinicians remain confused regarding where the drug distributes and location of the tumor, when the drug is released and when to irradiate the tumor, and how the drug presents antitumor activity, all of which hinders assessment of the cancer patient's condition and formulation of a follow-up treatment scheme for clinicians. Here, a supramolecular self-assembly theranostic nanosystem (MWNs) was designed for enhanced reactive oxygen species (ROS)-mediated cell apoptosis guided by dual-modality tumor imaging. Specifically, merocyanine was introduced in cyanine dye to extend its conjugated π-scaffolds, which could preferentially self-assemble into nanovesicles owing to its amphipathy. Furthermore, withaferin A (WA), used as a chemotherapeutic drug, was loaded to construct MWNs. The assembled or disassembled MWNs behaved differently in photoacoustic (PA) intensity and fluorescence signal intensity. The MWNs exhibited stronger PA signals and quenched fluorescence, which monitors their distribution and images the tumor location in vivo, while the disassembled MWNs showed weak PA signals and recovered fluorescence, indicating the release of drug and instructing the appropriate time to irradiate for photodynamic therapy (PDT). Thus, ROS generation introduced by PDT and released WA led to cell apoptosis. This intelligent nanosystem for precise cancer therapy that reveals where the tumor is, when to irradiate the tumor, and how the tumor is cured might establish the basis for biomedical applications of finely controlled platform.

Promising natural lysine specific demethylase 1 inhibitors for cancer treatment: advances and outlooks.

Lysine specific demethylase 1 (LSD1), a transcriptional corepressor or coactivator that serves as a demethylase of histone 3 lysine 4 and 9, has become a potential therapeutic target for cancer therapy. LSD1 mediates many cellular signaling pathways and regulates cancer cell proliferation, invasion, migration, and differentiation. Recent research has focused on the exploration of its pharmacological inhibitors. Natural products are a major source of compounds with abundant scaffold diversity and structural complexity, which have made a major contribution to drug discovery, particularly anticancer agents. In this review, we briefly highlight recent advances in natural LSD1 inhibitors over the past decade. We present a comprehensive review on their discovery and identification process, natural plant sources, chemical structures, anticancer effects, and structure-activity relationships, and finally provide our perspective on the development of novel natural LSD1 inhibitors for cancer therapy.

Biosynthesis and bioactivities of microbial genotoxin colibactins.

Covering: up to 2021Colibactin(s), a group of secondary metabolites produced by the pks island (clb cluster) of Escherichia coli, shows genotoxicity relevant to colorectal cancer and thus significantly affects human health. Over the last 15 years, substantial efforts have been exerted to reveal the molecular structure of colibactin, but progress is slow owing to its instability, low titer, and elusive and complex biosynthesis logic. Fortunately, benefiting from the discovery of the prodrug mechanism, over 40 precursors of colibactin have been reported. Some key biosynthesis genes located on the pks island have also been characterised. Using an integrated bioinformatics, metabolomics, and chemical synthesis approach, researchers have recently characterised the structure and possible biosynthesis processes of colibactin, thereby providing new insights into the unique biosynthesis logic and the underlying mechanism of the biological activity of colibactin. Early developments in the study of colibactin have been summarised in several previous reviews covering various study periods, whereas the two most recent reviews have focused primarily on the chemical synthesis of colibactin. The present review aims to provide an update on the biosynthesis and bioactivities of colibactin.

Knockdown of NRMT enhances sensitivity of retinoblastoma cells to cisplatin through upregulation of the CENPA/Myc/Bcl2 axis.

Chemotherapy resistance of tumor cells causes failure in anti-tumor therapies. Recently, N-terminal regulator of chromatin condensation 1 methyltransferase (NRMT) is abnormally expressed in different cancers. Hence, we speculate that NRMT may pay a crucial role in the development of chemosensitivity in retinoblastoma. We characterized the upregulation of NRMT in the developed cisplatin (CDDP)-resistant retinoblastoma cell line relative to parental cells. Loss-of-function experiments demonstrated that NRMT silencing enhanced chemosensitivity of retinoblastoma cells to CDDP. Next, NRMT was identified to enrich histone-H3 lysine 4 trimethylation in the promoter of centromere protein A (CENPA) by chromatin immunoprecipitation assay. Rescue experiments suggested that CENPA reduced chemosensitivity by increasing the viability and proliferation and reducing apoptosis of CDDP-resistant retinoblastoma cells, which was reversed by NRMT. Subsequently, CENPA was witnessed to induce the transcription of Myc and to elevate the expression of B cell lymphoma-2. At last, in vivo experiments confirmed the promotive effect of NRMT knockdown on chemosensitivity of retinoblastoma cells to CDDP in tumor-bearing mice. Taken together, NRMT is an inhibitor of chemosensitivity in retinoblastoma. Those findings shed new light on NRMT-targeted therapies for retinoblastoma.

Discovery of quinazoline derivatives as a novel class of potent and in vivo efficacious LSD1 inhibitors by drug repurposing.

Histone lysine-specific demethylase 1 (LSD1) is an important epigenetic modulator, and is implicated in malignant transformation and tumor pathogenesis in different ways. Therefore, the inhibition of LSD1 provides an attractive therapeutic target for cancer therapy. Based on drug repurposing strategy, we screened our in-house chemical library toward LSD1, and found that the EGFR inhibitor erlotinib, an FDA-approved drug for lung cancer, possessed low potency against LSD1 (IC50 = 35.80 µM). Herein, we report our further medicinal chemistry effort to obtain a highly water-soluble erlotinib analog 5k (>100 mg/mL) with significantly enhanced inhibitory activity against LSD1 (IC50 = 0.69 µM) as well as higher specificity. In MGC-803 cells, 5k suppressed the demethylation of LSD1, indicating its cellular activity against the enzyme. In addition, 5k had a remarkable capacity to inhibit colony formation, suppress migration and induce apoptosis of MGC803 cells. Furthermore, in MGC-803 xenograft mouse model, 5k treatment resulted in significant reduction in tumor size by 81.6% and 96.1% at dosages of 40 and 80 mg/kg/d, respectively. Our findings indicate that erlotinib-based analogs provide a novel structural set of LSD1 inhibitors with potential for further investigation, and may serve as novel candidates for the treatment of LSD1-overexpressing cancers.

Mutanofactin promotes adhesion and biofilm formation of cariogenic Streptococcus mutans.

Cariogenic Streptococcus mutans is known as a predominant etiological agent of dental caries due to its exceptional capacity to form biofilms. From strains of S. mutans isolated from dental plaque, we discovered, in the present study, a polyketide/nonribosomal peptide biosynthetic gene cluster, muf, which directly correlates with a strong biofilm-forming capability. We then identified the muf-associated bioactive product, mutanofactin-697, which contains a new molecular scaffold, along with its biosynthetic logic. Further mode-of-action studies revealed that mutanofactin-697 binds to S. mutans cells and also extracellular DNA, increases bacterial hydrophobicity, and promotes bacterial adhesion and subsequent biofilm formation. Our findings provided an example of a microbial secondary metabolite promoting biofilm formation via a physicochemical approach, highlighting the importance of secondary metabolism in mediating critical processes related to the development of dental caries.