Tumor-derived nanovesicles enhance cancer synergistic chemo-immunotherapy by promoting cGAS/STING pathway activation and immunogenetic cell death.

AIMS: Checkpoint blockade immunotherapy is a promising therapeutic modality that has revolutionized cancer treatment; however, the therapy is only effective on a fraction of patients due to the tumor environment. In tumor immunotherapy, the cGAS-STING pathway is a crucial intracellular immune response pathway. Therefore, this study aimed to develop an immunotherapy strategy based on the cGAS-STING pathway. MATERIALS AND METHODS: The physicochemical properties of the nanoparticles EM@REV@DOX were characterized by TEM, DLS, and WB. Subcutaneous LLC xenograft tumors were used to determine the biodistribution, antitumor efficacy, and immune response. Blood samples and tissues of interest were harvested for hematological analysis and H&E staining. SIGNIFICANCE: Overall, our designed nanovesicles provide a new perspective on tumor immunotherapy by ICD and cGAS-STING pathway, promoting DCs maturation, macrophage polarization, and activating T cells, offering a meaningful strategy for accelerating the clinical development of immunotherapy. KEY FINDINGS: EM@REV@DOX accumulated in the tumor site through EPR and homing targeting effect to release REV and DOX, resulting in DNA damage and finally activating the cGAS-STING pathway, thereby promoting DCs maturation, macrophage polarization, and activating T cells. Additionally, EM@REV@DOX increased the production of pro-inflammatory cytokines (e.g., TNF-α and IFN-ß). As a result, EM@REV@DOX was effective in treating tumor-bearing mice and prolonged their lifespans. When combined with αPD-L1, EM@REV@DOX significantly inhibited distant tumor growth, extended the survival of mice, and prevented long-term postoperative tumor metastasis, exhibiting great potential in antitumor immunotherapy.

Plasma proteome profiling reveals dynamic of cholesterol marker after dual blocker therapy.

Dual blocker therapy (DBT) has the enhanced antitumor benefits than the monotherapy. Yet, few effective biomarkers are developed to monitor the therapy response. Herein, we investigate the DBT longitudinal plasma proteome profiling including 113 longitudinal samples from 22 patients who received anti-PD1 and anti-CTLA4 DBT therapy. The results show the immune response and cholesterol metabolism are upregulated after the first DBT cycle. Notably, the cholesterol metabolism is activated in the disease non-progressive group (DNP) during the therapy. Correspondingly, the clinical indicator prealbumin (PA), free triiodothyronine (FT3) and triiodothyronine (T3) show significantly positive association with the cholesterol metabolism. Furthermore, by integrating proteome and radiology approach, we observe the high-density lipoprotein partial remodeling are activated in DNP group and identify a candidate biomarker APOC3 that can reflect DBT response. Above, we establish a machine learning model to predict the DBT response and the model performance is validated by an independent cohort with balanced accuracy is 0.96. Thus, the plasma proteome profiling strategy evaluates the alteration of cholesterol metabolism and identifies a panel of biomarkers in DBT.

Structural and aggregation changes of silver carp myosin induced with alcohols: Effects of ethanol, 1,2-propanediol, and glycerol.

This study investigated the effects of ethanol, 1,2-propanediol, and glycerol on the structure and aggregation behavior of silver carp (Hypophthalmichthys molitrix) myosin. All alcohols induced extensive alteration in the tertiary structure of myosin. Both ethanol and 1,2-propanediol further promoted an increase in the content of ß-sheets in myosin and induced myosin aggregation. While glycerol had almost no impact on the secondary structure of myosin. Molecular dynamics simulations revealed that increasing the concentration of ethanol and 1,2-propanediol affected the overall structural changes in the myosin heavy chain (MHC), while glycerol exerted a more pronounced effect on the MHC tail when compared to the MHC head. Disruption of the hydration layers induced by ethanol and 1,2-propanediol contributed to local structural changes in myosin. Glycerol at a concentration of 20% induced the formation of a larger hydration layer around the MHC tail, which facilitated the stabilization of the protein structure.

Engineering the Band Topology in a Rhombohedral Trilayer Graphene Moiré Superlattice.

Moiré superlattices have become a fertile playground for topological Chern insulators, where the displacement field can tune the quantum geometry and Chern number of the topological band. However, in experiments, displacement field engineering of spontaneous symmetry-breaking Chern bands has not been demonstrated. Here in a rhombohedral trilayer graphene moiré superlattice, we use a thermodynamic probe and transport measurement to monitor the Chern number evolution as a function of the displacement field. At a quarter filling of the moiré band, a novel Chern number of three is unveiled to compete with the well-established number of two upon turning on the electric field and survives when the displacement field is sufficiently strong. The transition can be reconciled by a nematic instability on the Fermi surface due to the pseudomagnetic vector field potentials associated with moiré strain patterns. Our work opens more opportunities to active control of Chern numbers in van der Waals moiré systems.

Genome-wide evolutionary analysis of TKL_CTR1-DRK-2 gene family and functional characterization reveals that TaCTR1 positively regulates flowering time in wheat.

BACKGROUND: Flowering time has an important effect on regional adaptation and yields for crops. The tyrosine kinase-like (TKL) gene family is widely existed and participates in many biological processes in plants. Furthermore, only few TKLs have been characterized functions in controlling flowering time in wheat. RESULTS: Here, we report that TaCTR1, a tyrosine kinase-like (TKL) gene, regulates flowering time in wheat. Based on identification and evolutionary analysis of TKL_CTR1-DRK-2 subfamily in 15 plants, we proposed an evolutionary model for TaCTR1, suggesting that occurrence of some exon fusion events during evolution. The overexpression of TaCTR1 caused early flowering time in transgenic lines. Transcriptomics analysis enabled identification of mass differential expression genes including plant hormone (ET, ABA, IAA, BR) signaling, flavonoid biosynthesis, phenolamides and antioxidant, and flowering-related genes in TaCTR1 overexpression transgenic lines compared with WT plants. qRT-PCR results showed that the expression levels of ethylene (ET) signal-related genes (ETR, EIN, ERF) and flowering-related genes (FT, PPD1, CO, PRR, PHY) were altered in TaCTR1-overexpressing wheat compared with WT plants. Metabonomics analysis showed that flavonoid contents were altered. CONCLUSIONS: Thus, the results show that TaCTR1 plays a positive role in controlling flowering time by activating various signaling pathways and regulating flowering-related genes, and will provide new insights on the mechanisms of wheat flowering regulation.

Efficient Green Spin Light-Emitting Diodes Enabled by Ultrafast Energy- and Spin-Funneling in Chiral Perovskites.

Introducing molecular chirality into perovskite crystal structures has enabled the control of carrier spin states, giving rise to circularly polarized luminescence (CPL) in thin films and circularly polarized electroluminescence (CPEL) in LEDs. Spin-LEDs can be fabricated either through a spin-filtering layer enabled by chiral-induced spin selectivity or a chiral emissive layer. The former requires a high degree of spin polarization and a compatible spinterface for efficient spin injection, which might not be easily integrated into LEDs. Alternatively, a chiral emissive layer can also generate circularly polarized electroluminescence, but the efficiency remains low and the fundamental mechanism is elusive. In this work, we report an efficient green LED based on quasi-two-dimensional (quasi-2D) chiral perovskites as the emitting layer (EML), where CPEL is directly produced without separate carrier spin injection. The optimized chiral perovskite thin films exhibited strong CPL at 535 nm with a photoluminescence quantum yield (PLQY) of 91% and a photoluminescence dissymmetry factor (glum) of 8.6 × 10-2. Efficient green spin-LEDs were successfully demonstrated, with a large EL dissymmetry factor (gEL) of 7.8 × 10-2 and a maximum external quantum efficiency (EQE) of 13.5% at room temperature. Ultrafast transient absorption (TA) spectroscopic study shows that the CPEL is generated from a rapid energy transfer accompanied by spin transfer from 2D to 3D perovskites. Our study not only demonstrates a reliable approach to achieve high performance spin-LEDs but also reveals the fundamental mechanism of CPEL with an emissive layer of chiral perovskites.

Low salinity influences the dose-dependent transcriptomic responses of oysters to cadmium.

Species in estuaries tend to undergo both cadmium (Cd) and low salinity stress. However, how low salinity affects the Cd toxicity has not been fully understood. Investigating the impacts of low salinity on the dose-response relationships between Cd and biological endpoints has potential to enhance our understanding of the combined effects of low salinity and Cd. In this work, changes in the transcriptomes of Pacific oysters were analyzed following exposure to Cd (5, 20, 80 µg/L Cd2+) under normal (31.4 psu) and low (15.7 psu) salinity conditions, and then the dose-response relationship between Cd and transcriptome was characterized in a high-throughput manner. The benchmark dose (BMD) of gene expression, as a point of departure (POD), was also calculated based on the fitted dose-response model. We found that low salinity treatment significantly influenced the dose-response relationships between Cd and transcripts in oysters indicated by altered dose-response curves. In details, a total of 219 DEGs were commonly fitted to best models under both normal and low salinity conditions. Nearly three quarters of dose-response curves varied with salinity condition. Some monotonic dose-response curves in normal salinity condition even were replaced by nonmonotonic curves in low salinity condition. Low salinity treatment decreased the PODs of differentially expressed genes induced by Cd, suggesting that gene differential expression was more prone to being triggered by Cd in low salinity condition. The changed sensitivity to Cd in low salinity condition should be taken into consideration when using oyster as an indicator to assess the ecological risk of Cd pollution in estuaries.

Association of past and current sleep duration with structural brain differences: A large population-based study from the UK Biobank.

OBJECTIVE: This study aimed to examine the association between past/current sleep duration and macro-/micro-structural brain outcomes and explore whether hypertension or social activity plays a role in such association. METHODS: Within the UK Biobank, 40 436 dementia-free participants (age 40-70 years) underwent a baseline assessment followed by a brain magnetic resonance imaging (MRI) scan 9 years later. Past (baseline) and current (MRI scans) sleep duration (hours/day) were recorded and classified as short (≤5), intermediate (6-8), and long (≥9). Brain structural volumes and diffusion markers were assessed by MRI scans. RESULTS: Compared with past intermediate sleep, past short sleep was related to smaller cortex volumes (standardized ß [95 % CI]: -0.04 [-0.07, -0.02]) and lower regional fractional anisotropy (FA) (-0.08 [-0.13, -0.03]), while past long sleep was related to smaller regional subcortical volumes (standardized ß: -0.04 to -0.07 for thalamus, accumbens, and hippocampus). Compared to current intermediate sleep, current short sleep was associated with smaller cortex volumes (-0.03 [-0.05, -0.01]), greater white matter hyperintensities (WMH) volumes (0.04 [0.01, 0.08]), and lower regional FA (-0.07 [-0.11, -0.02]). However, current long sleep was related to smaller total brain (-0.03 [-0.05, -0.02]), grey matter (-0.05 [-0.07, -0.03]), cortex (-0.05 [-0.07, -0.03]), regional subcortical volumes [standardized ß: -0.05 to -0.09 for putamen, thalamus, hippocampus, and accumbens]), greater WMH volumes (0.06 [0.03, 0.09]), as well as lower regional FA (-0.05 [-0.09, -0.02]). The association between current long sleep duration and poor brain health was stronger among people with hypertension or low frequency of social activity (all Pinteraction <0.05). CONCLUSIONS: Both past and current short/long sleep are associated with smaller brain volume and poorer white matter health in the brain, especially in individuals with hypertension and low frequency of social activity. Our findings highlight the need to maintain 6-8 h' sleep duration for healthy brain aging.

Distinguishing optimal candidates for primary tumor resection in patients with metastatic lung adenocarcinoma: A predictive model based on propensity score matching.

Background: Primary tumor resection is associated with survival benefits in patients with metastatic lung adenocarcinoma (mLUAD). However, there are no established methods to determine which individuals would benefit from surgery. Therefore, we developed a model to predict the patients who are likely to benefit from surgery in terms of survival. Methods: Data on patients with mLUAD were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Depending on whether surgery was performed on the primary tumor, patients were categorized into two groups: cancer-directed surgery (CDS) and no-cancer-directed surgery (No-CDS). Propensity Score Matching (PSM) was utilized to address bias between the CDS and No-CDS groups. The prognostic impact of CDS was assessed using Kaplan-Meier analysis and Cox proportional hazard models. Subsequently, we constructed a nomogram to predict the potential for surgical benefits based on multivariable logistic regression analysis using preoperative factors. Results: A total of 89,039 eligible patients were identified, including 6.4% (5705) who underwent surgery. Following PSM, the CDS group demonstrated a significantly longer median overall survival (mOS) compared with the No-CDS group (23 [21-25] vs. 7 [7-8] months; P < 0.001). The nomogram showed robust performance in both the training and validation sets (area under the curve [AUC]: 0.698 and 0.717, respectively), and the calibration curves exhibited high consistency. The nomogram proved clinically valuable according to decision curve analysis (DCA). According to this nomogram, surgical patients were categorized into two groups: no-benefit candidates and benefit candidates groups. Compared with the no-benefit candidate group, the benefit candidate group was associated with longer survival (mOS: 25 vs. 6 months, P < 0.001). Furthermore, no difference in survival was observed between the no-benefit candidates and the no-surgery groups (mOS: 6 vs. 7 months, P = 0.9). Conclusions: A practical nomogram was developed to identify optimal CDS candidates among patients with mLUAD.

Revealing the impact of thermal annealing on the perovskite/organic bulk heterojunction interface in photovoltaic devices.

Perovskite/organic bulk heterojunction (BHJ) integrated solar cells have tremendous development potential to exceed the Shockley-Queisser limit efficiency of single-junction photovoltaics, due to the merits of spectra response extension. However, the presence of energy level barriers and severe non-radiative recombination at the interface between perovskite and BHJ greatly hindered the transport and collection of charge carriers, usually leading to large Voc and photocurrent loss, as well as the stability degradation of integrated devices. Therefore, investigating the interface properties of perovskite/BHJ is crucial for understanding the charge transport process and enhancing device performance. In this study, we effectively regulated the interface properties and charge transport in perovskite/BHJ integrated devices using a thermal annealing process. Using Kelvin probe microscopy, photoluminescence, and transient absorption spectroscopy, we revealed that moderate annealing treatment would contribute to forming close interface contact and provide more channels or pathways for charge transfer, which is advantageous for the interface charge collection and device performance. In addition, the lone pair electrons of acyl, thiophene and pyrrole function groups in polymer PDPP3T and PCBM can act as the Lewis base and provide electrons to the under-coordinated lead atoms or clusters in the perovskite, effectively passivating traps on the surface and grain boundaries of the perovskite through Lewis acid-base coordination. Finally, we improved the photovoltaic conversion efficiency of the device to 21.57% with enhanced stability using an optimized thermal annealing process. This study provides a comprehensive understanding of the integrated perovskite/BHJ interface properties, which could be extended to other optoelectronic devices based on a similar integrated structure.

LILRB2 promotes immune escape in breast cancer cells via enhanced HLA-A degradation.

PURPOSE: Increased expression of leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2) is associated with immune evasion in breast cancer (BC). The aim of this study to elucidate the role of LILRB2 in BC progression. METHODS: LILRB2 expression in tumor tissues was detected by immunohistochemical staining. Human leukocyte antigen A (HLA-A) expression in BC cells was detected by Western blotting, and HLA-A ubiquitination was detected by immunoprecipitation and histidine pulldown assay. An in-situ tumor model was established in nude BALB/c mice to verify the role of LILRB2 in immune escape. Finally, the functions and potential mechanisms of LILRB2 in BC progression were explored using in silico data. RESULTS: LILRB2 was upregulated in BC tissues and cells, and correlated positively with poor prognosis. LILRB2 promoted BC progression by downregulating HLA-A expression. Mechanistically, LILRB2 facilitates the ubiquitination and subsequent degradation of HLA-A by promoting the interaction between the ubiquitin ligase membrane-associated ring finger protein 9 (MARCH9) and HLA-A. In syngeneic graft mouse models, LILRB2-expressing BC cells evaded CD8 + T cells and inhibited the secretion of cytokines by the cytotoxic CD8 + T cells. CONCLUSION: LILRB2 downregulates HLA-A to promote immune evasion in BC cells and is a promising new target for BC treatment.

Comprehensive pan-cancer analysis reveals prognostic implications of TMEM92 in the tumor immune microenvironment.

BACKGROUND: Transmembrane protein 92 (TMEM92) has been implicated in the facilitation of tumor progression. Nevertheless, comprehensive analyses concerning the prognostic significance of TMEM92, as well as its role in immunological responses across diverse cancer types, remain to be elucidated. METHODS: In this study, data was sourced from a range of publicly accessible online platforms and databases, including TCGA, GTEx, UCSC Xena, CCLE, cBioPortal, HPA, TIMER2.0, GEPIA, CancerSEA, GDSC, exoRBase, and ImmuCellAI. We systematically analyzed the expression patterns of TMEM92 at both mRNA and protein levels across diverse human organs, tissues, extracellular vesicles (EVs), and cell lines associated with multiple cancer types. Subsequently, analyses were conducted to determine the relationship between TMEM92 and various parameters such as prognosis, DNA methylation, copy number variation (CNV), the tumor microenvironment (TME), immune cell infiltration, genes with immunological relevance, tumor mutational burden (TMB), microsatellite instability (MSI), mismatch repair (MMR), and half-maximal inhibitory concentration (IC50) values. RESULTS: In the present study, we observed a pronounced overexpression of TMEM92 across a majority of cancer types, which was concomitantly associated with a less favorable prognosis. A notable association emerged between TMEM92 expression and both DNA methylation and CNV. Furthermore, a pronounced relationship was discerned between TMEM92 expression, the TME, and the degree of immune cell infiltration. Intriguingly, while TMEM92 expression displayed a positive correlation with macrophage presence, it inversely correlated with the infiltration level of CD8 + T cells. Concurrently, significant associations were identified between TMEM92 and the major histocompatibility complex, TMB, MSI, and MMR. Results derived from Gene Set Enrichment Analysis and Gene Set Variation Analysis further substantiated the nexus of TMEM92 with both immune and metabolic pathways within the oncogenic context. CONCLUSIONS: These findings expanded the understanding of the roles of TMEM92 in tumorigenesis and progression and suggest that TMEM92 may have an immunoregulatory role in several malignancies.

Tunable Surface Charge of Layered Double Hydroxide Membranes Enabling Osmotic Energy Harvesting from Anion Transport.

Membrane-based osmotic energy harvesting is a promising technology with zero carbon footprint. High-performance ion-selective membranes (ISMs) are the core components in such applications. Recent advancement in 2D nanomaterials opens new avenues for building highly efficient ISMs. However, the majority of the explored 2D nanomaterials have a negative surface charge, which selectively enhances cation transport, resulting in the underutilization of half of the available ions. In this study, ISMs based on layered double hydroxide (LDH) with tunable positive surface charge are studied. The membranes preferentially facilitate anion transport with high selectivity. Osmotic energy harvesting device based on these membranes reached a power density of 2.31 W m-2 under simulated river/sea water, about eight times versus that of a commercial membrane tested under the same conditions, and up to 7.05 W m-2 under elevated temperature and simulated brine/sea water, and long-term stability with consistent performance over a 40-day period. A prototype reverse electrodialysis energy harvesting device, comprising a pair of LDH membranes and commercial cation-selective membranes, is able to simultaneously harvest energy from both cations and anions achieving a power density of 6.38 W m-2 in simulated river/sea water, demonstrating its potential as building blocks for future energy harvesting systems.

Incremental regression of localization context for automatic segmentation of ossified ligamentum flavum from CT data.

PURPOSE: Segmentation of ossified ligamentum flavum (OLF) plays a crucial role in developing computer-assisted, image-guided systems for decompressive thoracic laminectomy. Manual segmentation is time-consuming, tedious, and label-intensive. It also suffers from inter- and intra-observer variability. Automatic segmentation is highly desired. METHODS: A two-stage, localization context-aware framework is developed for automatic segmentation of ossified ligamentum flavum. In the first stage, localization heatmaps of OLFs are obtained via incremental regression. In the second stage, the obtained heatmaps are then treated as the localization context for a segmentation U-Net. Our framework can directly map a whole volumetic data to its volume-wise labels. RESULTS: We designed and conducted comprehensive experiments on datasets of 100 patients to evaluate the performance of the proposed method. Our method achieved an average Dice similarity coefficient of 61.2 ± 7.6%, an average surface distance of 1.1 ± 0.5 mm, and an average positive predictive value of 62.0 ± 12.8%. CONCLUSION: To the best knowledge of the authors, this is the first study aiming for automatic segmentation of ossified ligamentum flavum. Results from the comprehensive experiments demonstrate the superior performance of the proposed method over the state-of-the-art methods.

Chemotherapy-elicited extracellular vesicle CXCL1 from dying cells promotes triple-negative breast cancer metastasis by activating TAM/PD-L1 signaling.

BACKGROUND: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, and chemotherapy still serves as the cornerstone treatment functioning by inducing cytotoxic cell death. Notably, emerging evidence suggests that dying cell-released signals may induce cancer progression and metastasis by modulating the surrounding microenvironment. However, the underlying molecular mechanisms and targeting strategies are yet to be explored. METHODS: Apoptotic TNBC cells induced by paclitaxel or adriamycin treatment were sorted and their released extracellular vesicles (EV-dead) were isolated from the cell supernatants. Chemokine array analysis was conducted to identify the crucial molecules in EV-dead. Zebrafish and mouse xenograft models were used to investigate the effect of EV-dead on TNBC progression in vivo. RESULTS: It was demonstrated that EV-dead were phagocytized by macrophages and induced TNBC metastasis by promoting the infiltration of immunosuppressive PD-L1+ TAMs. Chemokine array identified CXCL1 as a crucial component in EV-dead to activate TAM/PD-L1 signaling. CXCL1 knockdown in EV-dead or macrophage depletion significantly inhibited EV-dead-induced TNBC growth and metastasis. Mechanistic investigations revealed that CXCL1EV-dead enhanced TAM/PD-L1 signaling by transcriptionally activating EED-mediated PD-L1 promoter activity. More importantly, TPCA-1 (2-[(aminocarbonyl) amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide) was screened as a promising inhibitor targeting CXCL1 signals in EVs to enhance paclitaxel chemosensitivity and limit TNBC metastasis without noticeable toxicities. CONCLUSIONS: Our results highlight CXCL1EV-dead as a novel dying cell-released signal and provide TPCA-1 as a targeting candidate to improve TNBC prognosis.

Ecosystem service tradeoff and synergistic relationship in the Yellow River Delta High-Efficiency Eco-Economic Zone.

Exploring the tradeoff and synergy relationship among ecosystem services in the Yellow River Delta High-Efficiency Eco-Economic Zone is of great practical significance for regional ecosystem service function zoning and high-quality development. Using the InVEST model, spatial auto-correlation and trade-off synergism (ESTD) model, we analyzed the spatial and temporal variations of five ecosystem services (habitat quality, carbon storage, soil conservation, water conservation, and water purification), as well as their trade-off and synergistic relationships at the township scale from 2000 to 2020. The results showed that habitat quality, carbon storage, and nitrogen and phosphorus output decreased as a whole from 2000 to 2020, and soil conservation and water purification increased. Habitat quality showed a distribution pattern of high in the north and low in the south, and carbon sto-rage, nitrogen and phosphorus output, soil conservation and water purification showed a pattern of low in the north and high in the south. During the study period, synergistic relationships among the five ecosystem services were predominant in both time cross-section and time period, but there were still differences, with synergistic relationships mainly between carbon storage and other services in time cross-section, and between habitat quality and other ser-vices in time period. Our results can provide theoretical guidance and practical reference for the enhancement of ecosystem services and the zoning of ecosystem functions, as well as basic support for the optimization of spatial patterns of national territory.

Developing liver-targeted naringenin nanoparticles for breast cancer endocrine therapy by promoting estrogen metabolism.

Endocrine therapy is standard for hormone receptor-positive (HR+) breast cancer treatment. However, current strategies targeting estrogen signaling pay little attention to estradiol metabolism in the liver and is usually challenged by treatment failure. In a previous study, we demonstrated that the natural compound naringenin (NAR) inhibited HR+ breast cancer growth by activating estrogen sulfotransferase (EST) expression in the liver. Nevertheless, the poor water solubility, low bio-barrier permeability, and non-specific distribution limited its clinical application, particularly for oral administration. Here, a novel nano endocrine drug NAR-cell penetrating peptide-galactose nanoparticles (NCG) is reported. We demonstrated that NCG presented specific liver targeting and increased intestinal barrier permeability in both cell and zebrafish xenotransplantation models. Furthermore, NCG showed liver targeting and enterohepatic circulation in mouse breast cancer xenografts following oral administration. Notably, the cancer inhibition efficacy of NCG was superior to that of both NAR and the positive control tamoxifen, and was accompanied by increased hepatic EST expression and reduced estradiol levels in the liver, blood, and tumor tissue. Moreover, few side effects were observed after NCG treatment. Our findings reveal NCG as a promising candidate for endocrine therapy and highlight hepatic EST targeting as a novel therapeutic strategy for HR+ breast cancer.

Antidepressant-like effects of hyperoside on chronic stress-induced depressive-like behaviors in mice: Gut microbiota and short-chain fatty acids.

BACKGROUND: The antidepressant effect of hyperoside (HYP), which is the main component of Hypericum perforatum, is not established. This study aimed to determine the effects of HYP on depression. METHODS: The antidepressant-like effect of HYP was studied in mice induced by chronic restraint stress (CRS). The effects of HYP on behavior, inflammation, neurotransmitters, gut microbiota, and short-chain fatty acids (SCFAs) were studied in CRS mice. RESULTS: HYP improved depressive-like behavior in mice induced by CRS. Nissl staining analysis showed that HYP improved neuronal damage in CRS mice. Western blot (WB) analysis showed that HYP increased the expression levels of BDNF and PSD95 in the hippocampus of CRS mice. The results of ELISA showed that HYP down-regulated the expression levels of IL-6, IL-1ß, TNF-α, and CORT in the hippocampus, blood, and intestinal tissues of mice and up-regulated the expression levels of 5-HT and BDNF. Hematoxylin and eosin (HE) staining results indicate that HYP can improve the intestinal histopathological injury of CRS mice. The results of 16S rRNA demonstrated that HYP attenuated the dysbiosis of the gut microbiota of depressed mice, along with altering the concentration of SCFAs. LIMITATIONS: In the present study, direct evidence that HYP improves depressive behaviors via gut microbiota and SCFAs is lacking, and only female mice were evaluated, which limits the understanding of the effects of HYP on both sexes. CONCLUSIONS: HYP can improve CRS-induced depressive-like behaviors in mice, which is associated with regulating the gut microbiota and SCFAs concentration.

Effects of different wall-breaking methods on the nutrient release of Ganoderma lucidum spore powder during in vitro digestion.

BACKGROUND: The hard double-walled structure of Ganoderma lucidum spore powder (GLSP) is difficult for the human body to digest, so it is very important to break the wall of GLSP. In this study, the wall of GLSP was broken by mechanical milling at room temperature (MM-R) and ultra-fine grinding at low temperature (UFG-L), respectively. RESULTS: Compared with MM-R, UFG-L could better retain the sporangium powder's morphological and structural integrity. During in vitro digestion, compared with unbroken GLSP, the released amounts of polysaccharides and triterpenes from broken GLSP were significantly increased, and they increased with the increase of specific surface area. The bioaccessibility of polysaccharide and triterpene from unbroken GLSP after the intestinal stage were 29.52% and 5.37%, respectively. The bioaccessibility of polysaccharides and triterpene from broken GLSP by MM-R after the intestinal phase were 39.73-72.45% and 16.44-24.97%, while those by UFG-L were 44.53-104.18% and 12.96-32.90%, respectively. CONCLUSION: The active ingredients of broken GLSP showed better digestion and absorption abilities than unbroken GLSP. Moreover, the specific surface area of GLSP by UFG-L was lower than that by MM-R, and the bioaccessibility of GLSP by UFG-L was higher than that by MM-R. © 2024 Society of Chemical Industry.

Brain-Targeted Black Phosphorus-Based Nanotherapeutic Platform for Enhanced Hypericin Delivery in Depression.

Depression is a significant global health concern that remains inadequately treated due to the limited effectiveness of conventional drug therapies. One potential therapeutic agent, hypericin (HYP), is identified as an effective natural antidepressant. However, its poor water solubility, low bioavailability, and limited ability to penetrate the brain parenchyma have hindered its clinical application. To address these shortcomings and enhance the therapeutic efficacy of HYP, it is loaded onto black phosphorus nanosheets (BP) modified with the neural cell-targeting peptide RVG29 to synthesize a nanoplatform named BP-RVG29@HYP (BRH). This platform served as a nanocarrier for HYP and integrated the advantages of BP with advanced delivery methods and precise targeting strategies. Under the influence of 808 nm near-infrared irradiation (NIR), BRH effectively traversed an in vitro BBB model. In vivo experiments validated these findings, demonstrating that treatment with BRH significantly alleviated depressive-like behaviors and oxidative stress in mice. Importantly, BRH exhibited an excellent safety profile, causing minimal adverse effects, which highlighted its potential as a promising therapeutic agent. In brief, this novel nanocarrier holds great promise in the development of antidepressant drugs and can create new avenues for the treatment of depression.