Wearable EEG-Based Brain-Computer Interface for Stress Monitoring.

Detecting stress is important for improving human health and potential, because moderate levels of stress may motivate people towards better performance at cognitive tasks, while chronic stress exposure causes impaired performance and health risks. We propose a Brain-Computer Interface (BCI) system to detect stress in the context of high-pressure work environments. The BCI system includes an electroencephalogram (EEG) headband with dry electrodes and an electrocardiogram (ECG) chest belt. We collected EEG and ECG data from 40 participants during two stressful cognitive tasks: the Cognitive Vigilance Task (CVT), and the Multi-Modal Integration Task (MMIT) we designed. We also recorded self-reported stress levels using the Dundee Stress State Questionnaire (DSSQ). The DSSQ results indicated that performing the MMIT led to significant increases in stress, while performing the CVT did not. Subsequently, we trained two different models to classify stress from non-stress states, one using EEG features, and the other using heart rate variability (HRV) features extracted from the ECG. Our EEG-based model achieved an overall accuracy of 81.0% for MMIT and 77.2% for CVT. However, our HRV-based model only achieved 62.1% accuracy for CVT and 56.0% for MMIT. We conclude that EEG is an effective predictor of stress in the context of stressful cognitive tasks. Our proposed BCI system shows promise in evaluating mental stress in high-pressure work environments, particularly when utilizing an EEG-based BCI.

Highly specific screening of aspirin resistance-related single-nucleotide polymorphisms using ligase chain reaction strategy.

Aspirin (ASP) is currently the drug of choice for antiplatelet therapy. However, approximately 5%-45 % of patients are resistant to ASP and do not achieve the expected result. At present, a few studies have investigated the correlation between ASP resistance (AR) and single-nucleotide polymorphism (SNP). Traditional detection methods are time-consuming and laborious, affecting the accuracy of personalized medicine. This study aimed to establish a new assay to identify four SNPs associated with AR. A large amount of double-stranded DNA was formed after multiple cycles of specific exponential amplification by ligase chain reaction, the specific melting peak of which was visible in the detection curve, with a detection limit of 10-11mol/L. The specificity experiments of different proportions of wild-type and mutant plasmid standards showed that the novel method could detect up to 1 % allele frequency and the specificity was good. Clinical blood samples of 57 patients were tested in this study. The results were consistent with those of sequencing and more accurate and reliable than those of the high-resolution melting method. The technique used in this study was simple, sensitive and specific compared with the traditional method. Statistical analysis revealed that AR was significantly correlated with the rs12041331 site of the PEAR1 gene and the rs1695 site of the GSTP1 gene, providing an important reference value for the study of AR.

Lighting up arginine metabolism reveals its functional diversity in physiology and pathology.

Arginine is one of the most metabolically versatile amino acids and plays pivotal roles in diverse biological and pathological processes; however, sensitive tracking of arginine dynamics in situ remains technically challenging. Here, we engineer high-performance fluorescent biosensors, denoted sensitive to arginine (STAR), to illuminate arginine metabolism in cells, mice, and clinical samples. Utilizing STAR, we demonstrate the effects of different amino acids in regulating intra- and extracellular arginine levels. STAR enabled live-cell monitoring of arginine fluctuations during macrophage activation, phagocytosis, efferocytosis, and senescence and revealed cellular senescence depending on arginine availability. Moreover, a simple and fast assay based on STAR revealed that serum arginine levels tended to increase with age, and the elevated serum arginine level is a potential indicator for discriminating the progression and severity of vitiligo. Collectively, our study provides important insights into the metabolic and functional roles of arginine, as well as its potential in diagnostic and therapeutic applications.

Advancing research on odor-induced sweetness enhancement: A EEG local-global fusion transformer network for sweetness quantification combined with EEG technology.

Reducing sugar intake is crucial for health, and odor sweetening enhances food enjoyment and quality perception. Current research relies on subjective manual sensory evaluations, which are poorly reproducible. Traditional methods also fail to capture dynamic neural responses to odor-induced sweetness. We propose an electroencephalogram local-global fusion transformer network (EEG-LGFNet) model to decode this impact objectively. Electroencephalogram data were collected from 16 subjects under different odor and sucrose stimuli. The model captures complex neural signals by integrating local and global feature extraction mechanisms. Its performance was validated across three-time windows, demonstrating efficacy over various temporal ranges. Analysis of the coefficient of determination across brain regions confirmed the importance of the frontal, central, and parietal areas of sweetness perception. The EEG-LGFNet model excelled in quantifying odor-enhanced sweetness, significantly outperforming state-of-the-art models. This research offers new insights into odor sweetening, with applications in food development, personalized nutrition, and neuroscience.

[Key Issues and Challenges in Establishing Regionally Differentiated Water Quality Standard in China].

The goal of environmental management in China is transitioning from pollution control to the improvement of ecological quality. The establishment of regional differential water quality standards can better adapt to the ecological characteristics and development needs of different regions. Given the shortcomings of current water quality standards and the needs of technological development, this study analyzed the causes and influencing factors of regional differences in water quality standards and summarized China's regional variations in areas such as the characteristics of receiving water bodies, social attributes, climate conditions, physicochemical properties of water, and aquatic biotic populations. It also examined the impact of regional characteristics on the assessment of biological toxicity. Based on these analyses, the study identified key scientific questions that may arise in the development of regional differential water quality standards in China and outlined future critical research directions in this field. These directions include developing theories and methods for determining the effluent dilution coefficient, establishing methods for identifying regional key water quality indicators and assessing their impact on water quality standards, determining regional characteristic species and their influence on water quality standards, and formulating theories and methods for categorizing different regions across the country. The aim of the study was to provide a reference for the scientific establishment of water quality standards in China.

An image-based investigation on color associations among 100 Chinese emotion words.

ABSTRACTImage data serves as a valuable resource for investigating relationships between colors and emotions. This study conducts an image-based visual corpus analysis on the color associations of 100 Chinese emotion words, aiming to uncover the pivotal roles of colors in understanding emotional concepts. The study addresses two primary objectives: (i) examining the interrelations among four affective properties (valence, arousal, prototypicality, and emotionality) and four image-based color attributes (Jz: a dimension depicting black-white color distinction, Az: a dimension for green-red, Bz: a dimension for blue-yellow, and color variability) associated with these emotion words; and (ii) assessing the efficacy of image-based color information in profiling affective (dis)similarities among different emotion words. The empirical results reveal (i) significant positive correlations between color variability and arousal, Jz and valence, Az and arousal, Bz and valence, as well as a negative correlation between Jz and prototypicality; (ii) the effectiveness of image-based color information in depicting the valence-dominated affective (dis)similarities among the 100 Chinese emotion words. This study contributes image-based empirical support to complement existing research on color-emotion mappings. Moreover, it advances methodological approaches by advocating for the utilisation of image data to address theoretical inquiries in cognitive science.

Macrophage corpses for immunoregulation and targeted drug delivery in treatment of collagen-induced arthritis mice.

The role of pro-inflammatory macrophages (M1) in rheumatoid arthritis (RA) is significant, as they produce excessive cytokines. Targeting efferocytosis is a potential manner to repolarize M1 macrophages into pro-resolving M2 phenotype, which restores immune homeostasis by releasing anti-inflammatory mediators. In this study, liquid nitrogen-treated dead macrophages (DM) are employed to act as a dead cell-derived active targeted drug carrier for shikonin (SHK) and induce efferocytosis in M1 macrophages with the enhancement of SHK as an AMP-activated protein kinase (AMPK)-activator. The synergistic activation of AMPK leads to uncoupled protein 2 (UCP2) upregulation and reprograms M1 macrophages into M2 phenotypes by promoting oxidative phosphorylation. In the mouse model of collagen-induced arthritis, the intravenous administration of DM/SHK leads to a consistent transformation of M1 macrophages into the M2 phenotype within the infiltrative synovium. This transformation of macrophages results in the restoration of immune homeostasis in the synovium through an increase in the production of pro-resolving mediators. Additionally, it inhibits synovial proliferation and infiltration and provides protection against erosion of cartilage and bone. In summary, LNT-based DM serves as an active targeting drug carrier to M1 macrophages and also acts synergistically with SHK to target immunometabolism.

Hetero-structured Ru-Mo2C nanoparticles loaded on N,P co-doped carbon for a pH universal hydrogen evolution reaction.

Considering the extensive research studies on Ru and Mo2C for the hydrogen evolution reaction (HER), the construction of heterostructure catalysts containing both Ru and Mo2C nanoparticles can further improve the catalytic activity by the synergistic effect of different species. In this work, we report the synthesis of N,P co-doped carbon coated Ru and Mo2C nanoparticles for the HER using a ZnMo metal-organic framework (MOF) as the precursor. The addition of phosphomolybdic acid during the synthesis of a Zn-MOF not only provides a Mo source for the formation of Mo2C, but also induces a nano-bowl structure. After anchoring RuCl3 in the ZnMo-MOF and thermal annealing, Ru and Mo2C nanoparticles encapsulated in N,P doped carbon (Ru-Mo2C@NPC) were synthesized and the nano-bowl morphology was well preserved. Due to the co-existence of the highly active catalytic species Ru and Mo2C, a large specific surface area owing to the evaporation of Zn during the calcination process, and the nano-bowl-like morphology that boosts mass transfer, Ru-Mo2C@NPC exhibits good catalytic activity for the HER over a wide pH range, with overpotentials of 62, 64 and 170 mV in 0.5 M H2SO4, 1 M KOH and 1 M PBS solution at 10 mA cm-2, surpassing the values for many Ru and Mo2C based catalysts. This work provides a feasible route for designing high performance HER catalysts.

BLU-945, a potent and selective next-generation EGFR TKI, has antitumor activity in models of osimertinib-resistant non-small-cell lung cancer.

Introduction: Despite the availability of several epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), most patients with non-small-cell lung cancer (NSCLC) eventually develop resistance to these agents. Notably, EGFR_C797S mutations confer resistance to the third-generation EGFR-TKI osimertinib and no approved post-osimertinib targeted pharmacology options are currently available. BLU-945 is a novel, reversible, and orally available next-generation EGFR-TKI that selectively targets EGFR-activating (EGFRm) and resistance mutations (including EGFR_C797S) with nanomolar potency while sparing wild-type EGFR in vitro. Methods: In vitro activity of BLU-945 as a single agent and in combination with osimertinib was tested in engineered EGFR-mutant cell lines as well as patient-derived cells and patient-derived organoids. In vivo activity was evaluated in osimertinib-resistant patient-derived xenograft mouse models. Three patient cases from the global, first-in-human, phase I/II SYMPHONY trial (NCT04862780) demonstrating the clinical efficacy of BLU-945 were reported. Results: In vitro BLU-945 demonstrated inhibited cell viability and growth of EGFR-mutant/osimertinib-resistant cell lines. BLU-945 demonstrated in vivo tumor shrinkage in osimertinib-resistant models of NSCLC (osimertinib second line: EGFR_L858R/C797S and third line: EGFR_ex19del/T790M/C797S and L858R/T790M/C797S) both as monotherapy and in combination with osimertinib. BLU-945 also demonstrated tumor shrinkage in patients from the SYMPHONY trial. Conclusion: Our findings demonstrate the preclinical and early clinical activity of BLU-945 in EGFRm NSCLC progressing on previous EGFR-TKIs.

The impact of specific health warning messages on Chinese young people's perception of smoking risks and quitting intentions.

INTRODUCTION: Although a substantial body of research has analyzed the effectiveness of cigarette package warning labels in tobacco control, the very general health warnings messages (HWMs) on cigarette packaging in China have shown limited effectiveness in deterring youth from smoking. Therefore, this study investigates the impact of specific and more detailed warning text messages on Chinese young people's risk perception of smoking and their intention to quit. METHODS: We employed a randomized survey experiment to examine the impact of specific text-based warning labels on Chinese young people's risk perception of smoking and intention to quit. The total effective sample size was 1064 participants. The subjects were divided into three groups: the first group served as the control group, which was shown the existing cigarette package warning labels; the second group was shown cigarette package warning labels related to cardiovascular, digestive, and respiratory diseases; and the third group was shown cigarette package warning labels related to sexual dysfunction. RESULTS: The respiratory disease-related warnings significantly increased young people's awareness of smoking-related respiratory risks (p<0.01). The impact of warning labels for the three common diseases on enhancing young people's overall risk perception of smoking (p<0.05) and their intention to quit exhibited only weak statistical significance (p<0.05). In contrast, warning labels related to sexual dysfunction significantly increased young people's risk perception of smoking (p<0.001) and their intention to quit (p<0.001), with a much higher level of statistical significance compared to those related to the other three common diseases. CONCLUSIONS: Detailed descriptions of the risks associated with all four diseases were positively correlated with awareness of smoking-related harm and the intention to quit. However, warnings related to sexual dysfunction had a greater level of statistical significance compared to those related to the other three common diseases. This stronger significance may be attributed to young people's heightened concern about sexual dysfunction.

GLO1 regulates hepatocellular carcinoma proliferation and migration through the cell cycle pathway.

BACKGROUND: Hepatocellular carcinoma (HCC) is a malignant tumor characterized by a high mortality rate. The occurrence and progression of HCC are linked to oxidative stress. Glyoxalase-1 (GLO1) plays an important role in regulating oxidative stress, yet the underlying mechanism remains unclear. GLO1 may serve as a prognostic biomarker and therapeutic target for HCC. METHODS: Based on TCGA database hepatocellular carcinoma samples, we conducted a bioinformatics analysis to explore the correlation between GLO1 expression and HCC cell proliferation and viability. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed that differentially expressed genes (DEGs) were mainly enriched in the cell cycle pathway. We analyzed the relationships between GLO1 and 24 genes enriched in the cell cycle pathway using a protein-protein interaction (PPI) network. Finally, experimental validation was performed to assess GLO1's impact on the distribution of cells at different cell cycle stages and on the proliferation and migration of HCC cells. RESULTS: Our study demonstrated that GLO1 was overexpressed in HCC tissues and was associated with a poor prognosis. Data analysis indicated that overexpression of GLO1 activated the cell cycle pathway and positively correlated with expression of the majority of key cell cycle genes. Experimental validation showed that GLO1 expression affects the number of HCC cells in G2 and S phases and regulates HCC cell proliferation and migration. CONCLUSIONS: GLO1 represents a promising therapeutic target for HCC, providing valuable insights into its role in the viability and proliferation of HCC cells.

Exploring the Blood Biomarkers and Potential Therapeutic Agents for Human Acute Mountain Sickness Based on Transcriptomic Analysis, Inflammatory Infiltrates and Molecular Docking.

A high-altitude, low-pressure hypoxic environment has severe effects on the health and work efficiency of its residents, and inadequate preventive measures and adaptive training may lead to the occurrence of AMS. Acute exposure to hypoxia conditions can have a less-favorable physiological effect on the human immune system. However, the regulation of the immune system in high-altitude environments is extremely complex and remains elusive. This study integrated system bioinformatics methods to screen for changes in immune cell subtypes and their associated targets. It also sought potential therapeutically effective natural compound candidates. The present study observed that monocytes, M1 macrophages and NK cells play a crucial role in the inflammatory response in AMS. IL15RA, CD5, TNFSF13B, IL21R, JAK2 and CXCR3 were identified as hub genes, and JAK2 was positively correlated with monocytes; TNFSF13B was positively correlated with NK cells. The natural compound monomers of jasminoidin and isoliquiritigenin exhibited good binding affinity with JAK2, while dicumarol and artemotil exhibited good binding affinity with TNFSF13B, and all are expected to become a potential therapeutic agents.

Effective Antitumor Synergistic Treatment with Fiber-Photothermal Therapy and Heat Shock Protein Inhibitors.

Effective treatment of malignant tumors remains a thorny issue in current medicine. As a new type of anticancer strategy, photothermal therapy (PTT) has attracted tremendous attention due to its favorable therapeutic effectiveness, high spatial-temporal controllability, and low occurrence of side effects. However, the efficacy of PTT is significantly reduced due to the limited penetration of light and heat-induced overexpression of heat shock protein (Hsp). Herein, we propose an antitumor synergistic therapy that combines fiber-optic PTT and Hsp inhibitors. A rare-earth-doped optical fiber was used as the PTT actuator, and the Hsp inhibitor AT533 was loaded on the fiber surface by use of a hydrogel layer. PTT fibers can be guided to reach tumor lesions directly without being subject to the light penetration limit. The Hsp inhibitor can be released upon the softening of the hydrogel layer under photoheating to deactivate Hsp in the tumor and thus reduce the resistance of the tumor to PTT. This synergistic treatment enhanced the effect of PTT and successfully eradicated tumors in colorectal cancer (CRC) xenograft mouse models, providing a feasible way to realize antitumor and antirecurrence treatment. More importantly, the success of the synergistic treatment of PTT and Hsp inhibition opens new avenues for the development of multimodal and multitype synergistic fiber-optic treatments, which offer pronounced enhancement of therapeutic effectiveness for treating cancer.

PhI(OAc)2-Promoted Site-Selective C-H Chlorination of (Hetero)arenes with p-Toluenesulfonyl Chloride.

An efficient and practical system for metal-free catalytic chlorination of (hetero)arenes by using readily available and inexpensive TsCl and PhI(OAc)2 is described. This newly developed protocol has been achieved by the nonsymmetric iodane generated by a combination of PhI(OAc)2 and TsCl. The broad substrate scope, good functional group tolerance, excellent regioselectivity, and short reaction times make this method attractive for the late-stage chlorination of complex drug-like scaffolds.

Association between intensive blood pressure lowering and stroke-free survival among patients with and without Diabetes.

This study pooled data from SPRINT (Systolic Blood Pressure Intervention Trial) and ACCORD-BP (Action to Control Cardiovascular Risk in Diabetes Blood Pressure) trial to estimate the treatment effect of intensive BP on stroke prevention, and investigate whether stroke risk score impacted treatment effect. Of all the potential manifestations of the hypertension, the most severe outcomes were stroke or death. A composite endpoint of time to death or stroke (stroke-free survival [SFS]), whichever occurred first, was defined as the outcome of interest. Participants without prevalent stroke were stratified into stroke risk tertiles based on the predicted revised Framingham Stroke Risk Score. The stratified Cox model was used to calculate the hazard ratio (HR) for the intensive BP treatment. 834 (5.92%) patients had SFS events over a median follow-up of 3.68 years. A reduction in the risk for SFS was observed among the intensive BP group as compared with the standard BP group (HR: 0.76, 95% CI: 0.65, 0.89; risk difference: 0.98([0.20, 1.76]). Further analyses demonstrated the significant benefit of intensive BP treatment on SFS only among participants having a high stroke risk (risk tertile 1: 0.76 [0.52, 1.11], number needed to treat [NNT] = 861; risk tertile 2: 0.87[0.65, 1.16], NNT = 91; risk tertile 3: 0.69[0.56, 0.86], NNT = 50). Intensive BP treatment lowered the risk of SFS, particularly for those at high risk of stroke.

Abemaciclib increases the risk of venous thromboembolism in breast cancer: Integrate meta-analysis, pharmacovigilance database analysis, and in vitro validation.

BACKGROUND: Recently, cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have emerged as a novel treatment strategy for breast cancer. However, increasing reports of CDK4/6i-associated venous thromboembolism (VTE) have garnered attention. This study assessed CDK4/6i-associated VTE in breast cancer, and examined the effect of CDK4/6i on platelet/coagulation function for the first time in vitro. METHODS: PubMed and Embase databases were searched for studies published from the establishment of the database to December 31, 2022 for randomized controlled trials (RCTs) and real-world studies of CDK4/6i in patients with breast cancer, and the data obtained from the included studies were used for meta-analysis. A disproportionality analysis by extracting adverse drug reaction signals of CDK4/6i-associated VTE from the FDA Adverse Event Reporting System (FAERS) database was also conducted. Additionally, the in vitro effect of CDK4/6i on platelet function was assessed based on platelet aggregation tests and flow cytometry, and coagulation function was assessed based on the blood clotting function test. FINDINGS: A total of 16,903 patients in 13 RCTs and 6,490 patients in 9 real-world studies were included in the meta-analysis. In RCTs, VTE occurred in 193 (2.1 %) and 55 (0.7 %) patients in the CDK4/6i and control groups, respectively. In real-world studies, the aggregate incidence rate of VTE was 4.2 % (95 % CI: 2.1, 6.3). The meta-analysis of RCTs revealed that abemaciclib (Odds ratio [OR]: 4.40 [95 % CI: 2.74,7.05], p < 0.001) and palbociclib (OR: 2.35 [95 % CI: 1.34, 4.12], p < 0.01) significantly increased the risk of VTE in patients with breast cancer compared to placebo. FAERS database analysis revealed that abemaciclib (reporting odds ratio [ROR]: 1.63 [95 % CI: 1.36, 1.97]; IC025: 0.67) and ribociclib (ROR: 1.17 [95 % CI: 1.0, 1.39]; IC025: 0.18) demonstrated a significantly increased signal of VTE. Similarly, findings from in vitro experiments demonstrated that abemaciclib enhanced agonist-induced platelet activation, especially when collagen was used as the inducer, and this effect became more prominent with increasing its concentration. INTERPRETATION: Use of abemaciclib may increase the risk of VTE in patients with breast cancer, which may be partially attributed to the effect of abemaciclib on platelet function. Close monitoring of VTE occurrence is highly recommended while using abemaciclib, especially in patients at a high risk of VTE.

Polyoxometalate-Based Single-Atom Catalyst with Precise Structure and Extremely Exposed Active Site for Efficient H2 Evolution.

Single-atom catalysts with precise structure and extremely high catalytic efficiency remain a fervent focus in the fields of materials chemistry and catalytic science. Herein, a nickel-substituted polyoxometalate (POM) {NiSb6O4(H2O)3[ß-Ni(hmta)SbW8O31]3}15- (NiPOM) with one extremely exposed nickel site [NiO3(H2O)3] was synthesized using the conventional aqueous method. The uniform dispersion of single nickel center with well-defined structure was facilely achieved by anchoring nanosized NiPOM on graphene oxide (GO). The resulting NiPOM/GO can couple with CdS photoabsorber for the construction of low-cost and ultra-efficient hydrogen evolution system. The H2 yield can reach to 2753.27 mmol gPOM -1 h-1, which represents a record value among all the POM-based photocatalytic systems. Remarkablely, an extremely high hydrogen yield of 3647.28 mmol gPOM -1 h-1 was achieved with simultaneous photooxidation of commercial waste plastic, representing the first POM-based photocatalytic system for H2 evolution and waste plastic conversion. This work highlights a straightforward strategy for constructing extremely exposed single-metal site with precise microenvironment by facilely manipulating nanosized molecular cluster to control individual atom.

Effects of different adzuki bean flour additions on structural and functional characteristics of extruded buckwheat noodles.

BACKGROUND: Understanding the effects of different additions of adzuki bean flour (ABF) on structural and functional characteristics of extruded buckwheat noodles is important in developing high-quality starchy foods with desirable glycemic indexes. This study explored how varying amounts of ABF in extruded buckwheat noodles influenced their structural and functional characteristics. RESULTS: The findings indicated that adding ABF substantially boosted the levels of protein and flavonoids, while decreasing the content of fat and starch. Adding ABF to the noodles extended the optimum cooking time and led to a reduction in both the stickiness of the cooked noodles and the pore size of the starch gel structure, compared with pure buckwheat noodles. Fourier transform infrared spectroscopy indicated that R1047/1022 increased with the content of ABF increased, while R1022/995 decreased. X-ray diffraction showed that the relative crystallinity of buckwheat noodles was enhanced with increasing ABF amount. Adding ABF notably significantly decreased the estimated glycemic index. The buckwheat noodles extruded with 20% ABF addition demonstrated notably stronger α-glucosidase inhibitory effects than those extruded with no ABF addition. CONCLUSION: The present study demonstrates that the additions of ABF improved the structure and hypoglycemic activity of extruded buckwheat noodles while decreasing starch digestibility, and the optimal value was reached at an ABF addition of 20%. The study might fill gaps in starch noodle research and provide a new strategy for the development of functional food in the food industry. © 2024 Society of Chemical Industry.

Hyaluronic acid-coated polypeptide nanogel enhances specific distribution and therapy of tacrolimus in rheumatoid arthritis.

Rheumatoid arthritis (RA) involves chronic inflammation, oxidative stress, and complex immune cell interactions, leading to joint destruction. Traditional treatments are often limited by off-target effects and systemic toxicity. This study introduces a novel therapeutic approach using hyaluronic acid (HA)-conjugated, redox-responsive polyamino acid nanogels (HA-NG) to deliver tacrolimus (TAC) specifically to inflamed joints. The nanogels' disulfide bonds enable controlled TAC release in response to high intracellular glutathione (GSH) levels in activated macrophages, prevalent in RA-affected tissues. In vitro results demonstrated that HA-NG/TAC significantly reduced TAC toxicity to normal macrophages and showed high biocompatibility. In vivo, HA-NG/TAC accumulated more in inflamed joints compared to non-targeted NG/TAC, enhancing therapeutic efficacy and minimizing side effects. Therapeutic evaluation in collagen-induced arthritis (CIA) mice revealed HA-NG/TAC substantially reduced paw swelling, arthritis scores, synovial inflammation, and bone erosion while suppressing pro-inflammatory cytokine levels. These findings suggest that HA-NG/TAC represents a promising targeted drug delivery system for RA, offering potential for more effective and safer clinical applications.

Structural Optimization of Isoquinoline Derivatives from Lycobetaine and Their Inhibitory Activity against Neuroendocrine Prostate Cancer Cells.

Neuroendocrine prostate cancer (NEPC) is a highly aggressive cancer that is resistant to hormone therapy and characterized by poor prognosis, as well as limited therapeutic options. Since the natural product lycobetaine was reported to exhibit good antitumor activities against various types of cancers, we initially simplified the scaffold of lycobetaine to obtain the active compound 1, an isoquinoline derivative with an aryl moiety substitution at the 4-position, which showed apparent antiproliferative activities against NPEC cell line LASCPC-01 in vitro. Subsequently, we carried out structural optimization and systematic structure-activity relationship (SAR) studies on compound 1, leading to the discovery of compound 46, which demonstrated potent inhibitory activities against the LASCPC-01 cell line with an IC50 value of 0.47 µM. Moreover, compound 46 displayed remarkable selectivity over prostate cancer cell line PC-3 with a selectivity index greater than 190-fold. Further cell-based mechanism studies revealed that compound 46 and lycobetaine can effectively induce G1 cell cycle arrest and apoptosis dose dependently. However, lycobetaine inhibited the expression of neuroendocrine markers, while compound 46 slightly upregulated these proteins. This suggested that compound 46 might exert its antitumor activities through a different mechanism than lycobetaine, warranting further study.