Two C-terminal isoforms of Aplysia tachykinin-related peptide receptors exhibit phosphorylation-dependent and phosphorylation-independent desensitization mechanisms.

Diversity, a hallmark of G protein-coupled receptor (GPCR) signaling, partly stems from alternative splicing of a single gene generating more than one isoform for a receptor. Additionally, receptor responses to ligands can be attenuated by desensitization upon prolonged or repeated ligand exposure. Both phenomena have been demonstrated and exemplified by the deuterostome tachykinin signaling system, although the role of phosphorylation in desensitization remains a subject of debate. Here, we describe the signaling system for tachykinin-related peptides (TKRPs) in a protostome, mollusk Aplysia. We cloned the Aplysia TKRP precursor, which encodes three TKRPs (apTKRP-1, apTKRP-2a, and apTKRP-2b) containing the FXGXR-amide motif. In situ hybridization and immunohistochemistry showed predominant expression of TKRP mRNA and peptide in the cerebral ganglia. TKRPs and their posttranslational modifications were observed in extracts of central nervous system ganglia using mass spectrometry. We identified two Aplysia TKRP receptors (apTKRPRs), named apTKRPR-A and apTKRPR-B. These receptors are two isoforms generated through alternative splicing of the same gene and differ only in their intracellular C termini. Structure-activity relationship analysis of apTKRP-2b revealed that both C-terminal amidation and conserved residues of the ligand are critical for receptor activation. C-terminal truncates and mutants of apTKRPRs suggested that there is a C-terminal phosphorylation-independent desensitization for both receptors. Moreover, apTKRPR-B also exhibits phosphorylation-dependent desensitization through the phosphorylation of C-terminal Ser/Thr residues. This comprehensive characterization of the Aplysia TKRP signaling system underscores the evolutionary conservation of the TKRP and TK signaling systems, while highlighting the intricacies of receptor regulation through alternative splicing and differential desensitization mechanisms.

Resistance to gemcitabine is mediated by the circ_0036627/miR-145/S100A16 axis in pancreatic cancer.

The development of gemcitabine (GEM) resistance severely limits the treatment efficacy in pancreatic cancer (PC) and increasing evidence highlights the vital roles of circular RNAs (circRNAs) in the tumorigenesis, progression and drug resistance of PC. However, the circRNAs underlying GEM resistance development of PC remains to be clarified. The current research aims to unveil the roles of circ_0036627 in dictating the aggressiveness and GEM sensitivity in PC. We reported the increased expression of circ_0036627 in PC tissues and PC cell lines. Elevated circ_0036627 expression level was correlated with advanced tumour grade and poor overall survival in PC patients. Functional assays and in vivo experiments demonstrated that circ_0036627 overexpression was required for the proliferation, migration invasion and GEM resistance in PC cells. circ_0036627 knockdown suppressed tumour development in vivo. The molecular analysis further showed that circ_0036627 increased S100A16 expression by sponging microRNA-145 (miR-145), a tumour-suppressive miRNA that could significantly attenuate PC cell proliferation, migration, invasion and GEM resistance. Furthermore, our findings suggested that S100A16 acted as an oncogenic factor to promote aggressiveness and GEM resistance in PC cells. In conclusion, the current findings provide new mechanistic insights into PC aggressiveness and GEM resistance, suggesting the critical role of circ_0036627/miR-145/S100A16 axis in PC progression and drug resistance development and offering novel therapeutic targets for PC therapy.

Research on the wear trend analysis model and application method of diffraction grating ruling tools.

Tool wear is one of the main causes of failure during diffraction grating ruling. However, no theoretical model for tool wear analysis has been available to date. A mathematical model is established here to solve for the friction coefficient at the tool contact position for the first time. Based on the ruling principles for diffraction gratings, four parameters comprising the tool cutting edge radius, knife angle, pitch angle, and tool ruling depth, are introduced into the model. The positive pressure and shear stress acting on the tool contact surface element during plastic deformation of the metal film layer are given, and an integral is performed over the area where the tool meets the metal film layer. Equations describing the friction coefficients at different positions on the tip point and the main edge are derived. The friction coefficients at the tip point and main edge positions are then calculated using the model. The cutting edge radius, tool tip angle, and pitch angle are used as variables. The maximum value distribution of the friction coefficients of the anti-wear ruling tool is analyzed, and the principle that parameter selection for the anti-wear ruling tool should meet requirements for a large cutting edge radius, small pitch angle, and large tool tip angle is proposed for the first time. This principle provides the key to solving the technical problem where tool wear occurs easily during ruling of large-area echelle gratings, which has puzzled researchers for many years. Finally, a ruling experiment is performed using a 79 gr/mm echelle grating. Under the large pitch angle condition, the tool jumping phenomenon occurs because of excessive friction force, which results in ruling failure. The numerical analysis results are verified. The research results in this paper can provide a theoretical basis for anti-wear tool design and ruling process optimization.

High-resolution, broad-spectral-range Raman measurement using a spatial heterodyne spectrometer with separate filters and multi-gratings.

We propose a high-resolution, broad-spectral-range spatial heterodyne Raman spectrometer (SHRS) having separate filters and multi-gratings (SFMG). A prototype of the SFMG-SHRS is built using multi-gratings with four sub-gratings having groove densities of 320, 298, 276, and 254 gr/mm and separate filters with filter bands corresponding to the sub-gratings. We use the SFMG-SHRS to measure the Raman spectra of inorganic and organic compounds with various integration times, laser power, and transparent containers, compare measurements of microplastics with and without the separate filters, and measure mixtures of inorganic powders and organic solutions. The designed SFMG-SHRS makes high-resolution, broad-spectral-range Raman measurements with improved signal-to-noise ratios and visibility of weak Raman peaks even in the presence of fluorescence.

Development of a high-resolution, broadband spatial heterodyne Raman spectrometer based on field-widened grating-echelle structure.

We propose a spatial heterodyne Raman spectrometer (SHRS) based on a field-widened grating-echelle (FWGE). A normal grating is combined with an echelle grating in a conventional spatial heterodyne spectrometer to eliminate ghost images without using masks, and prevents interference among the spatial frequencies of different diffraction orders. Mathematical expressions and derivation processes are given for the spectral parameters in the FWGE-SHRS and a verification breadboard system is fabricated. The FWGE-SHRS measures Raman spectra of single chemicals and mixed targets with different integration times, laser powers, concentrations, and transparent containers. The results of the experiments demonstrate that the FWGE-SHRS is suitable for high-resolution, broadband Raman measurements for a wide range of applications.

Chronic Stress-Induced Elevation of Melanin-Concentrating Hormone in the Locus Coeruleus Inhibits Norepinephrine Production and Associated With Depression-Like Behaviors in Rats.

BACKGROUND: Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide that projects throughout the central nervous system, including the noradrenergic locus coeruleus (LC). Our previous study suggested that MCH/MCH receptor 1 (MCHR1) in the LC may be involved in the regulation of depression. The present study investigated whether the role of MCH/MCHR1 in the LC in depression-like behaviors is associated with the regulation of norepinephrine. METHOD: Chronic unpredictable stress (CUS) and an acute intra-LC microinjection of MCH induced depression-like behaviors in rats. The MCHR1 antagonist SNAP-94847 was also microinjected in the LC in rats that were suffering CUS or treated with MCH. The sucrose preference, forced swim, and locomotor tests were used for behavioral evaluation. Immunofluorescence staining, enzyme-linked immunosorbent assay, western blot, and high-performance liquid chromatography with electrochemical detection were used to explore the mechanism of MCH/MCHR1 in the regulation of depression-like behaviors. RESULTS: CUS induced an abnormal elevation of MCH levels and downregulated MCHR1 in the LC, which was highly correlated with the formation of depression-like behaviors. SNAP-94847 exerted antidepressant effects in CUS-exposed rats by normalizing tyrosine hydroxylase, dopamine ß hydroxylase, and norepinephrine in the LC. An acute microinjection of MCH induced depression-like behaviors through its action on MCHR1. MCHR1 antagonism in the LC significantly reversed the MCH-induced downregulation of norepinephrine production by normalizing MCHR1-medicated cAMP-PKA signaling. CONCLUSIONS: Our study confirmed that the MCH/MCHR1 system in the LC may be involved in depression-like behaviors by downregulating norepinephrine production. These results improve our understanding of the pathogenesis of depression that is related to the MCH/MCHR1 system in the LC.

Direct Current Pulse Atmospheric Pressure Plasma Jet Treatment on Electrochemically Deposited NiFe/Carbon Paper and Its Potential Application in an Anion-Exchange Membrane Water Electrolyzer.

An atmospheric pressure plasma jet (APPJ) is used to process electrochemically deposited NiFe on carbon paper (NiFe/CP). The reactive oxygen and nitrogen species (RONs) of the APPJ modify the surface properties, chemical bonding types, and oxidation states of the material at the self-sustained temperature of the APPJ. The APPJ treatment further enhances the hydrophilicity and creates a higher disorder level in the carbon material. Moreover, the metal carbide bonds of NiFe/CP formed in the electrochemical deposition (ED) process are converted to metal oxide bonds after APPJ processing. The potential application of APPJ treatment on NiFe/CP in alkaline water electrolysis is demonstrated. With more oxygen-containing species and better hydrophilicity after APPJ treatment, APPJ-treated NiFe/CP is applied as the electrocatalyst for the oxygen evolution reaction (OER) in alkaline water electrolysis. APPJ-treated NiFe/CP is also used in a custom-made anion-exchange membrane water electrolyzer (AEMWE); this should contribute toward realizing the practical large-scale application of AEM for hydrogen production.

A cascade nanosystem with "Triple-Linkage" effect for enhanced photothermal and activatable metal ion therapy for hepatocellular carcinoma.

Due to the limitations of single-model tumor therapeutic strategies, multimodal combination therapy have become a more favorable option to enhance efficacy by compensating for its deficiencies. However, in nanomaterial-based multimodal therapeutics for tumors, exploiting synergistic interactions and cascade relationships of materials to achieve more effective treatments is still a great challenge. Based on this, we constructed a nanoplatform with a "triple-linkage" effect by cleverly integrating polydopamine (PDA), silver nanoparticles (AgNPs), and glucose oxidase (GOx) to realize enhanced photothermal therapy (PTT) and activatable metal ion therapy (MIT) for hepatocellular carcinoma (HCC) treatment. First, the non-radiative conversion of PDA under light conditions was enhanced by AgNPs, which directly enhanced the photothermal conversion efficiency of PDA. In addition, GOx reduced the synthesis of cellular heat shock proteins by interfering with cellular energy metabolism, thereby enhancing cellular sensitivity to PTT. On the other hand, H2O2, a by-product of GOx-catalyzed glucose, could be used as an activation source to activate non-toxic AgNPs to release cytotoxic Ag+, achieving activatable Ag+-mediated MIT. In conclusion, this nanosystem achieved efficient PTT and MIT for HCC by exploiting the cascade effect among PDA, AgNPs, and GOx, providing a novel idea for the design of multimodal tumor therapeutic systems with cascade regulation.

Complicated obstructive uropathy after kidney biopsy: A case report highlighting the risk of biopsy-related acute kidney injury in a patient with unilateral kidney hypoplasia.

Unilateral kidney hypoplasia is a congenital condition characterized by the underdevelopment of one kidney. Although often asymptomatic, it can cause severe renal complications in patients combined with contralateral renal injury, leading to acute renal failure. This case report describes a patient with unilateral kidney hypoplasia who underwent a kidney biopsy on the contralateral normal-sized kidney and subsequently developed oliguric acute kidney injury. This report discusses the challenges encountered while diagnosing and managing this rare case, highlighting the importance of awareness and recognition to perform timely intervention and optimize the patient's outcome.

Clinical effect of qingre bawei capsules combined with budesonide in the treatment of acute exacerbation of chronic obstructive pulmonary disease.

OBJECTIVE: To assess the clinical effect of Qingre Bawei capsules combined with budesonide in the treatment of acute exacerbation of chronic obstructive pulmonary disease. METHODS: The retrospective study was conducted at the Baoding No.1 Central Hospital, China, and comprised data of patients with acute exacerbation of COPD admitted between June 1, 2020, and June 30, 2022. The patients were divided into two groups based on treatment methods. The group A had been treated with Qingre Bawei capsules in combination with budesonide, while the group B had been treated with budesonide alone. Both the groups had been treated for 2 consecutive weeks. The changes in blood gas indicators, inflammation indicators, and lung function indicators were compared between two groups of patients before and 24 hours after treatment. The time for clinical symptom disappearance and adverse reactions between the two groups of patients was also noted. RESULTS: Of the 120 patients, 60(50%) were in group A; 41(68.3%) males and 19(31.7%) females, with mean age 65.28±4.36 years (range: 47-78 years) and mean course of disease 31.22±4.75 hours (range: 6-65 hours). 60(50%) patients were in group B; 43(71.7%) males and 17(28.3%) females with mean age 65.31±4.31 years (range: 48-78 years) and mean course of disease 31.29±4.71 hours (range: 8-68 hours). The disappearance time of clinical symptoms in group A was better than group B (p<0.05). The levels of blood gas indicators, inflammation indicators, and lung function indicators in both groups significantly improved (p<0.05), but the degree of improvement in group A was better than group B (p<0.05); The total effective rate of group A was better than group B (p<0.05). None of the patients in either group experienced any significant adverse reaction. CONCLUSIONS: Qingre Bawei capsules combined with budesonide had a significantly better therapeutic effect on cases of acute exacerbation of chronic obstructive pulmonary disease compared to budesonide alone.

Efficacy and safety of Usights UC100 illuminated microcatheter in microcatheter-assisted trabeculotomy.

AIM: To evaluate the efficacy and safety of Usights UC100 illuminated microcatheter in microcatheter-assisted trabeculotomy (MAT). METHODS: Totally 10 eyes of 10 patients with primary open angle glaucoma (POAG) who underwent MAT facilitated by Usights UC100 (5 eyes) or iTrack (5 eyes) were reviewed. The success of this surgery was defined as intraocular pressure (IOP) <22 mm Hg with >30% reduction, without oral glaucoma medications, or additional glaucoma surgery. RESULTS: The mean pre-operative IOP was 25.38±10.22 mm Hg in the Usights UC100 group and 19.98±3.87 mm Hg in the iTrack group. MAT was achieved in all eyes in both groups. The success rates for the Usights UC100 group and iTrack groups were in all and 4 eyes, respectively. Both microcatheters produced a statistically significant reduction in IOP, and eyes using Usights UC100 achieved a lower IOP than the iTrack group at 3mo follow-up (12.58±1.52 and 14.84±1.89 mm Hg, respectively), but no statistical significance was there. No severe side effects were observed in either group. CONCLUSION: MAT using Usights UC100 or iTrack both achieve significant pressure reduction in cases of POAG, and Usights UC100 is as safe as iTrack.

Persistent convex ST-segment elevation in a patient with a history of prior intracerebral haemorrhage.

Management of patients with acute chest pain poses a significant challenge in identifying those requiring urgent coronary reperfusion. Electrocardiogram (ECG) constitutes the cornerstone in making prompt clinical decisions by identifying ST-segment elevation, commonly associated with ST-segment elevation myocardial infarction. It is important to note that ST-segment elevation can also be a manifestation of various cardiac and non-cardiac conditions, from acute myocarditis, early repolarization syndrome, acute pericarditis, and left bundle branch block to unknown origins. The similarity of ECG changes among these conditions complicates clinical differential diagnosis, necessitating a detailed medical history and thorough examinations. Here, we presented a case of a 52-year-old female with chest pain and unidentified convex ST-segment elevation. Considering the negative emergent coronary angiography results, normal echocardiography, and long-lasting ST-segment elevation for the following 1 year, the final diagnosis was non-myocardial infarction, probably related to a prior cerebral haemorrhage.

Personalized Federated Graph Learning on Non-IID Electronic Health Records.

Understanding the latent disease patterns embedded in electronic health records (EHRs) is crucial for making precise and proactive healthcare decisions. Federated graph learning-based methods are commonly employed to extract complex disease patterns from the distributed EHRs without sharing the client-side raw data. However, the intrinsic characteristics of the distributed EHRs are typically non-independent and identically distributed (Non-IID), significantly bringing challenges related to data imbalance and leading to a notable decrease in the effectiveness of making healthcare decisions derived from the global model. To address these challenges, we introduce a novel personalized federated learning framework named PEARL, which is designed for disease prediction on Non-IID EHRs. Specifically, PEARL incorporates disease diagnostic code attention and admission record attention to extract patient embeddings from all EHRs. Then, PEARL integrates self-supervised learning into a federated learning framework to train a global model for hierarchical disease prediction. To improve the performance of the client model, we further introduce a fine-tuning scheme to personalize the global model using local EHRs. During the global model updating process, a differential privacy (DP) scheme is implemented, providing a high-level privacy guarantee. Extensive experiments conducted on the real-world MIMIC-III dataset validate the effectiveness of PEARL, demonstrating competitive results when compared with baselines.

Assessment of the causal relationship between gut microbiota and cardiovascular diseases: a bidirectional Mendelian randomization analysis.

BACKGROUND: Previous studies have shown an association between gut microbiota and cardiovascular diseases (CVDs). However, the underlying causal relationship remains unclear. This study aims to elucidate the causal relationship between gut microbiota and CVDs and to explore the pathogenic role of gut microbiota in CVDs. METHODS: In this two-sample Mendelian randomization study, we used genetic instruments from publicly available genome-wide association studies, including single-nucleotide polymorphisms (SNPs) associated with gut microbiota (n = 14,306) and CVDs (n = 2,207,591). We employed multiple statistical analysis methods, including inverse variance weighting, MR Egger, weighted median, MR pleiotropic residuals and outliers, and the leave-one-out method, to estimate the causal relationship between gut microbiota and CVDs. Additionally, we conducted multiple analyses to assess horizontal pleiotropy and heterogeneity. RESULTS: GWAS summary data were available from a pooled sample of 2,221,897 adult and adolescent participants. Our findings indicated that specific gut microbiota had either protective or detrimental effects on CVDs. Notably, Howardella (OR = 0.955, 95% CI: 0.913-0.999, P = .05), Intestinibacter (OR = 0.908, 95% CI:0.831-0.993, P = .03), Lachnospiraceae (NK4A136 group) (OR = 0.904, 95% CI:0.841-0.973, P = .007), Turicibacter (OR = 0.904, 95% CI: 0.838-0.976, P = .01), Holdemania (OR, 0.898; 95% CI: 0.810-0.995, P = .04) and Odoribacter (OR, 0.835; 95% CI: 0.710-0.993, P = .04) exhibited a protective causal effect on atrial fibrillation, while other microbiota had adverse causal effects. Similar effects were observed with respect to coronary artery disease, myocardial infarction, ischemic stroke, and hypertension. Furthermore, reversed Mendelian randomization analyses revealed that atrial fibrillation and ischemic stroke had causal effects on certain gut microbiotas. CONCLUSION: Our study underscored the importance of gut microbiota in the context of CVDs and lent support to the hypothesis that increasing the abundance of probiotics or decreasing the abundance of harmful bacterial populations may offer protection against specific CVDs. Nevertheless, further research is essential to translate these findings into clinical practice.

Formulating and Representing Multiagent Systems With Hypergraphs.

Graph-learning methods, especially graph neural networks (GNNs), have shown remarkable effectiveness in handling non-Euclidean data and have achieved great success in various scenarios. Existing GNNs are primarily based on message-passing schemes, that is, aggregating information from neighboring nodes. However, the diversity and complexity of complex systems from real-world circumstances are not sufficiently taken into account. In these cases, the individual should be treated as an agent, with the ability to perceive their surroundings and interact with other individuals, rather than just be viewed as nodes in existing graph approaches. Additionally, the pairwise interactions used in existing methods also lack the expressiveness for the higher-order complex relations among multiple agents, thus limiting the performance in various tasks. In this work, we propose a Multiagent Hypergraph Force-learning method dubbed MHGForce. First, we formalize the multiagent system (MAS) and illustrate its connection to graph learning. Then, we propose a generalized multiagent hypergraph-learning framework. In this framework, we integrate message-passing and force-based interactions to devise a pluggable method. The method empowers graph approaches to excel in downstream tasks while effectively maintaining structural information in the representations. Experimental results on the Cora, Citeseer, Cora-CA, Zoo, and NTU2012 datasets in node classification demonstrate the effectiveness and generality of our proposed method. We also discuss the characteristics of the MHGForce and explore its role through parametric analysis and visualization. Finally, we give a discussion, conclude our work, and propose future directions.

Potential marker genes for chronic obstructive pulmonary disease revealed based on single-cell sequencing and Mendelian randomization analysis.

BACKGROUND: Progress is being made in the prevention and treatment of chronic obstructive pulmonary disease (COPD), but it is still unsatisfactory. With the development of genetic technology, validated genetic information can better explain COPD. OBJECTIVE: The study utilized scRNA-seq and Mendelian randomization analysis of eQTLs to identify crucial genes and potential mechanistic pathways underlying COPD pathogenesis. MEHODS: Single-cell sequencing data were used to identify marker genes for immune cells in the COPD process. Data on eQTLs for immune cell marker genes were obtained from the eQTLGen consortium. To estimate the causal effect of marker genes on COPD, we selected an independent cohort (ukb-b-16751) derived from the UK Biobank database for two-sample Mendelian randomization analysis. Subsequently, we performed immune infiltration analysis, gene set enrichment analysis (GSEA), and co-expression network analysis on the key genes. RESULTS: The 154 immune cell-associated marker genes identified were mainly involved in pathways such as vacuolar cleavage, positive regulation of immune response and regulation of cell activation. Mendelian randomization analysis screened four pairs of marker genes (GZMH, COTL1, CSTA and CD14) were causally associated with COPD. These four key genes were significantly associated with immune cells. In addition, we have identified potential transcription factors associated with these key genes using the Cistrome database, thus contributing to a deeper understanding of the regulatory network of these gene expressions. CONCLUSIONS: This eQTLs Mendelian randomization study identified four key genes (GZMH, COTL1, CSTA, and CD14) causally associated with COPD, providing new insights for prevention and treatment of COPD.

Honokiol and magnolol: A review of structure-activity relationships of their derivatives.

Honokiol (HK) and magnolol (MAG) are typical representatives of neolignans possessing a wide range of biological activities and are employed as traditional medicines in Asia. In the past few decades, HK and MAG have been proven to be promising chemical scaffolds for the development of novel neolignan drugs. This review focuses on recent advances in the medicinal chemistry of HK and MAG derivatives, especially their structure-activity relationships. In addition, it also presents a comprehensive summary of the pharmacology, biosynthetic pathways, and metabolic characteristics of HK and MAG. This review can provide pharmaceutical chemists deeper insights into medicinal research on HK and MAG, and a reference for the rational design of HK and MAG derivatives.

Metformin suppresses NFE2L1 pathway activation to inhibit gap junction beta protein expression in NSCLC.

OBJECTIVE: Non-small-cell lung cancer (NSCLC) is a deadly form of cancer that exhibits extensive intercellular communication which contributed to chemoradiotherapy resistance. Recent evidence suggests that arrange of key proteins are involved in lung cancer progression, including gap junction proteins (GJPs). METHODS AND RESULTS: In this study, we examined the expression patterns of GJPs in NSCLC, uncovering that both gap junction protein, beta 2 (GJB2) and gap junction protein, beta 2 (GJB3) are increased in LUAD and LUSC. We observed a correlation between the upregulation of GJB2, GJB3 in clinical samples and a worse prognosis in patients with NSCLC. By examining the mechanics, we additionally discovered that nuclear factor erythroid-2-related factor 1 (NFE2L1) had the capability to enhance the expression of connexin26 and connexin 31 in the NSCLC cell line A549. In addition, the use of metformin was discovered to cause significant downregulation of gap junction protein, betas (GJBs) by limiting the presence of NFE2L1 in the cytoplasm. CONCLUSION: This emphasizes the potential of targeting GJBs as a viable treatment approach for NSCLC patients receiving metformin.

Polydopamine-Based Resveratrol-Hyaluronidase Nanomedicine Inhibited Pancreatic Cancer Cell Invasive Phenotype in Hyaluronic Acid Enrichment Tumor Sphere Model.

The dense storm microenvironment formed by an excessively cross-linked extracellular matrix, such as hyaluronic acid and collagens, serves as a major barrier that prevents drugs from reaching the deeper tumor. Current traditional two-dimensional (2D) cultures are not capable of modeling this drug delivery barrier in vitro. Thus, tumor spheroids have become increasingly important in cancer research due to their three-dimensional structure. Currently, various methods have been developed to construct tumor spheroids. However, there are still challenges, such as lengthy construction time, complex composition of added growth factors, and high cultivation costs. To address this technical bottleneck, our study combined the GelMA hydrogel system to develop a rapid and high-yield method for tumor spheroids generation. Additionally, we proposed an evaluation scheme to assess the effects of drugs on tumor spheroids. Building on the hyaluronic acid-rich pathological tumor microenvironment, we constructed a resveratrol-loaded nano-drug delivery system with tumor stroma modulation capability and used a three-dimensional (3D) tumor sphere model to simulate in vivo tumor conditions. This process was utilized to completely evaluate the ability of the nano-drug delivery system to enhance the deep penetration of resveratrol in the tumor microenvironment, providing new insights into future oncology drug screening, efficacy assessment, and drug delivery methods.