Identification of a novel 10-hydroxyevodiamine prodrug as a potent topoisomerase inhibitor with improved aqueous solubility for treatment of hepatocellular carcinoma.

Natural product evodiamine (Evo) and its synthetic derivatives represent an attractive dual Topo 1/2 inhibitors with broad-spectrum antitumor efficacy. However, the clinical applications of these compounds have been impeded by their poor aqueous solubility. Herein, a series of water-soluble 10-substituted-N(14)-phenylevodiamine derivatives were designed and synthesized. The most potent compound 45 featuring a quaternary ammonium salt fragment achieved robust aqueous solubility and nanomolar potency against a panel of human hepatoma cell lines Huh7, HepG2, SK-Hep-1, SMMC-7721, and SMMC-7721/DOX (doxorubicin-resistant cell). Further studies revealed that 45 could inhibit Topo 1 and Topo 2, induce apoptosis, arrest the cell cycle at the G2/M stage and inhibit the migration and invasion. Compound 45 exhibited potent antitumor activity (TGI = 51.1 %, 10 mg/kg) in the Huh7 xenograft model with acceptable safety profile. In addition, a 21-day long-term dose toxicity study confirmed that the maximum tolerated dose of compound 45 was 20 mg/kg. Overall, this study presented a promising Evo-derived candidate for the treatment of hepatocellular carcinoma.

In vitro modelling of the neurovascular unit for ischemic stroke research: Emphasis on human cell applications and 3D model design.

Ischemic stroke has garnered global medical attention as one of the most serious cerebrovascular diseases. The mechanisms involved in both the development and recovery phases of ischemic stroke are complex, involving intricate interactions among different types of cells, each with its own unique functions. To better understand the possible pathogenesis, neurovascular unit (NVU), a concept comprising neurons, endothelial cells, mural cells, glial cells, and extracellular matrix components, has been used in analysing various brain diseases, particularly in ischemic stroke, aiming to depict the interactions between cerebral vasculature and neural cells. While in vivo models often face limitations in terms of reproducibility and the ability to precisely mimic human pathophysiology, it is now important to establish in vitro NVU models for ischemic stroke research. In order to accurately portray the pathological processes occurring within the brain, a diverse array of NVU 2D and 3D in vitro models, each possessing unique characteristics and advantages, have been meticulously developed. This review presents a comprehensive overview of recent advancements in in vitro models specifically tailored for investigating ischemic stroke. Through a systematic categorization of these developments, we elucidate the intricate links between NVU components and the pathogenesis of ischemic stroke. Furthermore, we explore the distinct advantages offered by innovative NVU models, notably 3D models, which closely emulate in vivo conditions. Additionally, an examination of current therapeutic modalities for ischemic stroke developed utilizing in vitro NVU models is provided. Serving as a valuable reference, this review aids in the design and implementation of effective in vitro models for ischemic stroke research.

Cryo-EM structures of Candida albicans Cdr1 reveal azole-substrate recognition and inhibitor blocking mechanisms.

In Candida albicans, Cdr1 pumps azole drugs out of the cells to reduce intracellular accumulation at detrimental concentrations, leading to azole-drug resistance. Milbemycin oxime, a veterinary anti-parasitic drug, strongly and specifically inhibits Cdr1. However, how Cdr1 recognizes and exports azole drugs, and how milbemycin oxime inhibits Cdr1 remain unclear. Here, we report three cryo-EM structures of Cdr1 in distinct states: the apo state (Cdr1Apo), fluconazole-bound state (Cdr1Flu), and milbemycin oxime-inhibited state (Cdr1Mil). Both the fluconazole substrate and the milbemycin oxime inhibitor are primarily recognized within the central cavity of Cdr1 through hydrophobic interactions. The fluconazole is suggested to be exported from the binding site into the environment through a lateral pathway driven by TM2, TM5, TM8 and TM11. Our findings uncover the inhibitory mechanism of milbemycin oxime, which inhibits Cdr1 through competition, hindering export, and obstructing substrate entry. These discoveries advance our understanding of Cdr1-mediated azole resistance in C. albicans and provide the foundation for the development of innovative antifungal drugs targeting Cdr1 to combat azole-drug resistance.

Sterile water and regional citrate anticoagulation: A simple CRRT strategy for safe correction of severe hyponatraemia.

BACKGROUND: Hyponatraemia is a prevalent electrolyte disturbance observed in critically ill patients. The rapid correction of low plasma sodium levels by continuous renal replacement therapy (CRRT) carries the risk of developing osmotic demyelination syndrome (ODS), which can be prevented by implementing an individualized CRRT method. AIM: This study aims to introduce a CRRT protocol for the safe and gradual correction of severe hyponatraemia. STUDY DESIGN: This retrospective case series study was conducted in an intensive care unit (ICU). All four patients with severe hyponatraemia (<125 mmol/L) and renal failure between October 1, 2022, and September 30, 2023, were treated by CRRT with sterile water and regional citrate anticoagulation (RCA). Data on patient demographics, laboratory biochemical parameters, urine outputs and CRRT-related adverse events were collected. Laboratory parameters and urine outputs were compared by paired t-tests before and after CRRT. RESULTS: After CRRT, sodium levels were significantly increased (112.7 ± 6.7 vs. 141.9 ± 2.8 mmol/L, p = .005). Abnormal urine outputs, potassium, creatinine and bicarbonate were corrected (p for all <.05). Safe and gradual correction of hyponatraemia and internal environmental dysregulation was achieved in all patients without any complications related to CRRT, particularly ODS. CONCLUSION: It is a novel and simple strategy to correct severe hyponatraemia effectively while ensuring the safety of patients that can be easily implemented by experienced nurse staff. RELEVANCE TO CLINICAL PRACTICE: The sterile water-based protocol for postfilter dilution is safe to correct severe hyponatraemia with RCA and can be easily performed by experienced critical care nurses according to the precalculated formula. CRRT-trained, experienced ICU nurses are competent to initiate and adjust sterile water infusion discretely to prevent overcorrection of hyponatraemia.

Roles of osteocalcin in the central nervous system.

BACKGROUND: Bone-derived protein osteocalcin, which has beneficial effects on brain function, may be a future research direction for neurological disorders. A growing body of evidence suggests a link between osteocalcin and neurological disorders, but the exact relationship is contradictory and unclear. SCOPE OF REVIEW: The aim of this review is to summarize the current research on the interaction between osteocalcin and the central nervous system and to propose some speculative future research directions. MAJOR CONCLUSIONS: In the normal central nervous system, osteocalcin is involved in neuronal structure, neuroprotection, and the regulation of cognition and anxiety. Studies on osteocalcin-related abnormalities in the central nervous system are divided into animal model studies and human studies, depending on the subject. In humans, the link between osteocalcin and brain function is inconsistent. These conflicting data may be due to methodological inconsistencies. By reviewing the related literature on osteocalcin, some comorbidities of the bone and nervous system and future research directions related to osteocalcin are proposed.

Unveiling the formation and influence mechanisms of PCDD/F memory effect in wet scrubbers: Fundamental research and field verification.

The "memory effect" of polychlorinated dibenzo-p-dioxin and dibenzofurans (PCDD/Fs) in wet scrubber (WS) has become a frequent negative phenomenon in waste incineration field. This work focuses on studying the major influence factors and pathways of memory effect of PCDD/Fs in WS from the aspects of PCDD/F carriers and operating conditions. The PCDD/F contents of fillings used for over three years is 0.098 ng I-TEQ/g, which performs as a stable source of PCDD/Fs for thousands of hours with PCDD/F desorption rates ranged in 0.023-0.116 pg I-TEQ/g·h at 65 °C-93 °C. On the one hand, the filling layer has been the biggest PCDD/F storage part in WS (6845.1 µg). On the other hand, the generated yellow wrapping layer in long-term operation can limit the desorption of inner PCDD/Fs. The solubility of PCDD/Fs in scrubbing water (SW) performs a positive correlation with the content of suspended substances, and the increased temperature and pH value of SW both lead to a higher toxic concentration of PCDD/Fs dissolved from the fly ash to solutions. In addition, the built mass balance of PCDD/Fs around WS suggests the incomplete SW refreshing and sludge cleaning also contribute to the memory effect of PCDD/Fs through enhancing the liquid-phase PCDD/Fs in flue gas from SW. Based on this study, three suggestions are propounded on the operation of WS. The results of this study will provide essential evidence and guidelines for optimizing operation and inhibiting the PCDD/F memory effect in WS.

Spatially lipidomic characterization of patient-derived organoids by whole-mount autofocusing SMALDI mass spectrometry imaging.

BACKGROUND: Patient-derived organoids (PDOs) are multi-cellular cultures with specific three-dimensional (3D) structures. Tumor organoids (TOs) offer a personalized perspective for assessing treatment response. However, the presence of normal organoid (NO) residuals poses a potential threat to their utility for personalized medicine. There is a crucial need for an effective platform capable of distinguishing between TO and NO in cancer organoid cultures. RESULTS: We introduced a whole-mount (WM) preparation protocol for in-situ visualization of the lipidomic distribution of organoids. To assess the efficacy of this method, nine breast cancer organoids (BCOs) and six normal breast organoids (NBOs) were analyzed. Poly-l-lysine (PLL) coated slides, equipped with 12 well chambers, were utilized as a carrier for the high-throughput analysis of PDOs. Optimizing the fixation time to 30 min, preserved the integrity of organoids and the fidelity of lipid compounds. The PDOs derived from the same organoid lines exhibited similar lipidomic profiles. BCOs and NBOs were obviously distinguished based on their lipidomic signatures detected by WM autofocusing (AF) scanning microprobe matrix-assisted laser desorption/ionization (SMALDI) mass spectrometry imaging (MSI). SIGNIFICANCE: A whole-mount (WM) preparation protocol was developed to visualize lipidomic distributions of the organoids' surface. Using poly-l-lysine coated slides for high-throughput analysis, the method preserved organoid integrity and distinguished breast cancer organoids (BCOs) from normal breast organoids (NBOs) based on their unique lipidomic profiles using autofocusing scanning microprobe matrix-assisted laser desorption/ionization (SMALDI) mass spectrometry imaging.

Suicide Risk among Chinese Left-Behind Adolescents: Developmental Trajectories and Multi-Contextual Predictors.

Suicide is prevalent among left-behind youth, a group that has yet to be thoroughly explored in terms of the developmental dynamics of their suicide risk and associated factors. This study adopted a person-centered approach to investigate the developmental trajectories of suicide risk among Chinese left-behind adolescents, along with multi-dimensional predictors. A total of 774 left-behind adolescents (Mage = 13.60, 50.1% female) completed three surveys over a year, with six-month intervals. Result of Latent Class Growth Modeling identified three subgroups with distinct developmental trajectories: High Risk-Escalating (7.6% of participants started at the highest levels with a worsening trend), Risk-Holding (21.6% maintained a stable but risk level starting above the critical threshold), and Low Risk-Diminishing (70.8% started low and continued to decrease). Gender (being a female), increased levels of childhood maltreatment, psychological pain, and depression were risk factors for High Risk-Escalating and/or Risk-Holding trajectories, while increased sense of control and regulatory emotional self-efficacy played protective roles. The findings underscore the malignant developmental patterns of suicide risk among left-behind adolescents. The predictive factors play a crucial role in distinguishing and improving these developmental trajectories.

Mitochondria-Targeting AIEgens as Pyroptosis Inducers for Boosting Type-I Photodynamic Therapy of Tongue Squamous Cell Carcinoma.

The development of a photosensitizer (PS) that induces pyroptosis could be a star for photodynamic therapy (PDT), particularly with type-I PSs that produce reactive oxygen species (ROS) in a hypoxic tumor microenvironment. Since pyroptosis is a recently characterized cell death pathway, it holds promise for advancing PDT in oncology, with PSs playing a critical role. Herein, we develop a PS named Th-M with aggregation-induced emission (AIE) characteristics for type-I PDT against tongue squamous cell carcinoma (TSCC). Th-M stands out for its exceptional mitochondrial-targeting ability, which triggers mitochondrial dysfunction and leads to Caspase-3 and Gasdermin E (GSDME) cleavage under white light irradiation, inducing pyroptosis in TSCC cells. Our studies verify the effectiveness of Th-M in destroying cancer cells in vitro and suppressing tumor growth in vivo while also demonstrating a favorable biosafety profile. This work pioneers the application of Th-M as a mitochondria-targeted, type-I PS that leverages the mechanism of pyroptosis, offering a potent approach for the treatment of TSSC with promising implications for future PDT of cancers.

The protective effect of Ghrelin peptide on doxorubicin hydrochloride induced heart failure in rats.

BACKGROUND: To investigate the protective effect and mechanism of Ghrelin on Doxorubicin (Dox) hydrochloride induced heart failure (HF) and myocardial injury in rats. METHODS: 45 rats were randomly divided into control group, HF group and Ghrelin group. Dox hydrochloride was injected intraperitoneally to establish the model of HF in rats of HF group and Ghrelin group. Rats in the Ghrelin group were given intraperitoneal injection of Ghrelin twice a day, and rats in the HF group and control group were given equal volume of normal saline for a total of 6 weeks. The changes of echocardiography, cardiac hemodynamics, myocardial histology and plasma inflammatory factors were observed. RESULTS: After the Ghrelin intervention, compared with the HF group, the left ventricular end-diastolic diameter (LVDD) and left ventricular end-systolic diameter (LVSD) in the Ghrelin group was markedly reduced (P < 0.05), and left ventricular ejection fraction (LVEF) was significantly increased (P < 0.05). Compared with HF group, the left ventricular systolic pressure (LVSP), maximum rate of increase in left ventricular pressure (+ dP/dtmax) and maximum rate of decrease in left ventricular pressure (- dP/dtmax) of Ghrelin group was remarkedly increased (P < 0.05), left ventricular diastolic pressure (LVDP) decreased (P < 0.05). In the Ghrelin group, the degree and extent of cardiomyocyte degeneration and necrosis were remarkedly reduced compared with the HF group. The levels of TNF-α and iNOS in Ghrelin group were notably lower than those in HF group (P < 0.05), the IL-10 level increased markedly (P < 0.05). CONCLUSION: Ghrelin may reduce Dox-induced myocardial injury and improve cardiac function in rats by regulating inflammation and oxidative stress.

Synthesis and immunotherapy efficacy of a PD-L1 small-molecule inhibitor combined with its 131I-iodide labelled isostructural compound.

Although antibody-based immune checkpoint blockades have been successfully used in antitumor immunotherapy, the low response rate is currently the main problem. In this work, a small-molecule programmed cell death-ligand (PD-L1) inhibitor, LG-12, was developed and radiolabeled with 131I to obtain the chemically and biologically identical radiopharmaceutical [131I]LG-12, which aimed to improve the antitumor effect by combination of LG-12 and [131I]LG-12. LG-12 showed high inhibitory activity to PD-1/PD-L1 interaction. The results of cell uptake and biodistribution studies indicated that [131I]LG-12 could specifically bind to PD-L1 in B16-F10 tumors. It could induce immunogenic cell death and the release of high mobility group box 1 and calreticulin. The combination of [131I]LG-12 and LG-12 could significantly inhibit tumor growth and resulted in enhanced antitumor immune response. This PD-L1 small-molecule inhibitor based combination strategy has great potential for tumor treatment.

A zero-background fluorescent probe for sensing and imaging of glutathione via the "covalent-assembly" approach.

Developing selective and sensitive fluorescent probes for the detection of glutathione (GSH) concentration and intracellular distribution is of great significance for early diagnosis and treatment of diseases such as liver injury and cancer since GSH plays irreplaceable roles in regulating intracellular redox homeostasis. Herein, we present a new fluorescent probe that can be specifically activated by GSH through the conjugate addition and hydrolysis induced covalent-assembly approach for achieving zero-background interference fluorescence off-on sensing. Besides, the probe exhibited prominent selectivity and sensitivity, a low detection limit and cytotoxicity, thus successfully realizing specific real-time monitoring and tracking of GSH levels in living cells. As a consequence, this work might provide a potentially promising candidate for validating the function of GSH in various physiological and pathological processes, which is beneficial for early diagnosis and therapeutics of related diseases.

TRIM21-mediated ubiquitination of PLIN2 regulates neuronal lipid droplet accumulation after acute spinal cord injury.

To investigate the changes in neuronal lipid droplet (LD) accumulation and lipid metabolism after acute spinal cord injury (SCI), we established a rat model of compressive SCI. Oil Red O staining, BODIPY 493/503 staining, and 4-hydroxynonenal immunofluorescence staining were performed to determine overall LD accumulation, neuronal LD accumulation, and lipid peroxidation. Lipidomics was conducted to identify the lipid components in the local SCI microenvironment. We focused on the expression and regulation of perilipin 2 (PLIN2) and knocked down PLIN2 in vivo by intrathecal injection of adeno-associated virus 9-synapsin-short-hairpin RNA-PLIN2 (AAV9-SYN-shPlin2). Motor function was assessed using the Basso-Beattie-Bresnahan score. Proteins that interacted with PLIN2 were screened by immunoprecipitation (IP) and qualitative shotgun proteomics, and confirmed by co-IP. A ubiquitination assay was performed to validate whether ubiquitination was involved in PLIN2 degradation. Oil Red O staining indicated that LDs steadily accumulated after SCI. Fluorescent staining indicated the accumulation of LDs in neurons with increased lipid peroxidation. Lipidomics revealed significant changes in lipid components after SCI. PLIN2 expression significantly increased following SCI, and knockdown of PLIN2 using AAV9-SYN-Plin2 reduced neuronal LD accumulation. This intervention improved the neuronal survival and motor function of injured rats. IP and qualitative shotgun proteomics identified tripartite motif-containing protein 21 (TRIM21) as a direct binding protein of PLIN2, and this interaction was confirmed by co-IP in vitro and immunofluorescence staining in vivo. By manipulating TRIM21 expression, we found it was negatively correlated with PLIN2 expression. In conclusion, PLIN2 is involved in neuronal LD accumulation following SCI. TRIM21 mediated the ubiquitination and degradation of PLIN2 in neurons. Inhibition of PLIN2 enhanced the recovery of motor function after SCI.

Toxicity Evaluation and Transcriptome Analysis of Yellowstripe Goby (Mugilogobius chulae) in Response to 2,7-Dibromocarbazole Exposure during Early Development.

Polyhalogenated carbazoles (PHCZs) are a class of nitrogen-containing heterocyclic compounds that are widely distributed throughout the marine environment and sediment. These compounds share structural and toxicity similarities with dioxins. However, our understanding of the toxicological effects of PHCZs on marine organisms and their underlying molecular mechanisms remains limited. In this study, we employed the marine model organism Mugilogobius chulae as the experimental subject and selected 2,7-dibromocarbazole (2,7-DBCZ), a compound known for its high toxicity and detection frequency, to conduct both an acute toxicity test and transcriptome analysis on M. chulae embryos. Our findings revealed that the 96 h median lethal concentration (LC50) of 2,7-DBCZ for M. chulae embryos was 174 µg/L, with a median effective concentration (EC50) resulting in pericardial edema deformity of 88.82 µg/L. Transcriptome analysis revealed significant impacts on various systems in M. chulae embryos following exposure to 2,7-DBCZ, including the sensory, cardiovascular, immune, and endocrine systems. Furthermore, this compound perturbed signaling pathways such as phototransduction, protein folding and processing, amino acid metabolism, lipid transport, and exogenous compound metabolism. Notably, transcript abundance of the CYP1A gene associated with the activation of the AhR signaling pathway, similar to dioxin-like compounds, was 18.18 times higher than that in the control group. This observation suggests that M. chulae embryos mount a stress response when exposed to PHCZs. In summary, this study contributes to our understanding of the toxicological implications of PHCZ in marine fish and offers a theoretical foundation for risk assessment and regulatory frameworks for PHCZs in the marine environment.

Case Report: Bradycardia in neonatal lupus: differential diagnosis between atrioventricular block and premature atrial contractions with block.

Neonatal lupus may be associated with severe cardiac conduction problems, including high-degree or complete atrioventricular (AV) block, necessitating immediate pacemaker implantation during the neonatal period. However, cardiac manifestations of neonatal lupus may extend beyond AV block. Our case was a full-term female neonate, who presented with fetal arrhythmia and bradycardia with a heart rate of approximately 70-75 beats per minute after birth. Neonatal lupus was diagnosed later due to positive maternal and neonatal anti-SSA/Ro antibody. High-degree AV block was considered initially but bigeminy premature atrial contractions (PACs) with block was confirmed through a detailed evaluation of an electrocardiogram, which demonstrated unfixed PP intervals and fixed RR intervals. Atrial tachycardia (AT) developed when the neonate was 23 days old. The key point that differentiates high-degree AV block from PACs with block is the PP interval. The PP interval is fixed in high-degree AV block and unfixed in PACs with block. Careful differential diagnosis is required in neonates with bradycardia because it may lead to very different management. Our case presents a good illustration of why these arrhythmias need to be differentiated. Furthermore, our case may be the first of neonatal lupus with AT.

Mass Spectrometry Imaging of Amino Acids Enabled by Quaternized Pyridinium Salt MALDI Probe.

The distribution of small biomolecules, particularly amino acids (AAs), differs between normal cells and cancer cells. Imaging this distribution is crucial for gaining a deeper understanding of their physiological and pathological significance. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) provides accurate in situ visualization information. However, the analysis of AAs remains challenging due to the background interference by conventional MALDI matrices. On tissue chemical derivatization (OTCD) MSI serves as an important approach to resolve this issue. We designed, synthesized, and tested a series of pyridinium salt probes and screened out the 1-(4-(((2,5-dioxopyrrolidin-1-yl)oxy)carbonyl)phenyl)-2,4,6-triphenylpyridin-1-ium (DCT) probe with the highest reaction efficiency and the most effective detection. Moreover, a quantum chemistry calculation was executed to address mechanistic insight into the chemical nature of the novel probes. DCT was found to map 20 common AAs in normal mouse tissues for the first time, which allowed differentiation of AA distribution in normal, normal interstitium, tumor, and tumor interstitium regions and provided potential mechanistic insights for cancer research and other biomedical studies.

XPO1 serves as a prognostic marker involving AKT/MAPK/TGFBR1 pathway in OSCC.

BACKGROUND: Exportin 1 (XPO1) is a nuclear export protein that facilitates the transportation of various substances. XPO1 promotes tumor development as a poor prognostic factor in a variety of tumors and is a therapeutic target for screening inhibitors. However, the role of XPO1 in oral squamous cell carcinoma (OSCC) has yet to be determined. METHODS: The expression patterns of XPO1 mRNA in OSCC were investigated using bioinformatics tools, and the expression levels of XPO1 protein in OSCC specimens were confirmed by immunohistochemical assays. Survival analysis was conducted to evaluate the impact of XPO1 on prognosis. GO and KEGG enrichment analyses were utilized to uncover the signaling pathways mediated by XPO1. Additionally, we examined the association between XPO1 and AKT/MAPK/TGFBR1 and immune infiltration. RESULTS: XPO1 mRNA and protein expression levels were significantly enhanced in OSCC and associated with OSCC severity. Enhanced XPO1 expression was indicative of poor survival. Functional analysis showed that XPO1 mediated pathways associated with cell cycle and DNA replication and reduced immune infiltration in OSCC. Additionally, XPO1 mRNA and protein expression levels had significant positive relationships with AKT/MAPK/TGFBR1. CONCLUSIONS: XPO1, as a marker of poor prognosis in OSCC, can promote OSCC through AKT/MAPK/TGFBR1.

Discovery of 4-(Arylethynyl)piperidine Derivatives as Potent Nonsaccharide O-GlcNAcase Inhibitors for the Treatment of Alzheimer's Disease.

Inhibiting O-GlcNAcase and thereby up-regulation of the O-GlcNAc levels of tau was a potential approach for discovering AD treatments. Herein, a series of novel highly potent OGA inhibitors embracing a 4-(arylethynyl)piperidine moiety was achieved by capitalizing on the substrate recognition domain. Extensive structure-activity relationships resulted in compound 81 with significant enzymatic inhibition (IC50 = 4.93 ± 2.05 nM) and cellular potency (EC50 = 7.47 ± 3.96 nM in PC12 cells). It markedly increased the protein O-GlcNAcylation levels and reduced the phosphorylation on Ser199, Thr205, and Ser396 of tau in the OA-injured SH-SY5Y cell model, suggesting its potential role for AD treatment. In fact, an in vivo efficacy of ameliorating cognitive impairment was observed following treatment of APP/PS1 mice with compound 81 (100 mg/kg). Additionally, the appropriate plasma PK and beneficial BBB penetration properties were also observed. Compound 81 deserves to be further explored as an anti-AD agent.

Spatial analysis of the impact of urban built environment on cardiovascular diseases: a case study in Xixiangtang, China.

BACKGROUND: The built environment, as a critical factor influencing residents' cardiovascular health, has a significant potential impact on the incidence of cardiovascular diseases (CVDs). METHODS: Taking Xixiangtang District in Nanning City, Guangxi Zhuang Autonomous Region of China as a case study, we utilized the geographic location information of CVD patients, detailed road network data, and urban points of interest (POI) data. Kernel density estimation (KDE) and spatial autocorrelation analysis were specifically employed to identify the spatial distribution patterns, spatial clustering, and spatial correlations of built environment elements and diseases. The GeoDetector method (GDM) was used to assess the impact of environmental factors on diseases, and geographically weighted regression (GWR) analysis was adopted to reveal the spatial heterogeneity effect of environmental factors on CVD risk. RESULTS: The results indicate that the built environment elements and CVDs samples exhibit significant clustering characteristics in their spatial distribution, with a positive correlation between the distribution density of environmental elements and the incidence of CVDs (Moran's I > 0, p < 0.01). Further factor detection revealed that the distribution of healthcare facilities had the most significant impact on CVDs (q = 0.532, p < 0.01), followed by shopping and consumption (q = 0.493, p < 0.01), dining (q = 0.433, p < 0.01), and transportation facilities (q = 0.423, p < 0.01), while the impact of parks and squares (q = 0.174, p < 0.01) and road networks (q = 0.159, p < 0.01) was relatively smaller. Additionally, the interaction between different built environment elements exhibited a bi-factor enhancement effect on CVDs. In the local analysis, the spatial heterogeneity of different built environment elements on CVDs further revealed the regional differences and complexities. CONCLUSIONS: The spatial distribution of built environment elements is significantly correlated with CVDs to varying degrees and impacts differently across regions, underscoring the importance of the built environment on cardiovascular health. When planning and improving urban environments, elements and areas that have a more significant impact on CVDs should be given priority consideration.