The association between endometrial polyps and insulin resistance from the expression of PI3K and AKT proteins perspective.

BACKGROUND: Insulin resistance (IR) induces hyperinsulinemia, which activates downstream signaling pathways such as the phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) pathway, ultimately leading to abnormal proliferation and apoptosis of endometrial cells. This is thought to be a key pathogenic mechanism underlying the development of endometrial polyps (EP). This study aims to investigate the relationship between IR and the development of EP, the expression levels of downstream signaling molecules, including PI3K and AKT, and related laboratory parameters were examined. METHODS: A total of 100 patients who visited the gynecology outpatient clinic of Zhongda Hospital affiliated with Southeast University from May 2021 to March 2023 and were diagnosed with abnormal endometrial echoes by vaginal ultrasound and underwent hysteroscopic diagnostic curettage were enrolled in this study. General data and relevant hematological indicators were compared, and intraoperative specimens were obtained for pathological examination. Possible factors influencing the development of endometrial polyps were analyzed using Pearson correlation analysis and logistic regression analysis. RESULTS: In terms of body mass index, waist circumference, fasting insulin, insulin resistance index, serum total testosterone, and free testosterone index, women of childbearing age in the endometrial polyp group had higher values than those in the non-polyp group, while sex hormone-binding globulin in the endometrial polyp group was lower than that in the non-polyp group, and the differences were statistically significant (P < 0.05). The expression scores and mRNA expression levels of PI3K and AKT proteins were higher in the EP group than in the non-EP group (p < 0.05). Pearson correlation analysis showed a positive correlation between HOMA-IR and the expression scores of PI3K and AKT proteins (p < 0.01). CONCLUSIONS: Insulin resistance and abnormal activation of the phosphatidylinositol 3-kinase/protein kinase B signaling pathway may be potential pathogenic mechanisms for the development of endometrial polyps.

Recent advances in transdermal insulin delivery technology: A review.

Transdermal drug delivery refers to the administration of drugs through the skin, after which the drugs can directly act on or circulate through the body to the target organs or cells and avoid the first-pass metabolism in the liver and kidneys experienced by oral drugs, reducing the risk of drug poisoning. From the initial singular approach to transdermal drug delivery, there has been a shift toward combining multiple methods to enhance drug permeation efficiency and address the limitations of individual approaches. Technological advancements have also improved the accuracy of drug delivery. Optimizing insulin itself also enables its long-term release via needle-free injectors. In this review, the diverse transdermal delivery methods employed in insulin therapy and their respective advantages and limitations are discussed. By considering factors such as the principles of transdermal penetration, drug delivery efficiency, research progress, synergistic innovations among different methods, patient compliance, skin damage, and posttreatment skin recovery, a comprehensive evaluation is presented, along with prospects for potential novel combinatorial approaches. Furthermore, as insulin is a macromolecular drug, insights gained from its transdermal delivery may also serve as a valuable reference for the use of other macromolecular drugs for treatment.

N-Salicyloyl Tryptamine Derivatives as Potent Neuroinflammation Inhibitors by Constraining Microglia Activation via a STAT3 Pathway.

Neuroinflammation is an important factor that exacerbates neuronal death and abnormal synaptic function in neurodegenerative diseases (NDDs). Due to the complex pathogenesis and the presence of blood-brain barrier (BBB), no effective clinical drugs are currently available. Previous results showed that N-salicyloyl tryptamine derivatives had the potential to constrain the neuroinflammatory process. In this study, 30 new N-salicyloyl tryptamine derivatives were designed and synthesized to investigate a structure-activity relationship (SAR) for the indole ring of tryptamine in order to enhance their antineuroinflammatory effects. Among them, both in vitro and in vivo compound 18 exerted the best antineuroinflammatory effects by suppressing the activation of microglia, which is the culprit of neuroinflammation. The underlying mechanism of its antineuroinflammatory effect may be related to the inhibition of transcription, expression and phosphorylation of signal transducer and activator of transcription 3 (STAT3) that subsequently regulated downstream cyclooxygenase-2 (COX-2) expression and activity. With its excellent BBB permeability and pharmacokinetic properties, compound 18 exhibited significant neuroprotective effects in the hippocampal region of lipopolysaccharides (LPS)-induced mice than former N-salicyloyl tryptamine derivative L7. In conclusion, compound 18 has provided a new approach for the development of highly effective antineuroinflammatory therapeutic drugs targeting microglia activation.

A novel endolysin from an Enterococcus faecalis phage and application.

Enterococcus faecalis is the primary species detected in cases of secondary persistent infection resulting from root canal therapy failure. Due to the overuse of antibacterial agents, E. faecalis has developed resistance to these drugs, making it challenging to treat clinical diseases caused by E. faecalis infection. Therefore, there is an urgent need to explore new alternative drugs for treating E. faecalis infections. We aimed to clone and express the genes of phage endolysins, purify the recombinant proteins, and analyze their antibacterial activity, lysis profile, and ability to remove biofilm. The crude enzyme of phage endolysin pEF51 (0.715 mg/mL), derived from phage PEf771 infecting E. faecalis, exhibited superior bacterial inhibitory activity and a broader bactericidal spectrum than its parental phage PEf771. Furthermore, pEF51 demonstrated high efficacy in eliminating E. faecalis biofilm. Therapeutic results of the infected Sprague-Dawley (SD) rat model indicated that among 10 SD rats, only one developed a thoracic peritoneal abscess and splenic peritoneal abscess after 72 h of treatment with pEF51. This suggests that pEF51 could provide protection against E. faecalis infection in SD rats. Based on the 16S rDNA metagenomic data of the intestinal microbial community of SD rats, endolysin pEF51 exerted a certain influence on the diversity of intestinal microorganisms at the genus level. Thus, pEF51 may serve as a promising alternative to antibiotics in the management of E. faecalis infection.

Intelligent Fusion of Multi-Source Senses Information for Identifying the Nature of Five Flavors in Chinese Medicine: A Comprehensive Study of Five Classifications.

Objective: To develop a classification model for the five flavors of Chinese medicine using advanced multi-source intelligent sensory information fusion technology. The primary aim is to investigate the feasibility of applying this model to classify and identify the flavors of various Chinese medicines effectively. Methods: We selected 122 representative Chinese medicines, each exhibiting a single distinct flavor (sour, pungent, salty, sweet, bitter), along with 14 common foods. Utilizing the nature and flavors of these decoction pieces specified in Chinese Pharmacopeia (ChP)2020 and the inherent attributes of food components, we obtained valuable data from various sensors, including the PEN3 electronic nose, ASTREE electronic tongue, and SA402B electronic tongue. We then collected single-source data matrices from these sample sensors and a multi-source data matrix that combined the data from all sensors. Using discriminant analysis (DA), principal component analysis-discriminant analysis (PCA-DA), and K-nearest neighbor algorithm (KNN) three kinds of chemometric methods were used to establish five flavors and five-category discrimination models. The results were comprehensively evaluated with the highest correct rate of the model of leave-one-out cross-validation as the index. Results: Upon leave-one-out cross-validation, the correct judgment rate of the five flavors, five-category two-source fusion DA discrimination model (83.8%; ASTREE + SA402B) was significantly higher than the correct judgment rate of the single-source optimal DA and KNN model (73.5%; ASTREE). Following full-sample modeling, the correct judgment rate of the five flavors, five-category three-source fusion DA discrimination model (94.9%; PEN3+ASTREE+SA402B) rose substantially. This was higher than the correct judgment rate of the single-source optimal DA model (77.9%; ASTREE) and slightly higher than the two-source optimal correct judgment rate (89.7%; PEN3 + ASTREE). Conclusions: Compared to single-source identification, multi-source intelligent senses information fusion (MISIF) significantly improved accuracy, providing a new outlook for identifying flavor in Chinese medicine.

An octopamine-specific GRAB sensor reveals a monoamine relay circuitry that boosts aversive learning.

Octopamine (OA), analogous to norepinephrine in vertebrates, is an essential monoamine neurotransmitter in invertebrates that plays a significant role in various biological functions, including olfactory associative learning. However, the spatial and temporal dynamics of OA in vivo remain poorly understood due to limitations associated with the currently available methods used to detect it. To overcome these limitations, we developed a genetically encoded GPCR  activation-based (GRAB) OA sensor called GRABOA1.0. This sensor is highly selective for OA and exhibits a robust and rapid increase in fluorescence in response to extracellular OA. Using GRABOA1.0, we monitored OA release in the Drosophila mushroom body (MB), the fly's learning center, and found that OA is released in response to both odor and shock stimuli in an aversive learning model. This OA release requires acetylcholine (ACh) released from Kenyon cells, signaling via nicotinic ACh receptors. Finally, we discovered that OA amplifies aversive learning behavior by augmenting dopamine-mediated punishment signals via Octß1R in dopaminergic neurons, leading to alterations in synaptic plasticity within the MB. Thus, our new GRABOA1.0 sensor can be used to monitor OA release in real time under physiological conditions, providing valuable insights into the cellular and circuit mechanisms that underlie OA signaling.

An octopamine-specific GRAB sensor reveals a monoamine relay circuitry that boosts aversive learning.

Octopamine (OA), analogous to norepinephrine in vertebrates, is an essential monoamine neurotransmitter in invertebrates that plays a significant role in various biological functions, including olfactory associative learning. However, the spatial and temporal dynamics of OA in vivo remain poorly understood due to limitations associated with the currently available methods used to detect it. To overcome these limitations, we developed a genetically encoded GPCR activation-based (GRAB) OA sensor called GRABOA1.0. This sensor is highly selective for OA and exhibits a robust and rapid increase in fluorescence in response to extracellular OA. Using GRABOA1.0, we monitored OA release in the Drosophila mushroom body (MB), the fly's learning center, and found that OA is released in response to both odor and shock stimuli in an aversive learning model. This OA release requires acetylcholine (ACh) released from Kenyon cells, signaling via nicotinic ACh receptors. Finally, we discovered that OA amplifies aversive learning behavior by augmenting dopamine-mediated punishment signals via Octß1R in dopaminergic neurons, leading to alterations in synaptic plasticity within the MB. Thus, our new GRABOA1.0 sensor can be used to monitor OA release in real-time under physiological conditions, providing valuable insights into the cellular and circuit mechanisms that underlie OA signaling.

Spatial distribution of volatile organic compounds in contaminated soil and distinct microbial effect driven by aerobic and anaerobic conditions.

The vertical distribution of 35 volatile organic compounds (VOCs) was investigated in soil columns from two obsolete industrial sites in Eastern China. The total concentrations of ΣVOCs in surface soils (0-20 cm) were 134-1664 ng g-1. Contamination of VOCs in surface soil exhibited remarkable variability, closely related to previous production activities at the sampling sites. Additionally, the concentrations of ΣVOCs varied with increasing soil depth from 0 to 10 m. Soils at depth of 2 m showed ΣVOCs concentrations of 127-47,389 ng g-1. Among the studied VOCs, xylene was the predominant contaminant in subsoils (2 m), with concentrations ranging from n.d. to 45,400 ng g-1. Chlorinated alkanes and olefins demonstrated a greater downward migration ability compared to monoaromatic hydrocarbons, likely due to their lower hydrophobicity. As a result, this vertical distribution of VOCs led to a high ecological risk in both the surface and deep soil. Notably, the risk quotient (RQ) of xylene in subsoil (2 m, RQ up to 319) was much higher than that in surface soil. Furthermore, distinct effects of VOCs on soil microbes were observed under aerobic and anaerobic conditions. Specifically, after the 30-d incubation of xylene-contaminated soil, Ilumatobacter was enriched under aerobic condition, whereas Anaerolineaceae was enriched under anaerobic condition. Moreover, xylene contamination significantly affected methylotrophy and methanol oxidation functions for aerobic soil (t-test, p < 0.05). However, aromatic compound degradation and ammonification were significantly enhanced by xylene in anaerobic soil (t-test, p < 0.05). These findings suggest that specific VOC compound has distinct microbial ecological effects under different oxygen content conditions in soil. Therefore, when conducting soil risk assessments of VOCs, it is crucial to consider their ecological effects at different soil depths.

Advancements in gradient bone scaffolds: enhancing bone regeneration in the treatment of various bone disorders.

Bone scaffolds are widely employed for treating various bone disorders, including defects, fractures, and accidents. Gradient bone scaffolds present a promising approach by incorporating gradients in shape, porosity, density, and other properties, mimicking the natural human body structure. This design offers several advantages over traditional scaffolds. A key advantage is the enhanced matching of human tissue properties, facilitating cell adhesion and migration. Furthermore, the gradient structure fosters a smooth transition between scaffold and surrounding tissue, minimizing the risk of inflammation or rejection. Mechanical stability is also improved, providing better support for bone regeneration. Additionally, gradient bone scaffolds can integrate drug delivery systems, enabling controlled release of drugs or growth factors to promote specific cellular activities during the healing process. This comprehensive review examines the design aspects of gradient bone scaffolds, encompassing structure and drug delivery capabilities. By optimizing the scaffold's inherent advantages through gradient design, bone regeneration outcomes can be improved. The insights presented in this article contribute to the academic understanding of gradient bone scaffolds and their applications in bone tissue engineering.

Shared and distinct prefrontal cortex alterations of implicit emotion regulation in depression and anxiety: An fNIRS investigation.

BACKGROUND: Emotion regulation deficits, particularly in cognitive reappraisal, are crucial in depression and anxiety. However, research on the neural mechanisms of implicit emotion regulation is lacking, and it remains unclear whether these mechanisms are shared or distinct between the two disorders. METHODS: We investigated the neural mechanisms of implicit cognitive reappraisal in 28 individuals with major depressive disorder (MDD), 25 with generalized anxiety disorder (GAD), and 30 healthy controls (HC) using functional near-infrared spectroscopy (fNIRS). Participants completed an implicit cognitive reappraisal task and underwent neuropsychological and clinical assessments. RESULTS: We found that MDD patients reported higher levels of rumination and lower utilization of cognitive reappraisal, while GAD patients reported reduced use of perspective-taking. Notably, both MDD and GAD patients exhibited decreased activation in the dorsolateral prefrontal cortex (DLPFC) and orbitofrontal cortex (OFC) compared to HC participants during implicit cognitive reappraisal. Specifically, inadequate OFC activation was observed in MDD patients, while GAD patients demonstrated OFC deactivation during the task. Furthermore, DLPFC activation showed a negative correlation with depression severity in MDD patients, while OFC activation was positively correlated with perspective-taking in GAD patients. LIMITATIONS: fNIRS has limited depth and spatial resolution. CONCLUSION: Our fNIRS study is the first to reveal shared and distinct neurobiological profiles of depression and anxiety in implicit emotion regulation. These findings underscore the significance of reduced DLPFC/OFC activation in emotion regulation impairment and highlight unique OFC activation patterns in these disorders. These insights have potential implications for developing cognitive-behavioral therapy and transcranial magnetic stimulation as treatment approaches.

Improved green and red GRAB sensors for monitoring spatiotemporal serotonin release in vivo.

The serotonergic system plays important roles in both physiological and pathological processes, and is a therapeutic target for many psychiatric disorders. Although several genetically encoded GFP-based serotonin (5-HT) sensors were recently developed, their sensitivities and spectral profiles are relatively limited. To overcome these limitations, we optimized green fluorescent G-protein-coupled receptor (GPCR)-activation-based 5-HT (GRAB5-HT) sensors and developed a red fluorescent GRAB5-HT sensor. These sensors exhibit excellent cell surface trafficking and high specificity, sensitivity and spatiotemporal resolution, making them suitable for monitoring 5-HT dynamics in vivo. Besides recording subcortical 5-HT release in freely moving mice, we observed both uniform and gradient 5-HT release in the mouse dorsal cortex with mesoscopic imaging. Finally, we performed dual-color imaging and observed seizure-induced waves of 5-HT release throughout the cortex following calcium and endocannabinoid waves. In summary, these 5-HT sensors can offer valuable insights regarding the serotonergic system in both health and disease.

Association of hTERT Gene Polymorphism and Colorectal Cancer (CRC) Risk in the Chinese Han Population.

The catalytic subunit telomerase reverse transcriptase (hTERT) is a prerequisite for malignant transformation of human cells. Colorectal cancer (CRC) is a common malignant tumor. The genetic association of hTERT gene rs2853669 and rs2736098 polymorphisms with CRC was surveyed in the Chinese population. Two hundreds patients with CRC and 200 healthy controls were taken for blood sample collection. Sanger sequencing was applied for genotyping. Multiple logistic regression analysis was performed, and odds ratio (OR) together with confidence interval (CI) were calculated to obtain the corresponding association power. Among CRC cases (49.50%), hTERT gene rs2736098 GA genotype carriers were more prevalent compared with the control group (41.00%, P = 0.035), which increased the risk of CRC by 1.576 times (95% CI, 1.031-2.409). Distribution of the rs2736098 genotypes was significantly associated with TNM stage, tumor differentiation, tumor size and lymph node metastasis (P < 0.05). The frequencies of hTERT gene rs2853669 polymorphism were not significantly different between CRC patients and healthy controls. Logistic regression analysis indicated that both body mass index (BMI) and hTERT gene rs2736098 polymorphism remained significantly correlated with CRC susceptibility. The frequencies of hTERT gene rs2853669 polymorphism did not differ significantly between CRC patients and control group (P > 0.05). The hTERT gene rs2736098 polymorphism was correlated with CRC risk in the Chinese Han population, and the GA genotype was a risk element for the onset of CRC.

Integrating chemical similarity and bioequivalence: an overall evaluation of the quality consistency of traditional decoction and dispensing granule decoction of Amomum villosum.

OBJECTIVE: This study aims to investigate the quality consistency between traditional decoction (TD) of Amomum villosum and its dispensing granule decoction (DGD). Fifteen batches of TD and nine batches of dispensing granules (manufactured by A, B, and C) were prepared and evaluated for their consistency. METHODS: Firstly, The chemical similarity of TD and DGD was examined using GC and HPLC, coupled with hierarchical cluster analysis (HCA), criteria importance though intercrieria correlation(CRITIC) weighting method, and principal component analysis (PCA). Secondly, the gastrointestinal motility experiments in mice, along with the CRITIC weighting method, were employed to assess the bioequivalence of TD and DGD of Amomum villosum. Finally, the entropy weight technique-gray relative analysis(GRA) method was used to compare the quality of Amomum villosum decoctions. RESULTS: ①The CRITIC weighting method indicated significantly higher scores for TD than DGD (p < 0.01). HCA and PCA results demonstrated a clear distinction between TD and DGD. ②Gastrointestinal motility test results revealed no significant difference between TD and DGD in other indicators (p > 0.05).③Gray relative analysis results showed that the relative correlation of TD was more significant than that of DGD. CONCLUSION: The chemical composition of DGD and TD differed. The biological activity of DGD-A/B was consistent with that of TD, while the difference between DGD-C and TD was significant. A comprehensive evaluation showed that TD exhibited better quality than DGD. DGD manufacturers should optimize the preparation process to enhance product quality.

Assessing the short-term effects of PM2.5 and O3 on cardiovascular mortality using high-resolution exposure: a time-stratified case cross-over study in Southwestern China.

Air pollution is a major risk factor of cardiovascular disease (CVD). To date, limited studies have estimated the effects of ambient air pollution on CVD mortality using high-resolution exposure assessment, which might fail to capture the spatial variation in exposure and introduce bias in results. Besides, the three-year action plan (TYAP, 2018-2020) was released; thus, the constitution and health effect of air pollutants may have changed. In this study, we estimated the short-term effect exposed to particulate matters with parameter less than 2.5 µm (PM2.5) and ozone (O3) with 0.05° × 0.05° resolution on CVD mortality and measured the influence of TYAP in the associations. We used random forest models with spatial weight matrices to attain high-resolution pollutant concentrations and conditional Poisson regression to assess the relationship between air pollution and cardiovascular mortality. With an increase of 10 µg/m3 in PM2.5 and O3 during 2018-2021 in the Sichuan Basin (SCB), CVD mortality increased 1.0134 (95% CI 1.0102, 1.0166) and 1.0083 (95% CI 1.0060, 1.0107), respectively, using high-resolution air pollutant concentration, comparing to 1.0070 (95% CI 1.0052, 1.0087) and 1.0057 (95% CI 1.0037, 1.0078) using data from air quality monitoring stations (AQMs). After TYAP, the relative risk (RR) due to PM2.5 rose up to 1.0149 (95% CI 1.0054, 1.0243), and the RR due to O3 rose up to 1.0089 (95% CI 1.0030, 1.0148) in Sichuan Province. We found significantly positive association of cardiovascular mortality and air pollution in Sichuan Province. And using high-resolution exposure would be more accurate to estimate the effect of air pollution on CVD. After TYAP, the cardiovascular mortality risk estimation due to PM2.5 decreased in elderly in SCB, and the risk due to O3 increased in Sichuan Province.

A novel holin from an Enterococcus faecalis phage and application in vitro and in vivo.

Enterococcus faecalis, a conditional pathogenic bacterium, is prevalent in the intestinal, oral, and reproductive tracts of humans and animals, causing a variety of infectious diseases. E. faecalis is the main species detected in secondary persistent infection from root canal therapy failure. Due to the abuse of antibacterial agents, E. faecalis has evolved its resistant ability. Therefore, it is difficult to treat clinical diseases infected by E. faecalis. Exploring new alternative drugs for treating E. faecalis infection is urgent. We cloned and expressed the gene of phage holin, purified the recombinant protein, and analyzed the antibacterial activity, lysis profile, and ability to remove bacterial biofilm. It showed that the crude enzyme of phage holin pEF191 exhibited superior bacterial inhibiting activity and a broader lysis host range compared to the parent phage PEf771. In addition, pEF191 demonstrated high efficacy in eliminating E. faecalis biofilm. The therapeutic results of the Sprague-Dawley (SD) rats model infected showed that pEf191 did not affect SD rats, indicating that pEF191 provided greater protection against E. faecalis infection in SD rats. Based on the 16 S rDNA data of SD rats intestinal microorganism population, holin pEF191 exhibited no impact on the diversity of intestinal microorganisms at the phylum and genus levels and improved the relative abundance of favorable bacteria. Thus, pEF191 may serve as a promising alternative to antibiotics in the management of E. faecalis infection.

Research on rapid quality identification method of Panax notoginseng powder based on artificial intelligence sensory technology and multi-source information fusion technology.

Panax notoginseng powder (PNP) has high medicinal value and is widely used in the medical and health food industries. However, the adulteration of PNP in the market has dramatically reduced its efficacy. Therefore, this study intends to use artificial intelligence sensory (AIS) and multi-source information fusion (MIF) technology to try to establish a quality evaluation system for different grades of PNP and adulterated Panax notoginseng powder (AD-PNP). The highest accuracy rate reached 100% in identifying PNP grade and adulteration. In the prediction of adulteration ratio and total saponin content, the optimal determination coefficients of the test set were 0.9965 and 0.9948, respectively, and the root mean square errors were 0.0109 and 0.0123, respectively. Therefore, the grade identification method of PNP and the evaluation system of AD-PNP based on AIS and MIF technology can rapidly and accurately evaluate the quality of PNP.

Spatial distribution and risk assessment of polycyclic aromatic hydrocarbons in soils from contaminated sites in Eastern China.

A total of 16 polycyclic aromatic hydrocarbons (PAHs) were measured in 28 soil column samples from two contaminated industrial sites in Eastern China. The total concentration of 16 PAHs (∑PAHs) in the surface soil (0-20 cm) was measured up to 52,600 ng/g (dry weight basis) with a remarkable spatial difference in the studied contaminated sites. The concentrations of the ∑PAHs in soils decreased with the increase in soil depth (0-10 m). The surface and subsurface soil presented a tenfold higher concentration than the soil with depth greater than 4 m. Additionally, the vertical migration tendency of the PAHs was found to be correlated significantly with their hydrophobicity (R2 = 0.79, P < 0.01). Naphthalene (with lowest octanol-water partition coefficient among the studied PAHs) showed the greatest average soil depth at which its peak concentration occurred. Furthermore, risk quotient analysis by using benzo[a]pyrene as reference compound showed that 71.4% of the samples exhibited high ecological risk for soil. Moreover, the total carcinogenic risk of the PAHs in the surface soil samples was assessed at 5.61 × 10-5-1.28 × 10-4 and 4.41 × 10-6-9.43 × 10-5 for male and female workers, respectively, in which 67.9%-71.4% of the samples showed potential risk. Generally, these results suggest a further consideration of ecological and health risks associated with PAHs in contaminated sites in Eastern China.

Using a novel strategy to investigate the spatially autocorrelated and clustered associations between short-term exposure to PM2.5 and mortality and the attributable burden: A case study in the Sichuan Basin, China.

Due to the lack of statistical methods, few studies have investigated the spatial autocorrelated distribution in the association between short-term exposure to PM2.5 and mortality and used a statistical manner to explore the association-clustered regions, which play important roles in identifying high-sensitivity/susceptibility regions. The Sichuan Basin (SCB) is one of the most PM2.5-polluted areas, and the extreme economic imbalance may cause considerable spatial heterogeneity and clustering in PM2.5-mortality association. In this work, we used a recently proposed strategy by us to investigate the spatially autocorrelated and clustered association between daily PM2.5 and cardiorespiratory mortality from 2015 to 2019 in 130 counties of the SCB. First, generalized additive models were independently constructed to obtain the county-level association estimations. Then, an estimation-error-based spatial scan statistic was used to detect the association-clustered regions. Third, multivariate conditional meta autoregression was used to obtain the spatially autocorrelated association distribution, based on which the attributable deaths were mapped and their inequality was evaluated using the Gini coefficient and Lorenz curve. Results showed that two significantly association-clustered regions were detected. One is mainly located in the megacity Chengdu where PM2.5 presented a significantly stronger association with no threshold effect at low-level PM2.5 but a threshold at high-level PM2.5. In the other cluster, a threshold effect at low-level PM2.5 but no threshold at high-level PM2.5 were found. The mortality risk at low/middle-level PM2.5 decreased from Chengdu as the center to the surrounding areas. A total of 29,129 (2.0 %) deaths were attributable to the excess PM2.5 exposure. The attributable deaths also decreased from Chengdu as the center to the surrounding areas with Gini coefficients of 0.43 and 0.3 for absolute and relative attributable deaths, respectively. This novel strategy provided a new epidemiological perspective regarding the association and implicated that Chengdu is significantly deserving of more attention regarding PM2.5-related health loss.