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Emodin has recently been reported to have a powerful antiinflammatory effect, protecting the myocardium against ischemia/reperfusion (I/R) injury. Pyroptosis is a proinflammatory programmed cell death that is related to many diseases. The present study investigated the effect of emodin on pyroptosis in cardiomyocytes. Sprague Dawley rats were randomly divided into sham, I/R, and I/R+Emodin groups. I/R model was subjected to 30 minutes' ligation of left anterior descending coronary artery, followed by 2 hours of reperfusion. Cardiomyocytes were exposed to hypoxic conditions for 1 hour and normoxic conditions for 2 hours. The level of the pyroptosis was detected by Western blot, real-time PCR analysis, and ELISA. The level of gasdermin D-N domains was upregulated in cardiomyocytes during I/R or hypoxia/reoxygenation (H/R) treatment. Moreover, emodin increased the rate of cell survival in vitro and decreased the myocardial infarct size in vivo via suppressing the levels of I/R-induced pyroptosis. Additionally, the expression of TLR4, MyD88, phospho-IκBα, phospho-NF-κB, and the NLRP3 inflammasome was significantly upregulated in cardiomyocytes subjected to H/R treatment, while emodin suppressed the expression of these proteins. This study confirms that emodin treatment was able to alleviate myocardial I/R injury and inhibit pyroptosis in vivo and in vitro. The inhibitory effect of emodin on pyroptosis was mediated by suppressing the TLR4/MyD88/NF-κB/NLRP3 inflammasome pathway. Therefore, emodin may provide an alternative treatment for myocardial I/R injury.

Background This study investigated the relationships of neutrophil count (NC), neutrophil-to-lymphocyte ratio (NLR) and systemic immune-inflammation index (SII) with cerebral small vessel disease (CSVD). Methods A total of 3052 community-dwelling residents from the Poly-vasculaR Evaluation for Cognitive Impairment and vaScular Events (PRECISE) study were involved in this cross-sectional study. CSVD burden and imaging markers, including white matter hyperintensity (WMH), lacunes, cerebral microbleeds (CMBs) and enlarged perivascular spaces in basal ganglia (BG-EPVS), were assessed according to total CSVD burden score. The associations of NC, NLR and SII with CSVD and imaging markers were evaluated using logistic regression models. Furthermore, two-sample Mendelian randomization (MR) analysis was performed to investigate the genetically predicted effect of NC on CSVD. The prognostic performances of NC, NLR and SII for the presence of CSVD were assessed. Results At baseline, the mean age was 61.2 ± 6.7 years, and 53.5% of the participants were female. Higher NC was suggestively associated with increased total CSVD burden and modified total CSVD burden (Q4 vs. Q1: common odds ratio (cOR) 1.33, 95% CI 1.05–1.70; cOR 1.28, 95% CI 1.02–1.60) and marginally correlated with the presence of CSVD (OR 1.29, 95% CI 1.00–1.66). Furthermore, elevated NC was linked to a higher risk of lacune (OR 2.13, 95% CI 1.25–3.62) and moderate-to-severe BG-EPVS (OR 1.67, 95% CI 1.14–2.44). A greater NLR was related to moderate-to-severe BG-EPVS (OR 1.68, 95% CI 1.16–2.45). Individuals with a higher SII had an increased risk of modified WMH burden (OR 1.35, 95% CI 1.08–1.69) and moderate-to-severe BG-EPVS (OR 1.70, 95% CI 1.20–2.41). MR analysis showed that genetically predicted higher NC was associated with an increased risk of lacunar stroke (OR 1.20, 95% CI 1.04–1.39) and small vessel stroke (OR 1.21, 95% CI 1.06–1.38). The addition of NC to the basic model with traditional risk factors improved the predictive ability for the presence of CSVD, as validated by the net reclassification index and integrated discrimination index (all p  < 0.05). Conclusions This community-based population study found a suggestive association between NC and CSVD, especially for BG-EPVS and lacune, and provided evidence supporting the prognostic significance of NC.

MicroRNAs and autophagy play critical roles in cardiac hypoxia/reoxygenation (H/R)‐induced injury. Here, we investigated the function of miR‐21 in regulating autophagy and identified the potential molecular mechanisms involved. To determine the role of miR‐21 in regulating autophagy, H9c2 cells were divided into the following six groups: control group, H/R group, (miR‐21+ H/R) group, (miR‐21‐negative control + H/R) group, (BEZ235+ H/R) group and (miR‐21+ BEZ235+ H/R) group. The cells underwent hypoxia for 1 hr and reoxygenation for 3 hrs. Cell count kit‐8 was used to evaluate cell function and apoptosis was analysed by Western blotting. Western blotting and transmission electron microscopy were used to investigate autophagy. We found that miR‐21 expression was down‐regulated, and autophagy was remarkably increased in H9c2 cells during H/R injury. Overexpression of miR‐21 with a miR‐21 precursor significantly inhibited autophagic activity and decreased apoptosis, accompanied by the activation of the AKT/mTOR pathway. In addition, treatment with BEZ235, a novel dual Akt/mTOR inhibitor, resulted in a significant increase in autophagy and apoptosis. However, we found that miR‐21‐mediated inhibition of apoptosis and autophagy was partly independent of Akt/mTOR activation, as demonstrated in cells treated with both miR‐21 and BEZ235. We showed that miR‐21 could inhibit H/R‐induced autophagy and apoptosis, which may be at least partially mediated by the Akt/mTOR signalling pathway.

Variability of neuronal activity is considered as the fundamental mechanism for the flexible and optimal brain function. Moreover, different frequency neuro signal is related to specific function. While little is currently known regarding changes in spontaneous BOLD variability of schizophrenia. The current study used resting-state fMRI data from 53 chronic schizophrenic subjects and 67 healthy subjects to investigate this issue. The data-driven method was used to measure the BOLD variability (MSSD: mean square successive difference) in two different frequency bands respectively (slow-5: 0.01–0.027 Hz; slow-4:0.027–0.073 Hz). Schizophrenic subjects exhibited decreased BOLD variability in thalamus region, sensorimotor and visual networks, and increased BOLD variability in salience network compared to matched healthy controls. Moreover, the interaction effects between frequency and group were observed in thalamus and right dorsolateral prefrontal cortex (DLPFC). These findings identified that altered BOLD variability is frequency dependent in schizophrenia. Importantly, the severity of patients’ negative symptom was related to the increased BOLD variability of DLPFC within slow-4 frequency band, highlighting the evidence that abnormal BOLD variability of frontal cortex is likely to have effects on the pathophysiology of negative symptom in schizophrenia.

With the continuous development of China’s economy and the acceleration of urbanization, the phenomenon of high-quality cultivated land being converted to construction land is becoming increasingly prominent. In mountainous provinces such as Yunnan, the contradiction between cultivated land protection and blind expansion of construction land is becoming increasingly obvious. Based on the characteristic region of the mountainous province of Yunnan, this paper integrates remote sensing image interpretation of land use/land cover data in three phases (i.e., 2000, 2010, and 2020) with GIS technology and econometric methods. Through the interpretation of remote sensing images from 3 phases of Yunnan Province, a detailed calculation was conducted on the per capita cultivated land area (CULA) and per capita construction land area (COLA) and their changes in 129 counties in the province over the past 20 years (2000~2020). The spatiotemporal evolution laws and spatial pattern characteristics of CULA and COLA were analyzed, and then, the influencing factors in the quantitative characteristics of cultivated land and construction land in the province were studied further by using spatial econometric models. This study finds that the total and per capita CULA in Yunnan Province have significantly decreased over the past 20 years, which poses a threat to the national food security to a certain extent. At the same time, the total amounts of COLA and the per capita COLA have significantly increased, leading to the phenomenon of blind expansion and rough utilization of construction land. Compared with international research results, Yunnan can learn many lessons about controlling the reduction in CULA and the rapid expansion of COLA, among which the most important thing is to choose suitable urban and industrial development paths and adopt effective intensive land utilization methods. The research results of this study can provide a basic reference for mountainous provinces to formulate reasonable measures for cultivated land protection, prevent the disorderly expansion of construction land, and promote the coordinated development of urban and rural areas.

In the NOD-like receptor (NLR) family, the pyrin domain containing 3 (NLRP3) inflammasome is closely related to the progression of atherosclerosis. This study aimed to assess the effects of curcumin on NLRP3 inflammasome in phorbol 12-myristate 13-acetate (PMA)-induced macrophages and explore its underlying mechanism. Human monocytic THP-1 cells were pretreated with curcumin for 1 h and subsequently induced with PMA for 48 h. Total protein was collected for Western blot analysis. Cytokine interleukin (IL)-1β release and nuclear factor kappa B (NF-κB) p65 translocation were detected by ELISA assay and cellular NF-κB translocation kit, respectively. Curcumin significantly reduced the expression of NLRP3 and cleavage of caspase-1 and IL-1β secretion in PMA-induced macrophages. Moreover, Bay (a NF-κB inhibitor) treatment considerably suppressed the expression of NLRP3 inflammasome in PMA-induced THP-1 cells. Curcumin also markedly inhibited the upregulation of toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), phosphorylation level of IκB-α, and activation of NF-κB in PMA-induced macrophages. In addition, purinergic 2X7 receptor (P2X7R) siRNA was administered, and it significantly decreased NLRP3 inflammasome expression in PMA-induced macrophages. Furthermore, curcumin reversed PMA-stimulated P2X7R activation, which further reduced the expression of NLRP3 and cleavage of caspase-1 and IL-1β secretion. Silencing of P2X7R using siRNA also suppressed the activation of NF-κB pathway in PMA-induced macrophages, but P2X7R-silenced cells did not significantly decrease the expression of TLR4 and MyD88. Curcumin inhibited NLRP3 inflammasome through suppressing TLR4/MyD88/NF-κB and P2X7R pathways in PMA-induced macrophages.

ObjectiveThis study aims to investigate the associations of glymphatic system with the presence, severity and neuroimaging phenotypes of cerebral small vessel disease (CSVD) in a community-based population.MethodThis report included 2219 community-dwelling people aged 50–75 years who participated in the PolyvasculaR Evaluation for Cognitive Impairment and vaScular Events cohort. The diffusivity along perivascular spaces based on diffusion tensor imaging (DTI-ALPS index) was measured to assess glymphatic pathway. The presence and severity of CSVD were estimated using a CSVD score (points from 0 to 6) and a modified CSVD score (points from 0 to 4), which were driven by 4 neuroimaging features of CSVD, including white matter hyperintensity (WMH), enlarged perivascular spaces (EPVS), lacunes, cerebral microbleeds. Brain atrophy (BA) was also evaluated. Binary or ordinal logistic regression analyses were carried out to investigate the relationships of DTI-ALPS index with CSVD.ResultThe mean age was 61.3 (SD 6.6) years, and 1019 (45.9%) participants were men. The average DTI-ALPS index was 1.67±0.14. Individuals in the first quartile (Q1) of the DTI-ALPS index had higher risks of the presence of CSVD (OR 1.77, 95% CI 1.33 to 2.35, p<0.001), modified presence of CSVD (odds ratio (OR) 1.80, 95% CI 1.38 to 2.34, p<0.001), total burden of CSVD (common OR (cOR) 1.89, 95% CI 1.43 to 2.49, p<0.001) and modified total burden of CSVD (cOR 1.95, 95% CI 1.51 to 2.50, p<0.001) compared with those in the fourth quartile (Q4). Additionally, individuals in Q1 of the DTI-ALPS index had increased risks of WMH burden, modified WMH burden, lacunes, basal ganglia-EPVS and BA (all p<0.05).ConclusionA lower DTI-ALPS index underlay the presence, severity and typical neuroimaging markers of CSVD, implying that glymphatic impairment may interact with CSVD-related pathology in the general ageing population.Trial registration numberNCT03178448.

Worry is a form of repetitive negative thought. High worry-proneness is one risk factor leading to anxiety disorder. Several types of research indicated that anxiety disorder was highly associated with disrupted interoception. The insula is consistently considered to play a key role in interoception. However, the relationship between worry and the interoception network is poorly investigated in worry-prone individuals. Thus, it is essential to identify the neural characteristic of high worry-proneness subjects. A total of 32 high worry-proneness (HWP) subjects and 25 low worry-proneness (LWP) subjects were recruited and underwent magnetic resonance imaging scanning. Six subregions of insula were chosen as regions of interest. Then, seed-based static and dynamic functional connectivity were calculated. Increased static functional connectivity was observed between the ventral anterior insula and inferior parietal lobule in HWP compared to LWP. Decreased static functional connectivity was found between the left ventral anterior insula and the pregenual anterior cingulate cortex. Decreased dynamic functional connectivity was also shown between the right posterior insula and the inferior parietal lobule in HWP. Moreover, a post-hoc test exploring the effect of changed function within the insular region confirmed that a significant positive relationship between static functional connectivity (ventral anterior insula–inferior parietal lobule) and dynamic functional connectivity (posterior insula–inferior parietal lobule) in LWP but not in HWP. Our results might suggest that deficient insular function may be an essential factor related to high worry in healthy subjects.

Background Insulin resistance is an important cause of cardiovascular events and cerebral infarction development. We aimed to investigate the association of the triglyceride glucose (TyG) index with atherosclerotic burden and plaques in coronary, intra- and extracranial arteries in participants with non-diabetes, and compared the results with that of the homeostasis model assessment of insulin resistance (HOMA-IR). Methods Participants without diabetes in the PolyvasculaR Evaluation for Cognitive Impairment and vaScular Events (PRECISE) study were included. We categorized participants by tertiles of the TyG index and the concordance/discordance of the TyG index and HOMA-IR. Discordance was defined as a TyG index equal to or greater than the median and HOMA-IR less than the median, or vice versa. The atherosclerosis plaques and burden in coronary, intra- and extracranial arteries were evaluated. The association of HOMA-IR and TyG index with the presence of atherosclerotic plaques and atherosclerotic burden was assessed by binary and ordinal logistic regression models, respectively. Results Among 2,719 included participants, the average age was 60.9 (± 6.6) years, and 53.0% were female. Both TyG index and HOMA-IR were associated with increased odds of coronary/intra- and extracranial atherosclerotic plaques and burden after adjustment for age, sex, currenting smoking and drinking (all P < 0.05). However, the association between HOMA-IR and intracranial atherosclerosis was not statistically significant after adjustment for all potential confounders. Discordantly high TyG index with HOMA-IR had a higher odd of extracranial plaque (odds ratio [OR]: 1.34, 95% confidence interval [CI]: 1.04–1.71), extracranial atherosclerotic burden (common odds ratio [cOR]: 1.35, 95% CI 1.06–1.71), coronary plaque (OR: 1.30, 95% CI 1.01–1.68) and segment stenosis score (cOR: 1.39, 95% CI 1.09–1.78) as compared with concordantly low TyG index with HOMA-IR. The TyG index had a better net reclassification improvement ability than HOMA-IR for atherosclerotic plaques when adding to baseline model. Conclusion Elevated TyG index was associated with increased odds of atherosclerosis in coronary/intra- and extracranial arteries. Compared with HOMA-IR, the TyG index was more strongly associated with intracranial atherosclerosis. Moreover, discordantly high TyG index with HOMA-IR was also important for atherosclerosis identification.

BackgroundThe heterogeneity of cerebral small vessel disease (CSVD) within community populations remains underexplored. In this study, we aimed to establish an imaging biomarker-based research paradigm to investigate CSVD heterogeneity and assess differences in progression risk among population subgroups.MethodsThis study is a population-based prospective cohort that included participants aged 50–75 years from the Polyvascular Evaluation for Cognitive Impairment and Vascular Events study. Participants underwent two follow-up evaluations, with continuous monitoring for incident vascular events and mortality. Imaging markers, including white matter hyperintensities (WMH), lacunes, enlarged perivascular spaces (EPVS) and cerebral microbleeds (CMB) were rated on cranial MRI. Automated pipelines quantified WMH volume, and cognitive function was assessed using the Montreal Cognitive Assessment. K-means clustering identified subgroups with distinct CSVD imaging features. Mixed linear regression models predicted imaging progression and cognitive decline. Internal and external validation were performed using cross-validation and outcome-based Cox proportional hazards models, respectively.ResultsAmong 2332 participants, four distinct CSVD subgroups were identified. Subgroup 1 exhibited a globally high imaging burden, the greatest vascular risk factor load, and was classified as a high-risk, rapidly progressing arteriolosclerosis subtype. Subgroup 2 demonstrated a high lacune/CMB burden, moderate EPVS severity, low WMH load, few risk factors and elevated high high-density lipoprotein cholesterol levels, representing a protected, slowly progressing subtype. Subgroup 3 showed low lacune/CMB counts, moderate WMH and EPVS burden, multiple risk factors and prevalent renal impairment, forming a high-risk, rapidly progressing renal impairment subtype. Subgroup 4 presented moderate WMH burden, high lacune/CMB counts, low EPVS severity, the lowest risk profile and was identified as a global low-risk, slowly progressing subtype.ConclusionsCluster analysis effectively delineated heterogeneous CSVD subgroups in a community population, each exhibiting distinct progression risks. Imaging-based heterogeneity profiling may support population risk stratification and guide targeted intervention strategies.