Real-world effectiveness of early insulin therapy on the incidence of cardiovascular events in newly diagnosed type 2 diabetes.

Early insulin therapy is capable to achieve glycemic control and restore ß-cell function in newly diagnosed type 2 diabetes (T2D), but its effect on cardiovascular outcomes in these patients remains unclear. In this nationwide real-world study, we analyzed electronic health record data from 19 medical centers across China between 1 January 2000, and 26 May 2022. We included 5424 eligible patients (mean age 56 years, 2176 women/3248 men) who were diagnosed T2D within six months and did not have prior cardiovascular disease. Multivariable Cox regression models were used to estimate the associations of early insulin therapy (defined as the first-line therapy for at least two weeks in newly diagnosed T2D patients) with the incidence of major cardiovascular events including coronary heart disease (CHD), stroke, and hospitalization for heart failure (HF). During 17,158 persons years of observation, we documented 834 incident CHD cases, 719 stroke cases, and 230 hospitalized cases for HF. Newly diagnosed T2D patients who received early insulin therapy, compared with those who did not receive such treatment, had 31% lower risk of incident stroke, and 28% lower risk of hospitalization for HF. No significant difference in the risk of CHD was observed. We found similar results when repeating the aforesaid analysis in a propensity-score matched population of 4578 patients and with inverse probability of treatment weighting models. These findings suggest that early insulin therapy in newly diagnosed T2D may have cardiovascular benefits by reducing the risk of incident stroke and hospitalization for HF.

Association between urate-lowering therapy initiation and all-cause mortality in patients with type 2 diabetes and asymptomatic hyperuricemia.

AIMS: To assess the relationships between urate-lowering therapy (ULT) initiation with all-cause mortality in patients with asymptomatic hyperuricemia and Type 2 Diabetes (T2D). METHODS: This nationwide retrospective cohort study involved patients with T2D and asymptomatic hyperuricemia from 19 academic hospitals across China between 2000 and 2021. The primary exposure was ULT initiation, including allopurinol, febuxostat, or benzbromarone. The primary outcome was all-cause mortality. The secondary outcomes were cardiovascular (CV) and non-CV mortality. Propensity score matching was employed to create a 1:2 matched cohort with balanced likelihood of ULT initiation. Associations between ULT initiation with all-cause and CV mortality were assessed in the matched cohort. RESULTS: Among 42 507 patients, 5028 initiated ULT and 37 479 did not. In the matched cohort, comprising 4871 ULT initiators and 9047 noninitiators, ULT initiation was significantly associated with reduced risk of all-cause mortality (hazard ratio [HR] 0.77; 95% confidence interval [CI], 0.71-0.84), CV mortality (HR 0.86; 95% CI, 0.76-0.97), and non-CV mortality (HR 0.72; 95% CI, 0.64-0.80) over an average 3.0 years of follow-up. Among the ULT initiators, post-treatment SUA levels of 360-420 µmol/L was related to a significantly lower risk for all-cause mortality compared to levels >420 µmol/L (HR 0.74; 95% CI, 0.59-0.94) while levels ≤360 µmol/L did not (HR, 0.96; 95% CI, 0.81-1.14), suggesting a U-shaped relationship. CONCLUSIONS: Initiating ULT was associated with a significant reduction in all-cause mortality in patients with T2D and asymptomatic hyperuricemia. Notably, maintaining post-treatment SUA concentrations within 360-420 µmol/L could potentially enhance this reduced mortality.

Mapping global mangrove canopy height by integrating Ice, Cloud, and Land Elevation Satellite-2 photon-counting LiDAR data with multi-source images.

Large-scale and precise measurement of mangrove canopy height is crucial for understanding and evaluating wetland ecosystems' condition, health, and productivity. This study generates a global mangrove canopy height map with a 30 m resolution by integrating Ice, Cloud, and Land Elevation Satellite-2 (ICESat-2) photon-counting light detection and ranging (LiDAR) data with multi-source imagery. Initially, high-quality mangrove canopy height samples were extracted using meticulous processing and filtering of ICESat-2 data. Subsequently, mangrove canopy height models were established using the random forest (RF) algorithm, incorporating ICESat-2 canopy height samples, Sentinel-2 data, TanDEM-X DEM data and WorldClim data. Furthermore, a global 30 m mangrove canopy height map was generated utilizing the Google Earth Engine platform. Finally, the global map's accuracy was evaluated by comparing it with reference canopy heights derived from both space-borne and airborne LiDAR data. Results indicate that the global 30 m resolution mangrove height map was found to be consistent with canopy heights obtained from space-borne (r = 0.88, Bisa = -0.07 m, RMSE = 3.66 m, RMSE% = 29.86 %) and airborne LiDAR (r = 0.52, Bisa = -1.08 m, RMSE = 3.39 m, RMSE% = 39.05 %). Additionally, our findings reveal that mangroves worldwide exhibit an average height of 12.65 m, with the tallest mangrove reaching a height of 44.94 m. These results demonstrate the feasibility and effectiveness of using ICESat-2 data integrated with multi-source imagery to generate a global mangrove canopy height map. This dataset offers reliable information that can significantly support government and organizational efforts to protect and conserve mangrove ecosystems.

Incidence, risk factors, and outcomes of acute liver injury in hospitalized adults with acute kidney injury: a large multicenter study.

BACKGROUND: Acute kidney injury (AKI) and acute liver injury (ALI) were associated with poor outcomes during hospitalization, respectively. However, the clinical outcome of AKI combined with ALI (AKI-ALI) remains unknown. The current study aimed to describe AKI-ALI's incidences, risk factors, and outcomes. METHODS: The study population included patients aged 18-99 years with enough serum creatinine and liver testing hospitalized at 19 medical centers throughout China between 2000 and 2021. AKI was defined by Kidney Disease Improving Global Outcomes and ALI was defined by the change of liver enzymes based on Asia Pacific Association of Study of Liver consensus guidelines. Cox proportional hazard model was used to identify risk factors for AKI-ALI, and a time-dependent Cox proportional hazard regression model was used to estimate the association between AKI-ALI and in-hospital mortality. RESULTS: Among the 18,461 patients with AKI, 1689 (9.1%) combined with ALI. Male patients or those who have used nonsteroidal anti-inflammatory drugs or vasopressors, and who have heart failure or shock, with higher AST or GGT values, were associated with an increased risk of AKI-ALI. Compared with AKI-nonALI, patients with AKI-ALI were at higher risk of in-hospitalized mortality (hazard ratio [HR] 1.76, 95% confidence interval [CI] 1.54, 2.00). In addition, a stronger association between AKI-ALI and in-hospital mortality was found in those with lower AKI grades (p for interaction = 0.037). CONCLUSIONS: ALI was not uncommon among patients with AKI, especially in patients who used vasopressors and had shock. This study highlights the association between AKI-ALI and a significantly increased risk of mortality. It suggests that dynamic monitoring of liver function is essential, particularly in patients with AST and GGT exceeding the normal upper limit, to improve the in-hospital prognosis of AKI patients.

Dipeptidyl peptidase 4 inhibitors vs. metformin for new-onset dementia: a propensity score-matched cohort study.

BACKGROUND: Hypoglycemic pharmacotherapy interventions for alleviating the risk of dementia remains controversial, particularly about dipeptidyl peptidase 4 (DPP4) inhibitors versus metformin. Our objective was to investigate whether the initiation of DPP4 inhibitors, as opposed to metformin, was linked to a reduced risk of dementia. METHODS: We included individuals with type 2 diabetes over 40 years old who were new users of DPP4 inhibitors or metformin in the Chinese Renal Disease Data System (CRDS) database between 2009 and 2020. The study employed Kaplan-Meier and Cox regression for survival analysis and the Fine and Gray model for the competing risk of death. RESULTS: Following a 1:1 propensity score matching, the analysis included 3626 DPP4 inhibitor new users and an equal number of metformin new users. After adjusting for potential confounders, the utilization of DPP4 inhibitors was associated with a decreased risk of all-cause dementia compared to metformin (hazard ratio (HR) 0.63, 95% confidence interval (CI) 0.45-0.89). Subgroup analysis revealed that the utilization of DPP4 inhibitors was associated with a reduced incidence of dementia in individuals who initiated drug therapy at the age of 60 years or older (HR 0.69, 95% CI 0.48-0.98), those without baseline macrovascular complications (HR 0.62, 95% CI 0.41-0.96), and those without baseline microvascular complications (HR 0.67, 95% CI 0.47-0.98). CONCLUSION: In this real-world study, we found that DPP4 inhibitors presented an association with a lower risk of dementia in individuals with type 2 diabetes than metformin, particularly in older people and those without diabetes-related comorbidities.

Single-cell transcriptomics reveals the ameliorative effect of rosmarinic acid on diabetic nephropathy-induced kidney injury by modulating oxidative stress and inflammation.

Diabetic nephropathy (DN) is a severe complication of diabetes, characterized by changes in kidney structure and function. The natural product rosmarinic acid (RA) has demonstrated therapeutic effects, including anti-inflammation and anti-oxidative-stress, in renal damage or dysfunction. In this study, we characterized the heterogeneity of the cellular response in kidneys to DN-induced injury and RA treatment at single cell levels. Our results demonstrated that RA significantly alleviated renal tubular epithelial injury, particularly in the proximal tubular S1 segment and on glomerular epithelial cells known as podocytes, while attenuating the inflammatory response of macrophages, oxidative stress, and cytotoxicity of natural killer cells. These findings provide a comprehensive understanding of the mechanisms by which RA alleviates kidney damage, oxidative stress, and inflammation, offering valuable guidance for the clinical application of RA in the treatment of DN.

Exploring the potential of VGLL3 methylation as a prognostic indicator for intracranial aneurysm with gender-specific considerations.

DNA methylation is widely recognized to play a role in intracranial aneurysm (IA) pathogenesis. We investigated the levels of methylation of vestigial-like 3 (VGLL3) in IA and explored its potential as a prognostic indicator. A total of 48 patients with IA and 48 healthy controls were included in the present study. Methylation levels of CpG sites were assessed using bisulfite pyrosequencing, and levels of VGLL3, TEAD, and YAP in the blood were measured by real-time quantitative polymerase chain reaction testing. VGLL3 methylation was significantly higher in controls than in IA patients (P=0.001), and this phenomenon was more pronounced in females (P<0.001). Compared with the control group, the expression levels of VGLL3 and TEAD in the blood of IA patients were significantly increased, while YAP was significantly decreased. VGLL3 methylation was positively correlated with HDL (P=0.003) and female Lpa concentration (r = 0.426, P=0.03), and was also negatively correlated with age (P=0.003), APOE (P=0.005), and VGLL3 mRNA expression (P<0.001). Methylation and mRNA expression of VGLL3 may serve as indicators of IA risk in females (AUC = 0.810 and 0.809). VGLL3 methylation may participate in the pathogenesis of IA by regulating the expression of the VGLL3/TEAD/YAP pathway, and its gene methylation and expression levels have IA risk prediction value.

Accurate estimation of biological age and its application in disease prediction using a multimodal image Transformer system.

Aging in an individual refers to the temporal change, mostly decline, in the body's ability to meet physiological demands. Biological age (BA) is a biomarker of chronological aging and can be used to stratify populations to predict certain age-related chronic diseases. BA can be predicted from biomedical features such as brain MRI, retinal, or facial images, but the inherent heterogeneity in the aging process limits the usefulness of BA predicted from individual body systems. In this paper, we developed a multimodal Transformer-based architecture with cross-attention which was able to combine facial, tongue, and retinal images to estimate BA. We trained our model using facial, tongue, and retinal images from 11,223 healthy subjects and demonstrated that using a fusion of the three image modalities achieved the most accurate BA predictions. We validated our approach on a test population of 2,840 individuals with six chronic diseases and obtained significant difference between chronological age and BA (AgeDiff) than that of healthy subjects. We showed that AgeDiff has the potential to be utilized as a standalone biomarker or conjunctively alongside other known factors for risk stratification and progression prediction of chronic diseases. Our results therefore highlight the feasibility of using multimodal images to estimate and interrogate the aging process.

Incidence, risk factors and outcome of postoperative acute kidney injury in China.

BACKGROUND: Postoperative acute kidney injury (AKI) is a common condition after surgery, however, the available data about nationwide epidemiology of postoperative AKI in China from large and high-quality studies are limited. This study aimed to determine the incidence, risk factors and outcomes of postoperative AKI among patients undergoing surgery in China. METHODS: This was a large, multicentre, retrospective study performed in 16 tertiary medical centres in China. Adult patients (≥18 years of age) who underwent surgical procedures from 1 January 2013 to 31 December 2019 were included. Postoperative AKI was defined by the Kidney Disease: Improving Global Outcomes creatinine criteria. The associations of AKI and in-hospital outcomes were investigated using logistic regression models adjusted for potential confounders. RESULTS: Among 520 707 patients included in our study, 25 830 (5.0%) patients developed postoperative AKI. The incidence of postoperative AKI varied by surgery type, which was highest in cardiac (34.6%), urologic (8.7%) and general (4.2%) surgeries. A total of 89.2% of postoperative AKI cases were detected in the first 2 postoperative days. However, only 584 (2.3%) patients with postoperative AKI were diagnosed with AKI on discharge. Risk factors for postoperative AKI included older age, male sex, lower baseline kidney function, pre-surgery hospital stay ≤3 days or >7 days, hypertension, diabetes mellitus and use of proton pump inhibitors or diuretics. The risk of in-hospital death increased with the stage of AKI. In addition, patients with postoperative AKI had longer lengths of hospital stay (12 versus 19 days) and were more likely to require intensive care unit care (13.1% versus 45.0%) and renal replacement therapy (0.4% versus 7.7%). CONCLUSIONS: Postoperative AKI was common across surgery type in China, particularly for patients undergoing cardiac surgery. Implementation and evaluation of an alarm system is important for the battle against postoperative AKI.

Impact of ITO layer on the spatial optical distribution of semipolar (20-21) InGaN/GaN multiple quantum wells with surface morphology.

Textured surface with micro-facets have been widely observed in semipolar and nonpolar III-nitride heterostructures, mainly resulted from the anisotropic growth rate in the growth plane. Polarization and the intensity distribution of surface emissions are both affected by the surface morphology. The indium tin oxide (ITO) layer, serving as the current spreading layer, are usually employed to enhance the current injection efficiency and light extraction efficiency in III-nitride emitters. For semipolar orientation, the introduction of an ITO layer could weaken the anisotropic optical property, especially for the spatial intensity distribution. This paper reports the influence of the ITO layer on the spatial intensity distribution of semipolar (20-21) InGaN/GaN multiple quantum wells. The intensity distribution could be shaped from a rectangular-like pattern to a circular-like pattern with the deposition of an ITO layer. The ITO layer allows more light along the [11-20] direction to emit out at a small angle with respect to the surface normal. By further increasing the ITO thickness, the influence of surface fluctuation of semipolar sample decreases, leading to an improvement in the proportion of the light at small angles and a slight decrease in the overall integrated intensity of whole far field. These results will help pave the way to high-performance semipolar emitters with great potential in general illumination and backlighting.

Post-treatment level of LDL cholesterol and all-cause mortality in patients with atherosclerotic cardiovascular disease: evidence from real-world setting.

AIMS: This study aimed to evaluate the safety of the currently recommended target of LDL cholesterol (LDL-C) control on mortality in patients with atherosclerotic cardiovascular disease (ASCVD). METHODS AND RESULTS: Using deidentified electronic health record data, we conducted a multicentre retrospective cohort study involving individuals with documented ASCVD who had received statin treatment for at least 3 months across China. The primary outcomes assessed encompassed all-cause mortality, CV mortality, and non-CV mortality. Relationships between post-treatment LDL-C concentrations and outcomes were evaluated using restricted cubic spline curves based on Cox proportional hazards regression analyses. Additionally, competitive risk models were employed to explore associations between LDL-C levels and cause-specific mortality. Among 33 968 participants, we identified nearly linear associations of post-treatment LDL-C level with all-cause mortality and CV mortality during a median follow-up of 47 months. Notably, patients who achieved the recommended target of LDL-C (<1.4 mmol/L) were at significantly lower risks of all-cause mortality [hazard ratio (HR), 0.77; 95% confidence interval (CI), 0.69-0.86] and CV mortality (subdistribution HR, 0.68; 95% CI, 0.58-0.79), compared with those with LDL-C ≥ 3.4 mmol/L. This survival benefit was consistent in patients with different intensities of LDL-C reduction and other subgroup analyses. And no correlation was found between post-treatment LDL-C concentration and non-CV mortality. CONCLUSION: Our findings supported the safety of currently recommended target of LDL-C control and the 'lower is better' principle in patients with ASCVD.

Intensive control of LDL cholesterol (LDL-C) has been widely recommended for cardiovascular (CV) protection in patients with atherosclerotic CV disease. Nevertheless, a U-shaped association between LDL-C levels and all-cause mortality has been noted in several general population studies, prompting concerns regarding the safety of intensive lipid control. In this multicentre cohort comprising 33 968 patients at the highest CV risk, we found that patients with lower post-treatment LDL-C level were at lower risk of both all-cause and CV mortality, and this survival benefit was unaffected by intensity of LDL-C reduction, types of lipid-lowering agents, and other clinical characteristics.

Risk of Hospital-Acquired Acute Kidney Injury among Adult Opioid Analgesic Users: A Multicenter Real-World Data Analysis.

Introduction: Comprehensive data on the risk of hospital-acquired (HA) acute kidney injury (AKI) among adult users of opioid analgesics are lacking. This study aimed to systematically compare the risk of HA-AKI among the users of various opioid analgesics. Methods: This multicenter, retrospective real-world study analyzed 255,265 adult hospitalized patients who received at least one prescription of opioid analgesic during the first 30 days of hospitalization. The primary outcome was the time from the first opioid analgesic prescription to HA-AKI occurrence. 12 subtypes of opioid analgesics were analyzed, including 9 for treating moderate-to-severe pain and 3 for mild-to-moderate pain. We examined the association between the exposure to each subtype of opioid analgesic and the risk of HA-AKI using Cox proportional hazards models, using the most commonly used opioid analgesic as the reference group. Results: As compared to dezocine, the most commonly used opioid analgesic for treating moderate-to-severe pain, exposure to morphine, but not the other 7 types of opioid analgesics, was associated with a significantly increased risk of HA-AKI (adjusted hazard ratio: 1.56, 95% confidence interval: 1.40-1.78). The association was consistent in stratified analyses and in a propensity-matched cohort. There were no significant differences in the risk of HA-AKI among the opioid analgesic users with mild-to-moderate pain after adjusting for confounders. Conclusion: The use of morphine was associated with an increased risk of HA-AKI in adult patients with moderate-to-severe pain. Opioid analgesics other than morphine should be chosen preferentially in adult patients with high risk of HA-AKI when treating moderate-to-severe pain.

Epidemiology and outcomes of post-AKI proteinuria.

Background: Acute kidney injury (AKI) has been associated with increased risks of new-onset and worsening proteinuria. However, epidemiologic data for post-AKI proteinuria was still lacking. This study aimed to determine the incidence, risk factors and clinical correlations of post-AKI proteinuria among hospitalized patients. Methods: This study was conducted in a multicenter cohort including patients aged 18-100 years with hospital-acquired AKI (HA-AKI) hospitalized at 19 medical centers throughout China. The primary outcome was the incidence of post-AKI proteinuria. Secondary outcomes included AKI recovery and kidney disease progression. The results of both quantitative and qualitative urinary protein tests were used to define post-AKI proteinuria. Cox proportional hazard model with stepwise regression was used to determine the risk factors for post-AKI proteinuria. Results: Of 6206 HA-AKI patients without proteinuria at baseline, 2102 (33.9%) had new-onset proteinuria, whereas of 5137 HA-AKI with baseline proteinuria, 894 (17.4%) had worsening proteinuria after AKI. Higher AKI stage and preexisting CKD diagnosis were risk factors for new-onset proteinuria and worsening proteinuria, whereas treatment with renin-angiotensin system inhibitors was associated with an 11% lower risk of incident proteinuria. About 60% and 75% of patients with post-AKI new-onset and worsening proteinuria, respectively, recovered within 3 months. Worsening proteinuria was associated with a lower incidence of AKI recovery and a higher risk of kidney disease progression. Conclusions: Post-AKI proteinuria is common and usually transient among hospitalized patients. The risk profiles for new-onset and worsening post-AKI proteinuria differed markedly. Worsening proteinuria after AKI was associated with adverse kidney outcomes, which emphasized the need for close monitoring of proteinuria after AKI.

Biological effects and mechanisms of fisetin in cancer: a promising anti-cancer agent.

Fisetin, a natural flavonoid, possesses numerous biological activities that have been extensively studied in various diseases. When it comes to cancer, fisetin exhibits a range of biological effects, such as suppressing cell growth, triggering programmed cell death, reducing the formation of new blood vessels, protecting against oxidative stress, and inhibiting cell migration. Moreover, fisetin has the ability to enhance the effectiveness of chemotherapy. The anticancer properties of fisetin can be attributed to a diverse array of molecules and signaling pathways, including vascular endothelial growth factor (VEGF), mitogen-activated protein kinase (MAPK), nuclear factor-kappa B (NF-κB), PI3K/Akt/mTOR, and Nrf2/HO-1. Consequently, fisetin holds promise as a therapeutic agent for anticancer treatment. In this review, we place emphasis on the biological functions and various molecular targets of fisetin in anticancer therapy.

Immunosuppression versus Supportive Care on Kidney Outcomes in IgA Nephropathy in the Real-World Setting.

BACKGROUND: The efficacy of immunosuppression in the management of immunoglobulin A (IgA) nephropathy remains highly controversial. The study was conducted to assess the effect of immunosuppression, compared with supportive care, in the real-world setting of IgA nephropathy. METHODS: A cohort of 3946 patients with IgA nephropathy, including 1973 new users of immunosuppressive agents and 1973 propensity score-matched recipients of supportive care, in a nationwide register data from January 2019 to May 2022 in China was analyzed. The primary outcome was a composite of 40% eGFR decrease of the baseline, kidney failure, and all-cause mortality. A Cox proportional hazard model was used to estimate the effects of immunosuppression on the composite outcomes and its components in the propensity score-matched cohort. RESULTS: Among 3946 individuals (mean [SD] age 36 [10] years, mean [SD] eGFR 85 [28] ml/min per 1.73 m 2 , and mean [SD] proteinuria 1.4 [1.7] g/24 hours), 396 primary composite outcome events were observed, of which 156 (8%) were in the immunosuppression group and 240 (12%) in the supportive care group. Compared with supportive care, immunosuppression treatment was associated with 40% lower risk of the primary outcome events (adjusted hazard ratio, 0.60; 95% confidence interval, 0.48 to 0.75). Comparable effect size was observed for glucocorticoid monotherapy and mycophenolate mofetil alone. In the prespecified subgroup analysis, the treatment effects of immunosuppression were consistent across ages, sexes, levels of proteinuria, and values of eGFR at baseline. Serious adverse events were more frequent in the immunosuppression group compared with the supportive care group. CONCLUSIONS: Immunosuppressive therapy, compared with supportive care, was associated with a 40% lower risk of clinically important kidney outcomes in patients with IgA nephropathy.

Predicting in-hospital outcomes of patients with acute kidney injury.

Acute kidney injury (AKI) is prevalent and a leading cause of in-hospital death worldwide. Early prediction of AKI-related clinical events and timely intervention for high-risk patients could improve outcomes. We develop a deep learning model based on a nationwide multicenter cooperative network across China that includes 7,084,339 hospitalized patients, to dynamically predict the risk of in-hospital death (primary outcome) and dialysis (secondary outcome) for patients who developed AKI during hospitalization. A total of 137,084 eligible patients with AKI constitute the analysis set. In the derivation cohort, the area under the receiver operator curve (AUROC) for 24-h, 48-h, 72-h, and 7-day death are 95·05%, 94·23%, 93·53%, and 93·09%, respectively. For dialysis outcome, the AUROC of each time span are 88·32%, 83·31%, 83·20%, and 77·99%, respectively. The predictive performance is consistent in both internal and external validation cohorts. The model can predict important outcomes of patients with AKI, which could be helpful for the early management of AKI.

Cytotoxicity of 4 Wild Mushrooms in a Case of Yunnan Sudden Unexplained Death.

OBJECTIVES: To explore the cytotoxicity of four wild mushrooms involved in a case of Yunnan sudden unexplained death (YNSUD), to provide the experimental basis for prevention and treatment of YNSUD. METHODS: Four kinds of wild mushrooms that were eaten by family members in this YNSUD incident were collected and identified by expert identification and gene sequencing. Raw extracts from four wild mushrooms were extracted by ultrasonic extraction to intervene HEK293 cells, and the mushrooms with obvious cytotoxicity were screened by Cell Counting Kit-8 (CCK-8). The selected wild mushrooms were prepared into three kinds of extracts, which were raw, boiled, and boiled followed by enzymolysis. HEK293 cells were intervened with these three extracts at different concentrations. The cytotoxicity was detected by CCK-8 combined with lactate dehydrogenase (LDH) Assay Kit, and the morphological changes of HEK293 cells were observed under an inverted phase contrast microscope. RESULTS: Species identification indicated that the four wild mushrooms were Butyriboletus roseoflavus, Boletus edulis, Russula virescens and Amanita manginiana. Cytotoxicity was found only in Amanita manginiana. The raw extracts showed cytotoxicity at the mass concentration of 0.1 mg/mL, while the boiled extracts and the boiled followed by enzymolysis extracts showed obvious cytotoxicity at the mass concentration of 0.4 mg/mL and 0.7 mg/mL, respectively. In addition to the obvious decrease in the number of HEK293 cells, the number of synapses increased and the refraction of HEK293 cells was poor after the intervention of Amanita manginiana extracts. CONCLUSIONS: The extracts of Amanita manginiana involved in this YNSUD case has obvious cytotoxicity, and some of its toxicity can be reduced by boiled and enzymolysis, but cannot be completely detoxicated. Therefore, the consumption of Amanita manginiana is potentially dangerous, and it may be one of the causes of the YNSUD.

Extracellular vesicles released by glioma cells are decorated by Annexin A2 allowing for cellular uptake via heparan sulfate.

Extracellular vesicles (EVs) play a crucial role in regulating cell behavior by delivering their cargo to target cells. However, the mechanisms underlying EV-cell interactions are not well understood. Previous studies have shown that heparan sulfate (HS) on target cell surfaces can act as receptors for exosomes uptake, but the ligand for HS on EVs has not been identified. In this study, we isolated EVs from glioma cell lines and glioma patients and identified Annexin A2 (AnxA2) on EVs as a key HS-binding ligand and mediator of EV-cell interactions. Our findings suggest that HS plays a dual role in EV-cell interactions, where HS on EVs captures AnxA2, and on target cells, it acts as a receptor for AnxA2. Removal of HS from the EV surface inhibits EV-target cell interaction by releasing AnxA2. Furthermore, we found that AnxA2-mediated binding of EVs to vascular endothelial cells promotes angiogenesis, and that antibody against AnxA2 inhibited the ability of glioma-derived EVs to stimulate angiogenesis by reducing the uptake of EVs. Our study also suggests that the AnxA2-HS interaction may accelerate the glioma-derived EVs-mediated angiogenesis and that combining AnxA2 on glioma cells with HS on endothelial cells may effectively improve the prognosis evaluation of glioma patients.