Platelet Membrane-Coated Curcumin-PLGA Nanoparticles Promote Astrocyte-Neuron Transdifferentiation for Intracerebral Hemorrhage Treatment.

Intracerebral hemorrhage (ICH) is a hemorrhagic disease with high mortality and disability rates. Curcumin is a promising drug for ICH treatment due to its multiple biological activities, but its application is limited by its poor watersolubility and instability. Herein, platelet membrane-coated curcumin polylactic-co-glycolic acid (PLGA) nanoparticles (PCNPs) are prepared to achieve significantly improved solubility, stability, and sustained release of curcumin. Fourier transform infrared spectra and X-ray diffraction assays indicate good encapsulation of curcumin within nanoparticles. Moreover, it is revealed for the first time that curcumin-loaded nanoparticles can not only suppress hemin-induced astrocyte proliferation but also induce astrocytes into neuron-like cells in vitro. PCNPs are used to treat rat ICH by tail vein injection, using in situ administration as control. The results show that PCNPs are more effective than curcumin-PLGA nanoparticles in concentrating on hemorrhagic lesions, inhibiting inflammation, suppressing astrogliosis, promoting neurogenesis, and improving motor functions. The treatment efficacy of intravenously administered PCNPs is comparable to that of in situ administration, indicating a good targeting effect of PCNPs on the hemorrhage site. This study provides a potent treatment for hemorrhagic injuries and a promising solution for efficient delivery of water-insoluble drugs using composite materials of macromolecules and cell membranes.

Prognostic implications of systemic immune-inflammation index in myocardial infarction patients with and without diabetes: insights from the NOAFCAMI-SH registry.

BACKGROUND: It is well-known that systemic inflammation plays a crucial role in the pathogenesis and prognosis of acute myocardial infarction (AMI). The systemic immune-inflammation index (SII, platelet × neutrophil/lymphocyte ratio) is a novel index that is used for the characterization of the severity of systemic inflammation. Recent studies have identified the high SII level as an independent predictor of poor outcomes in patients with AMI. We aimed to investigate the prognostic implications of SII in AMI patients with and without diabetes mellitus (DM). METHODS: We included 2111 patients with AMI from February 2014 to March 2018. Multivariable Cox regression analyses were performed to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of all-cause death and cardiovascular (CV) death. Multiple imputation was used for missing covariates. RESULTS: Of 2111 patients (mean age: 65.2 ± 12.2 years, 77.5% were males) analyzed, 789 (37.4%) had DM. Generalized additive model analyses showed that as the SII increased, the C-reactive protein and peak TnT elevated while the LVEF declined, and these associations were similar in patients with and without DM. During a median of 2.5 years of follow-up, 210 all-cause deaths and 154 CV deaths occurred. When treating the SII as a continuous variable, a higher log-transformed SII was significantly associated with increased all-cause mortality (HR: 1.57, 95%CI: 1.02-2.43) and CV mortality (HR: 1.85, 95%CI 1.12-3.05), and such an association was also significant in the diabetics (HRs and 95%CIs for all-cause death and CV death were 2.90 [1.40-6.01] and 3.28 [1.43-7.57], respectively) while not significant in the nondiabetics (Pinteraction for all-cause death and CV death were 0.019 and 0.049, respectively). Additionally, compared to patients with the lowest tertiles of SII, those with the highest tertiles of SII possessed significantly higher all-cause mortality (HR: 1.82, 95%CI 1.19-2.79) and CV mortality (HR: 1.82, 95%CI 1.19-2.79) after multivariable adjustment, and this relationship remained pronounced in the diabetics (HRs and 95%CIs for all-cause death and CV death were 2.00 [1.13-3.55] and 2.09 [1.10-3.98], respectively) but was not observed in the nondiabetics (HRs and 95%CIs for all-cause death and CV death were 1.21 [0.75-1.97] and 1.60 [0.89-2.90], respectively). Our restricted cubic splines analyses indicated a pronounced linear association between SII and mortality only in diabetics. CONCLUSIONS: In AMI patients with DM, high SII is an independent predictor of poor survival and may be helpful for patient's risk stratification.

Long-term changes in frailty and incident type 2 diabetes: A prospective cohort study based on the UK Biobank.

AIMS: To estimate the association between long-term changes in frailty and the risk of incident type 2 diabetes (T2DM) and to evaluate the effect of preventing the worsening of frailty on the risk of T2DM. METHODS: We included 348 205 participants free of baseline T2DM and with frailty phenotype (FP) data from the UK Biobank; among them, 36 175 had at least one follow-up assessment. According to their FP score, participants were grouped into nonfrailty, prefrailty and frailty groups. Frailty assessed at baseline and at follow-up was used to derive the trajectory of frailty (ΔFP). Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Compared with those in the nonfrailty group at baseline, the HRs of T2DM for the prefrailty and frailty groups were 1.38 (95% CI 1.33-1.43) and 1.69 (95% CI 1.59-1.79), respectively (both p < 0.001), in the multivariable-adjusted model. During a median follow-up of 5.4 years after the final assessment, data for 472 T2DM patients were recorded. A 1-point increase in the final FP was associated with a 25% (95% CI 1.14-1.38; p < 0.001) increased risk of T2DM. For the trajectory of frailty, each 0.5-point/year increase in ΔFP was associated with a 52% (95% CI 1.18-1.97; p < 0.001) greater risk of T2DM, independent of the FP score at baseline. Compared with those that remained in the nonfrailty group, the greatest risk of T2DM over time was prefrailty aggravation (HR 3.03, 95% CI 2.00-4.58; p < 0.001). Using the frailty index did not materially change the results. CONCLUSIONS: Long-term changes in frailty were associated with the risk of incident T2DM, irrespective of baseline frailty status. Preventing the worsening of frailty may reduce T2DM risk.

Differentiating the impact of fine and coarse particulate matter on cause-specific cerebrovascular mortality: An individual-level, case-crossover study.

BACKGROUND AND OBJECTIVES: Many studies suggested that short-term exposure to fine particulate matter (PM2.5) and coarse particulate matter (PM2.5-10) was linked to elevated risk of cerebrovascular disease. However, little is known about the potentially differential effects of PM2.5 and PM2.5-10 on various types of cerebrovascular disease. METHODS: We collected individual cerebrovascular death records for all residents in Shanghai, China from 2005 to 2021. Residential daily air pollution data were predicted from a satellite model. The associations between particulate matters (PM) and cerebrovascular mortality were investigated by an individual-level, time-stratified, case-crossover design. The data was analyzed by the conditional logistic regression combined with the distributed lag model with a maximum lag of 7 days. Furthermore, we explored the effect modifications by sex, age and season. RESULTS: A total of 388,823 cerebrovascular deaths were included. Monotonous increases were observed for mortality of all cerebrovascular diseases except for hemorrhagic stroke. A 10 µg/m3 rise in PM2.5 was related to rises of 1.35% [95% confidence interval (CI): 1.04%, 1.66%] in mortality of all cerebrovascular diseases, 1.84% (95% CI: 1.25%, 2.44%) in ischemic stroke, 1.53% (95% CI: 1.07%, 1.99%) in cerebrovascular sequelae and 1.56% (95% CI: 1.08%, 2.05%) in ischemic stroke sequelae. The excess risk estimates per each 10 µg/m3 rise in PM2.5-10 were 1.47% (95% CI: 1.10%, 1.84%), 1.53% (95% CI: 0.83%, 2.24%), 1.93% (95% CI: 1.38%, 2.49%) and 2.22% (95% CI: 1.64%, 2.81%), respectively. The associations of both pollutants with all cerebrovascular outcomes were robust after controlling for co-pollutants. The associations were greater in females, individuals > 80 years, and during the warm season. CONCLUSIONS: Short-term exposures to both PM2.5 and PM2.5-10 may independently increase the mortality risk of cerebrovascular diseases, particularly of ischemic stroke and stroke sequelae.

Preparation, characterisation, and pharmacodynamic study of myricetin pH-sensitive liposomes.

AIMS: Myricetin (MYR) was incorporated into pH-sensitive liposomes in order to improve its bioavailability and anti-hyperuricemic activity. METHODS: The MYR pH-sensitive liposomes (MYR liposomes) were prepared using thin film dispersion method, and assessed by particle size (PS), polydispersed index (PDI), zeta potential (ZP), encapsulation efficiency, drug loading, and in vitro release rate. Pharmacokinetics and anti-hyperuricemic activities were also evaluated. RESULTS: The PS, PDI, ZP, encapsulation efficiency, and drug loading of MYR liposomes were 184.34 ± 1.05 nm, 0.215 ± 0.005, -38.46 ± 0.30 mV, 83.42 ± 1.07%w/w, and 6.20 ± 0.31%w/w, respectively. The release rate of MYR liposomes was higher than free MYR, wherein the cumulative value responded to pH. Besides, the Cmax of MYR liposomes was 4.92 ± 0.20 µg/mL. The level of uric acid in the M-L-H group (200 mg/kg) was reduced by 54.74%w/v in comparison with the model group. CONCLUSION: MYR liposomes exhibited pH sensitivity and could potentially enhance the oral bioavailability and anti-hyperuricemic efficacy of MYR.

Association between healthy lifestyle combinations and periodontitis in NHANES.

BACKGROUND: Periodontitis is closely associated with chronic systemic diseases. Healthy lifestyle interventions have health-enhancing effects on chronic systemic disorders and periodontitis, but the extent to which healthy lifestyle combinations are associated with periodontitis is unclear. Therefore, this study aimed to investigate the association between periodontitis and different healthy lifestyle combinations. METHODS: 5611 participants were included from the National Health and Nutrition Examination Survey (NHANES, 2009-2014). Six healthy lifestyles factors were defined as fulfilling either: non-smoking, moderate drinking, moderate body mass index (BMI), physical activity, healthy sleep and appropriate total energy intake. Then, the adjusted logistic regression models were performed to identify the association between the periodontitis and the scoring system composed of six lifestyles (0-6 scale). Finally, different scenarios were dynamically and randomly combined to identify the optimal and personalized combination mode. RESULTS: Higher healthy lifestyle scores were significantly associated with lower periodontitis prevalence (p < 0.05). Four lifestyle factors (smoking, drinking, BMI, and sleep) significantly varied between the periodontitis and healthy groups (p < 0.05). Smoking was considered as a strong independent risk factor for periodontitis in both former and current smokers. Results further indicated that the combination of these four lifestyles played the most essential role in determining the magnitude of periodontitis occurrence (odds ratio [OR]: 0.33; 95% confidence interval [CI]: 0.21 to 0.50). In the total population, the majority of three lifestyle combinations outperformed the two combination models, whereas the two-combination of nonsmoking-drinking (OR: 0.39; 95% CI: 0.27 to 0.58) had relatively lower periodontitis prevalence than the three-combination of healthy drinking-BMI-sleep (OR: 0.42; 95% CI: 0.26 to 0.66). CONCLUSION: This cross-sectional study suggests that smoking, drinking, BMI, and sleep are significantly related with periodontitis and smoking is the principal risk factor related among them. This study provides various customized lifestyle combinations for periodontitis prevention.

[A medical visual question answering approach based on co-attention networks].

Recent studies have introduced attention models for medical visual question answering (MVQA). In medical research, not only is the modeling of "visual attention" crucial, but the modeling of "question attention" is equally significant. To facilitate bidirectional reasoning in the attention processes involving medical images and questions, a new MVQA architecture, named MCAN, has been proposed. This architecture incorporated a cross-modal co-attention network, FCAF, which identifies key words in questions and principal parts in images. Through a meta-learning channel attention module (MLCA), weights were adaptively assigned to each word and region, reflecting the model's focus on specific words and regions during reasoning. Additionally, this study specially designed and developed a medical domain-specific word embedding model, Med-GloVe, to further enhance the model's accuracy and practical value. Experimental results indicated that MCAN proposed in this study improved the accuracy by 7.7% on free-form questions in the Path-VQA dataset, and by 4.4% on closed-form questions in the VQA-RAD dataset, which effectively improves the accuracy of the medical vision question answer.

Prognostic impact of new-onset atrial fibrillation in myocardial infarction with and without improved ejection fraction.

AIMS: Improvement in left ventricular ejection fraction (impEF) often presents in contemporary acute myocardial infarction (AMI) patients. New-onset atrial fibrillation (NOAF) during AMI is an important predictor of subsequential heart failure (HF), while its impact on the trajectory of post-MI left ventricular ejection fraction (LVEF) and prognostic implication in patients with and without impEF remains undetermined. We aimed to investigate the prognostic impacts of NOAF in AMI patients with and without impEF. METHODS AND RESULTS: Consecutive AMI patients without a prior history of AF between February 2014 and March 2018 with baseline LVEF ≤ 40% and had ≥1 LVEF measurement after baseline were included. ImpEF was defined as a baseline LVEF ≤ 40% and a re-evaluation showed both LVEF > 40% and an absolute increase of LVEF ≥ 10%. Persistently reduced EF (prEF) was defined as the second measurement of LVEF either ≤40% or an absolute increase of LVEF < 10%. The primary endpoint was a major adverse cardiac event (MACE) that was composed of cardiovascular death and HF hospitalization. Cox regression analysis and competing risk analysis were performed to assess the association of post-MI NOAF with MACE. Among 293 patients (mean age: 66.6 ± 11.3 years, 79.2% of males), 145 (49.5%) had impEF and 67 (22.9%) developed NOAF. Higher heart rate (odds ratio [OR]: 0.84, 95% confidence interval [CI]: 0.73-0.97; P = 0.015), prior MI (OR: 0.25, 95% CI: 0.09-0.69; P = 0.008), and STEMI (OR: 0.40, 95% CI: 0.21-0.77; P = 0.006) were independent predictors of post-MI impEF. Within up to 5 years of follow-up, there were 22 (15.2%) and 53 (35.8%) MACE in patients with impEF and prEF, respectively. NOAF was an independent predictor of MACE in patients with impEF (hazard ratio [HR]: 7.34, 95% CI: 2.49-21.59; P < 0.001) but not in those with prEF (HR: 0.78, 95% CI: 0.39-1.55; P = 0.483) after multivariable adjustment. Similar results were obtained when accounting for the competing risk of all-cause death (subdistribution HR and 95% CIs in impEF and prEF were 6.47 [2.32-18.09] and 0.79 [0.39-1.61], respectively). CONCLUSIONS: The NOAF was associated with an increased risk of cardiovascular outcomes in AMI patients with impEF.

The Combined Effects of the Most Important Dietary Patterns on the Incidence and Prevalence of Chronic Renal Failure: Results from the US National Health and Nutrition Examination Survey and Mendelian Analyses.

BACKGROUND: We aimed to comprehensively assess the relationship of specific dietary patterns and various nutrients with chronic kidney disease (CKD) and its progression. METHODS: The observational study data were from the NHANES 2005-2020. We calculated four dietary pattern scores (healthy eating index 2020 (HEI-2020), dietary inflammatory index (DII), alternative mediterranean diet (aMed), and dietary approaches to stop hypertension (DASH)) and the intakes of various nutrients and defined CKD, CKD-very high risk, and kidney dialysis. Associations between dietary patterns and nutrients and disease were assessed by means of two logistic regression models. Two-sample MR was performed with various food and nutrients as the exposure and CKD, kidney dialysis as the outcome. Sensitivity analyses were conducted to verify the reliability of the results. RESULTS: A total of 25,167 participants were included in the analyses, of whom 4161 had CKD. HEI-2020, aMed, and DASH were significantly negatively associated with CKD and CKD-very high risk at higher quartiles, while DII was significantly positively associated. A higher intake of vitamins and minerals may reduce the incidence and progression of CKD to varying degrees. The MR results, corrected for false discovery rates, showed that a higher sodium intake was associated with a higher prevalence of CKD (OR: 3.91, 95%CI: 2.55, 5.99). CONCLUSIONS: Adhering to the three dietary patterns of HEI-2020, aMed, and DASH and supplementing with vitamins and minerals benefits kidney health.

Effects of warming on rice production and metabolism process associated with greenhouse gas emissions.

Evaluating the impact of global warming on rice production and greenhouse gas (GHG) emissions is critical for ensuring food security and mitigating the consequences of climate change. Nonetheless, the impacts of warming on crop production, GHG emissions, and microbial mechanisms in the single-cropping rice systems remain unclear. Here, a two-year field experiment was conducted to explore the effects of warming (increased by 2.7-3.0 °C on average) in the rice growing season on crop production and functional microorganisms associated with GHG emissions. Results showed that warming resulted in significant reduction (p < 0.01) in the aboveground biomass and grain yield as well as in grain weight, the number of spikelets per panicle, and the seed-setting rate. However, it caused a significant increase (p < 0.01) in the number of panicles by 15.6 % and 34.9 %, respectively. Furthermore, warming significantly increased (p < 0.01) seasonal methane (CH4) emissions but reduced nitrous oxide (N2O) emissions, particularly in 2022.The relative abundance of genes associated with CH4 metabolism and nitrogen metabolism was increased by 40.7 % and 32.7 %, respectively, in response to warming. Moreover, warming had a positive impact on the abundance of genes related to CH4 production and oxidation processes but did not affect the denitrification processes associated with N2O production. These results showed that warming decreased rice yield and biomass in the single cropping rice system but increased CH4 emissions and global warming potential. Taken together, to address the increasing food demand of a growing population and mitigate the impacts of global warming, it is imperative to duce GHG emissions and enhance crop yields.

Atrial fibrillation increases the risk of all-cause dementia, Alzheimer's disease, and vascular dementia: A cohort study of 373, 415 participants in the UK Biobank.

BACKGROUND: Accumulated evidence has highlighted the association between atrial fibrillation and the risk of developing dementia. METHODS: This current cohort study utilized data from the UK Biobank to explore the association between atrial fibrillation (AF) and all-cause dementia (ACD), encompassing its main subtypes (Alzheimer's disease (AD), and vascular dementia (VD)). Cox proportional hazards models were applied to examine the association of AF and dementia with its primary subtypes after adjusting for different sets of covariates. Hazard ratios (HRs) with 95 % confidential intervals (CIs) were estimated to quantify the associated risks. Competing risk model was applied in sensitivity analysis. RESULTS: After exclusion, 373, 415 participants entered the primary analysis. Among these, 27, 934 (7.48 %) were with a history AF at baseline, while 345, 481 (92.52 %) were without. During a mean follow-up of 13.45 years, ACD was diagnosed in 1215 individuals with AF and 3988 individuals without AF. Participants with AF had higher risks of ACD (1.79 [1.67-1.91]), AD (1.48 [1.32-1.65]), and VD (2.46 [2.17-2.80]) in the fully adjusted Cox regression models. Results of subgroup and sensitivity analyses predominantly aligned with the positive associations in primary analysis. LIMITATIONS: The applicability of our findings to diverse ethnicities might require careful consideration and the behind biological mechanisms need to be further revealed. CONCLUSIONS: It indicated that people with atrial fibrillation had an increased future risk of all-cause dementia, Alzheimer's disease, vascular dementia. Atrial fibrillation screening and prevention strategies should take into account to prevent and delay the onset of dementia.

Histone deacetylase inhibitors VPA and WT161 ameliorate the pathological features and cognitive impairments of the APP/PS1 Alzheimer's disease mouse model by regulating the expression of APP secretases.

BACKGROUND: Alzheimer's disease (AD) is a degenerative neurological disorder. Recent studies have indicated that histone deacetylases (HDACs) are among the most prominent epigenetic therapy targets and that HDAC inhibitors have therapeutic effects on AD. Here, we identified sodium valproate (VPA), a pan-HDAC inhibitor, and WT161, a novel HDAC6 selective inhibitor, as potential therapeutic agents for AD. Underlying molecular mechanisms were investigated. METHODS: A cellular model, N2a-APPswe, was established via lentiviral infection, and the APPswe/PSEN1dE9 transgenic mouse model was employed in the study. LC-MS/MS was applied to quantify the concentration of WT161 in the mouse brain. Western blotting, immunohistochemical staining, thioflavin-S staining and ELISA were applied to detect protein expression in cells, tissues, or serum. RNA interference was utilized to knockdown the expression of specific genes in cells. The cognitive function of mice was assessed via the nest-building test, novel object recognition test and Morris water maze test. RESULTS: Previous studies have focused mainly on the impact of HDAC inhibitors on histone deacetylase activity. Our study discovered that VPA and WT161 can downregulate the expression of multiple HDACs, such as HDAC1 and HDAC6, in both AD cell and mouse models. Moreover, they also affect the expression of APP and APP secretases (BACE1, PSEN1, ADAM10). RNA interference and subsequent vitamin C induction further confirmed that the expression of APP and APP secretases is indeed regulated by HDAC1 and HDAC6, with the JNK pathway being the intermediate link in this regulatory process. Through the above pathways, VPA and WT161 effectively reduced Aß deposition in both AD cell and mouse models and significantly improved cognitive function in AD mice. CONCLUSIONS: In general, we have discovered that the HDAC6-JNK-APP secretases cascade is an important pathway for VPA and WT161 to exert their therapeutic effects on AD. Investigations into the safety and efficacy of VPA and WT161 were also conducted, providing essential preclinical evidence for assessing these two epigenetic drugs for the treatment of AD.

The immunomodulatory effects of mesenchymal stem cell-derived extracellular vesicles in Alzheimer's disease.

Neuroinflammation has been identified as another significant pathogenic factor in Alzheimer's disease following Aß amyloid deposition and tau protein hyperphosphorylation, activated in the central nervous system by glial cells in response to injury-related and pathogen-related molecular patterns. Moderate glial cell activity can be neuroprotective; however, excessive glial cell activation advances the pathology of Alzheimer's disease and is accompanied by structural changes in the brain interface, with peripheral immune cells entering the brain through the blood-brain barrier, creating a vicious circle. The immunomodulatory properties of mesenchymal stem cells (MSCs) are primarily conveyed through extracellular vesicles (EVs). MSC-EVs participate in chronic inflammatory and immune processes by transferring nucleic acids, proteins and lipids from the parent cell to the recipient cell, thus MSC-EVs retain their immunomodulatory capacity while avoiding the safety issues associated with living cell therapy, making them a promising focus for immunomodulatory therapy. In this review, we discuss the modulatory effects of MSC-EVs on Alzheimer's disease-associated immune cells and the mechanisms involved in their treatment of the condition. We have found a clinical trial of MSC-EVs in Alzheimer's disease treatment and outlined the challenges of this approach. Overall, MSC-EVs have the potential to provide a safe and effective treatment option for Alzheimer's disease by targeting neuroinflammation.

Residential Nitrogen Dioxide Exposure and Cause-Specific Cerebrovascular Mortality: An Individual-Level, Case-Crossover Study.

BACKGROUND: Existing studies have already shown a connection between nitrogen dioxide (NO2) exposure and cerebrovascular mortality. However, the differential effects of NO2 on cerebrovascular disease and its subtypes remain unclear and require further exploration. METHODS: Daily stroke mortality data between 2013 and 2021 in Shanghai, China were collected. Residential daily air pollution data for each decedent were predicted from a satellite model. An individual-level, time-stratified, case-crossover design was applied to examine the relationship between NO2 exposure and cerebrovascular mortality. A combination of conditional logistic regression and distributed lag models with a maximum lag of 7 days was used for data analysis. RESULTS: A total of 219,147 cases of cerebrovascular mortality were recorded. Among them, the proportion of sequelae of cerebrovascular disease, hemorrhagic stroke and ischemic stroke was 50.7%, 17.1% and 27.5%, respectively. The monotonic increases in mortality risks of cerebrovascular diseases, sequelae of cerebrovascular disease and ischemic stroke were observed, without any discernible thresholds. Each 10 µg/m3 increase in NO2 concentration was associated with increments of 3.62% [95% confidence interval (CI): 2.56%, 4.69%] for total cerebrovascular mortality, 4.29% (95% CI: 2.81%, 5.80%) for sequelae of cerebrovascular disease mortality and 4.30% (95% CI: 2.30%, 6.33%) for ischemic stroke mortality. No positive associations between NO2 exposure and hemorrhagic stroke mortality were observed. A greater risk of NO2 was observed in the warm season, in patients with less than 9 years of education and in those with single marital status. The effects of NO2 were robust to mutual adjustment of co-pollutants. CONCLUSIONS: Short-term exposures to NO2 may increase the risk of cerebrovascular mortality, specifically for ischemic stroke and sequelae of cerebrovascular disease.