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Background: The objective of this study is to estimate the causal relationship between plasma proteins and myocardial infarction (MI) through Mendelian randomization (MR), predict potential target-mediated side effects associated with protein interventions, and ensure a comprehensive assessment of clinical safety. Methods: From 3 proteome genome-wide association studies (GWASs) involving 9775 European participants, 331 unique blood proteins were screened and chosed. The summary data related to MI were derived from a GWAS meta-analysis, incorporating approximately 61,000 cases and 577,000 controls. The assessment of associations between blood proteins and MI was conducted through MR analyses. A phenome-wide MR (Phe-MR) analysis was subsequently employed to determine the potential on-target side effects of protein interventions. Results: Causal mediators for MI were identified, encompassing cardiotrophin-1 (CT-1) (odds ratio [OR] per SD increase: 1.16; 95% confidence interval [CI]: 1.13-1.18; p = 1.29 × 10 - 31 ), Selenoprotein S (SELENOS) (OR: 1.16; 95% CI: 1.13-1.20; p = 4.73 × 10 - 24 ), killer cell immunoglobulin-like receptor 2DS2 (KIR2DS2) (OR: 0.93; 95% CI: 0.90-0.96; p = 1.08 × 10 - 5 ), vacuolar protein sorting-associated protein 29 (VPS29) (OR: 0.92; 95% CI: 0.90-0.94; p = 8.05 × 10 - 13 ), and histo-blood group ABO system transferase (NAGAT) (OR: 1.05; 95% CI: 1.03-1.07; p = 1.41 × 10 - 5 ). In the Phe-MR analysis, memory loss risk was mediated by CT-1, VPS29 exhibited favorable effects on the risk of 5 diseases, and KIR2DS2 showed no predicted detrimental side effects. Conclusions: Elevated genetic predictions of KIR2DS2 and VPS29 appear to be linked to a reduced risk of MI, whereas an increased risk is associated with CT-1, SELENOS, and NAGAT. The characterization of side effect profiles aids in the prioritization of drug targets. Notably, KIR2DS2 emerges as a potentially promising target for preventing and treating MI, devoid of predicted detrimental side effects.
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It has been rarely reported that a stuck optical coherence tomography (OCT) catheter can lead to longitudinal stent deformation (LSD). This complication can result in incomplete stent apposition and dissection after stent implantation. In this study, we present a case where a bailout stent was implanted in the distal segment of the left anterior descending artery (LAD) after longitudinal stent deformation caused by a stuck OCT catheter. This approach was taken to prevent acute stent thrombosis, subacute stent thrombosis, in-stent restenosis (ISR), and death. The patients were followed up for one year, and no adverse events were observed.
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Extreme cold exposure has been widely considered as a cardiac stress and may result in cardiac function decompensation. This study was to examine the risk factors that contribute to changes in cardiovascular indicators of cardiac function following extreme cold exposure and to provide valuable insights into the preservation of cardiac function and the cardiac adaptation that occur in real-world cold environment. Seventy subjects were exposed to cold outside (Mohe, mean temperature -17 to -34°C) for one day, and were monitored by a 24-h ambulatory blood pressure device and underwent echocardiography examination before and after extreme cold exposure. After exposure to extreme cold, 41 subjects exhibited an increase in ejection fraction (EF), while 29 subjects experienced a decrease. Subjects with elevated EF had lower baseline coefficients of variation (CV) in blood pressure compared to those in the EF decrease group. Additionally, the average real variability (ARV) of blood pressure was also significantly lower in the EF increase group. Multivariate regression analysis indicated that both baseline CV and ARV of blood pressure were independent risk factors for EF decrease, and both indicators proved effective for prognostic evaluation. Correlation analysis revealed a correlation between baseline blood pressure CV and ARV, as well as EF variation after exposure to extreme cold environment. Our research clearly indicated that baseline cardiovascular indicators were closely associated with the changes in EF after extreme cold exposure. Furthermore, baseline blood pressure variability could effectively predict alterations in left cardiac functions when individuals were exposed to extreme cold environment.
Subject(s)
Blood Pressure Monitoring, Ambulatory , Blood Pressure , Humans , Male , Female , Blood Pressure/physiology , Middle Aged , Adult , Blood Pressure Monitoring, Ambulatory/methods , Echocardiography/methods , Stroke Volume/physiology , Extreme Cold/adverse effects , Risk Factors , Ventricular Function, Left/physiology , Cold Temperature/adverse effectsABSTRACT
BACKGROUND: Ischemic cardio-cerebrovascular disease is the leading cause of mortality worldwide. However, studies focusing on elderly and very elderly patients are scarce. Hence, our study aimed to characterize and investigate the long-term prognostic implications of ischemic cardio-cerebrovascular diseases in elderly Chinese patients. METHODS: This retrospective cohort study included 1026 patients aged ≥ 65 years who were categorized into the mono ischemic cardio-cerebrovascular disease (MICCD) (either coronary artery disease or ischemic stroke/transient ischemic attack) (n = 912) and the comorbidity of ischemic cardio-cerebrovascular disease (CICCD) (diagnosed with both coronary artery disease and ischemic stroke/transient ischemic attack at admission) (n = 114). The primary outcome was all-cause death. The mortality risk was evaluated using the Cox proportional hazards risk model with multiple adjustments by conventional and propensity-score-based approaches. RESULTS: Of the 2494 consecutive elderly patients admitted to the hospital, 1026 (median age 83 years [interquartile range]: 76.5-86.4; 94.4% men) met the inclusion criteria. Patients with CICCD consisted mostly of very elderly (79.2% vs. 66.1%, P < 0.001) individuals with a higher burden of comorbidities. Over a median follow-up of 10.4 years, 398 (38.8%) all-cause deaths were identified. Compared with the MICCD group, the CICCD group exhibited a higher adjusted hazard ratio (HR) (95% confidential interval, CI) of 1.71 (1.32-2.39) for long-term mortality after adjusting for potential confounders. The sensitivity analysis results remained robust. After inverse probability of treatment weighting (IPTW) modeling, the CICCD group displayed an even worse mortality risk (IPTW-adjusted HR: 2.07; 95% CI 1.47-2.90). In addition, anemia (adjusted HR: 1.48; 95% CI 1.16-1.89) and malnutrition (adjusted HR: 1.43; 95% CI 1.15-1.78) are also independent risk factors for all-cause mortality among elderly and very elderly patients. CONCLUSIONS: Our results thus suggest that elderly patients with ischemic cardio-cerebrovascular disease and anemia or malnutrition may have higher mortality, which may be predicted upon admission. These findings, however, warrant further investigation.
Subject(s)
Propensity Score , Humans , Male , Female , Aged , Aged, 80 and over , Retrospective Studies , China/epidemiology , Risk Factors , Cerebrovascular Disorders/mortality , Ischemic Stroke/mortality , Ischemic Stroke/epidemiology , Coronary Artery Disease/mortality , Coronary Artery Disease/complications , Cause of Death , Prognosis , Comorbidity , East Asian PeopleABSTRACT
Optical emitters in hexagonal boron nitride (hBN) are promising probes for single-molecule sensing platforms. When engineered in nanoparticle form, they can be integrated as detectors in nanodevices, yet positional control at the nanoscale is lacking. Here we demonstrate the functionalization of DNA origami nanopores with optically active hBN nanoparticles (NPs) with nanometer precision. The NPs are active under three wavelengths of visible illumination and display both stable and blinking emission, enabling their accurate localization by using wide-field optical nanoscopy. Correlative opto-structural characterization reveals deterministic binding of bright, multicolor hBN NPs at the pore rim due to π-π stacking interactions at site-specific locations on the DNA origami. Our work provides a scalable, bottom-up approach toward deterministic assembly of solid-state emitters on arbitrary structural elements based on DNA origami. Such a nanoscale arrangement of optically active components can advance the development of single-molecule platforms, including optical nanopores and nanochannel sensors.
Subject(s)
Boron Compounds , DNA , Nanopores , Boron Compounds/chemistry , DNA/chemistry , Nanotechnology/methods , Nanoparticles/chemistryABSTRACT
Brachial-ankle pulse wave velocity (baPWV) is a noninvasive index of vascular aging. However, the metabolic profile underlying vascular aging has not yet been fully elucidated. The current study aimed to identify circulating markers of vascular aging as assessed by baPWV and to elucidate its mechanism from a metabolomic perspective in older adults. A total of 60 and 61 Chinese male participants aged ≥80 years were recruited to the metabolome and validation cohorts, respectively. The baPWV of participants was measured using an automatic waveform analyzer. Plasma metabolic profile was investigated using ultra-performance liquid chromatography coupled with triple quadrupole linear ion trap tandem mass spectrometry. Orthogonal partial least squares (OPLS) regression modeling established the association between metabolic profile and baPWV to determine important metabolites predictive of vascular aging. Additionally, an enzyme-linked immunosorbent assay was employed to validate the metabolites in plasma and culture media of vascular smooth muscle cells in vitro. OPLS modeling identified 14 and 22 metabolites inversely and positively associated with baPWV, respectively. These 36 biomarkers were significantly enriched in seven metabolite sets, especially in cysteine and methionine metabolism (p <0.05). Notably, among metabolites involved in cysteine and methionine metabolism, S-adenosylmethionine (SAM) level was inversely related to baPWV, with a significant correlation coefficient in the OPLS model (p <0.05). Furthermore, the relationship between SAM and vascular aging was reconfirmed in an independent cohort and at the cellular level in vitro. SAM was independently associated with baPWV after adjustments for clinical covariates (ß = -0.448, p <0.001) in the validation cohort. In summary, plasma metabolomics identified an inverse correlation between SAM and baPWV in older males. SAM has the potential to be a novel biomarker and therapeutic target for vascular aging.
Subject(s)
Ankle Brachial Index , S-Adenosylmethionine , Humans , Male , Aged , Blood Pressure , Cysteine , Pulse Wave Analysis , Aging , Biomarkers , Risk FactorsABSTRACT
BACKGROUND: The number and proportion of the elderly population have been continuously increasing in China, leading to the elevated prevalence of chronic diseases and multimorbidity, which ultimately brings heavy burden to society and families. Meanwhile, the status of multimorbidity tends to be more complex in elderly inpatients than community population. In view of the above concerns, this study was designed to investigate the health status of elderly inpatients by analyzing clinical data in Chinese People's Liberation Army (PLA) General Hospital from 2008 to 2019, including the constitution of common diseases, comorbidities, the status of multimorbidity, in-hospital death and polypharmacy among elderly inpatients, so as to better understand the diseases spectrum and multimorbidity of elderly inpatients and also to provide supporting evidence for targeted management of chronic diseases in the elderly. METHODS: A clinical inpatients database was set up by collecting medical records of elderly inpatients from 2008 to 2019 in Chinese PLA General Hospital, focusing on diseases spectrum and characteristics of elderly inpatients. In this study, we collected data of inpatients aged ≥ 65 years old, and further analyzed the constitution of diseases, multimorbidity rates and mortality causes in the past decade. In addition, the prescriptions were also analyzed to investigate the status of polypharmacy in elderly inpatients. RESULTS: A total of 210,169 elderly patients were hospitalized from January 1st, 2008 to December 31st, 2019. The corresponding number of hospitalizations was 290,833. The average age of the study population was 72.67 years old. Of the total population, 73,493 elderly patients were re-admitted within one year, with the re-hospitalization rate of 25.27%. Malignant tumor, hypertension, ischemic heart disease, diabetes mellitus and cerebrovascular disease were the top 5 diseases. Among the study population, the number of patients with two or more long-term health conditions was 267,259, accounting for 91.89%, with an average of 4.68 diseases. In addition, the average number of medications taken by the study population was 5.4, among which, the proportion of patients taking more than 5 types of medications accounted for 55.42%. CONCLUSIONS: By analyzing the constitution of diseases and multimorbidity, we found that multimorbidity has turned out to be a prominent problem in elderly inpatients, greatly affecting the process of healthy aging and increasing the burden on families and society. Therefore, multidisciplinary treatment should be strengthened to make reasonable preventive and therapeutic strategies to improve the life quality of the elderly. Meanwhile, more attention should be paid to reasonable medications for elderly patients with multimorbidity to avoid preventable side effects caused by irrational medication therapy.
Subject(s)
East Asian People , Inpatients , Multimorbidity , Humans , Aged , Hospital Mortality , China/epidemiology , Chronic DiseaseABSTRACT
Atherosclerosis management heavily relies on the suppression of the inflammatory response of macrophages. Colchicine's potent anti-inflammatory properties make it a promising candidate for secondary prevention against cardiovascular disease. However, its high toxicity and numerous adverse effects limit its clinical use. To address this, there is an urgent need for specific drug delivery systems to boost the level of accumulation of colchicine within atherosclerotic plaques. In this study, the cluster of differentiation-44 receptor was verified to be overexpressed in inflammatory macrophages within plaques both in vitro and in vivo. Subsequently, a Prussian blue-based nanomedical loading system with hyaluronic acid (HA) coating was constructed, and its effects were observed on the atherosclerosis regression. Colchicine and Cy5.5 were encapsulated within Prussian blue nanoparticles through self-assembly, followed by conjugation with hyaluronic acid to create col@PBNP@HA. The formulated col@PBNP@HA displayed a cubic shape and scattered distribution. Importantly, col@PBNP@HA demonstrated specific cellular uptake into lipopolysaccharide-stimulated macrophages. In vitro experiments showed that col@PBNP@HA more effectively inhibited expression of inflammatory factors and scavenged reactive oxygen species compared with the control group, which were treated with colchicine. Furthermore, col@PBNP@HA exhibited its specific and higher accumulation in aortic plaque analysis via fluorescence imaging of aortas. After 4 weeks, administration of col@PBNP@HA resulted in significant atherosclerosis regression in the mice model, with therapeutic effects superior to those of free colchicine. Similar to colchicine, col@PBNP@HA inhibited the secretion of inflammation factors and scavenged ROS through the regulation of the toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (Myd88)/nuclear factor kappa-B (NF-κB) and peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) signaling pathway. In summary, col@PBNP@HA demonstrated specific targeting ability to inflammatory plaques and exerted beneficial effects on atherosclerosis regression through TLR4/Myd88/NF-κB and PGC-1α modulation.
Subject(s)
Atherosclerosis , Ferrocyanides , Nanoparticles , Plaque, Atherosclerotic , Animals , Mice , Plaque, Atherosclerotic/drug therapy , Toll-Like Receptor 4/metabolism , Toll-Like Receptor 4/therapeutic use , Hyaluronic Acid , NF-kappa B/metabolism , NF-kappa B/therapeutic use , Myeloid Differentiation Factor 88/metabolism , Atherosclerosis/drug therapy , Atherosclerosis/metabolismABSTRACT
Previous bismuth-based photocatalysts usually employ a strong acid solution (e.g., HNO3 solution) to obtain an ultrathin structure toward high photocatalytic activity. In this work, the ultrathin layered BiOIO3 nanosheets are successfully synthesized using just the glucose hydrothermal solution. The high-concentration glucose solution shows the obvious acidity after the hydrothermal process, which leads to the quick decrease in thickness of BiOIO3 nanosheets from â¼45.58 to â¼5.74 nm. The ultrathin structure can greatly improve charge carriers' separation and transfer efficiency. The generation of reductive iodide ions brings about oxygen vacancies in the ultrathin nanosheets, then the defect energy level is formed, causing the decreased band gap and improving the visible light absorption. Compared to thick BiOIO3 nanosheet with little oxygen vacancies, much higher carrier separation efficiency and visible light absorption are achieved in the ultrathin nanosheets with oxygen vacancies, resulting in an excellent photocatalytic performance (0.1980 min-1 for RhB degradation), which is much higher than most other bismuth-based photocatalysts. The superoxide radicals (â¢O2-) and holes (h+) are the major active species responsible for high photocatalytic activity. This work affords an environmentally friendly strategy to synthesize ultrathin photocatalysts with superior photocatalytic properties.
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BACKGROUND: Previous literature has established an association between acute silent ischemic lesions (ASILs) and elevated susceptibility to future adverse clinical outcomes. The present study endeavors to scrutinize the prognostic significance of preprocedural ASILs, as detected through diffusion-weighted imaging and apparent diffusion coefficient metrics, in relation to subsequent adverse events-namely, stroke, myocardial infarction, and all-cause death-following carotid revascularization in a cohort of patients with symptomatic carotid stenosis. MATERIALS AND METHODS: Subjects were extracted from a comprehensive retrospective dataset involving symptomatic carotid stenosis cases that underwent carotid revascularization at a tertiary healthcare institution in China, spanning January 2019 to March 2022. Of the 2663 initially screened patients (symptomatic carotid stenosis=1600; asymptomatic carotid stenosis=1063), a total of 1172 individuals with symptomatic carotid stenosis were retained for subsequent analysis. Stratification was implemented based on the presence or absence of ASILs. The primary endpoint constituted a composite measure of in-hospital stroke, myocardial infarction, or all-cause death. Both carotid endarterectomy (CEA) and carotid artery stenting (CAS) treatment modalities were individually subjected to propensity score-matched analyses. RESULTS: Among the 584 subjects who underwent CEA, 91 ASIL-positive and 91 ASIL-negative (NASIL) cases were propensity score-matched. Notably, the ASIL cohort demonstrated a statistically significant augmentation in the risk of primary outcomes relative to the NASIL group [10.99 vs. 1.10%; absolute risk difference, 9.89% (95% CI: 3.12-16.66%); RR, 10.00 (95% CI: 1.31-76.52); P =0.01]. Similarly, within the 588 CAS-treated patients, 107 ASIL-positive and 107 NASIL cases were matched, revealing a correspondingly elevated risk of primary outcomes in the ASIL group [9.35 vs. 1.87%; absolute risk difference, 7.48% (95% CI: 1.39-13.56%); RR, 5.00 (95% CI: 1.12-22.28); P =0.02]. CONCLUSIONS: ASILs portend an elevated risk for grave adverse events postcarotid revascularization, irrespective of the specific revascularization technique employed-be it CEA or CAS. Thus, ASILs may serve as a potent biomarker for procedural risk stratification in the context of carotid revascularization.
Subject(s)
Carotid Stenosis , Endarterectomy, Carotid , Myocardial Infarction , Stroke , Humans , Carotid Stenosis/complications , Carotid Stenosis/surgery , Retrospective Studies , Treatment Outcome , Stents/adverse effects , Carotid Arteries , Endarterectomy, Carotid/adverse effects , Endarterectomy, Carotid/methods , Stroke/etiology , Myocardial Infarction/etiology , Risk FactorsABSTRACT
Due to the characteristics of peroxide explosives, which are difficult to detect via conventional detection methods and have high explosive power, a fluorescent photoelectric detection system based on fluorescence detection technology was designed in this study to achieve the high-sensitivity detection of trace peroxide explosives in practical applications. Through actual measurement experiments and numerical simulation methods, the derivative dynamic time warping (DDTW) algorithm and the Spearman correlation coefficient were used to calculate the DDTW-Spearman distance to achieve time series correlation measurements. The detection sensitivity of triacetone triperoxide (TATP) and H2O2 was studied, and the detection of organic substances of acetone, acetylene, ethanol, ethyl acetate, and petroleum ether was carried out. The stability and specific detection ability of the fluorescent photoelectric detection system were determined. The research results showed that the fluorescence photoelectric detection system can effectively identify the detection data of TATP, H2O2, acetone, acetonitrile, ethanol, ethyl acetate, and petroleum ether. The detection limit of 0.01 mg/mL of TATP and 0.0046 mg/mL of H2O2 was less than 10 ppb. The time series similarity measurement method improves the analytical capabilities of fluorescence photoelectric detection technology.
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Equipped with hierarchical pores and three-dimensional (3D) center-radial channels, dendritic mesoporous nanoparticles (DMNs) make their pore volumes extremely large, specific surface areas super-high, internal spaces especially accessible, and so on. Other entities (like organic moieties or nanoparticles) can be modified onto the interfaces or skeletons of DMNs, accomplishing their functionalization for desirable applications. This comprehensive review emphasizes on the design and construction of DMNs-based systems which serve as sensors, adsorbents and catalysts for the detection, adsorption, and degradation of hazardous substances, mainly including the construction procedures of brand-new DMNs-based materials and the involved hazardous substances (like industrial chemicals, chemical dyes, heavy metal ions, medicines, pesticides, and harmful gases). The sensitive, adsorptive, or catalytic performances of various DMNs have been compared; correspondingly, the reaction mechanisms have been revealed strictly. It is honestly anticipated that the profound discussion could offer scientists certain enlightenment to design novel DMNs-based systems towards the detection, adsorption, and degradation of hazardous substances, respectively or comprehensively.
Subject(s)
Metals, Heavy , Nanoparticles , Hazardous Substances , Adsorption , Porosity , Nanoparticles/chemistryABSTRACT
This study aimed to construct a large animal model of coronary microvascular embolism, and investigate whether it could mimic the clinical imaging phenotypes of myocardial hypoperfusion in patients with ST-segment elevation myocardial infarction (STEMI). Nine minipigs underwent percutaneous coronary embolization with microspheres, followed by cardiac magnetic resonance (CMR) on week 1, 2 and 4 post operation. Microvascular obstruction (MVO) was defined as the isolated hypointense core within the enhanced area on late gadolinium enhancement images, which evolved during a 4-week follow-up. Fibrotic fraction of the segments was measured by Masson trichrome staining using a panoramic analysis software. Iron deposit and macrophage infiltration were quantified based on Perl's blue and anti-CD163 staining, respectively. Seven out of 9 (77.8%) minipigs survived and completed all of the imaging follow-ups. Four out of 7 (57.1%) minipigs were identified as transmural infarct with MVO. The systolic wall thickening (SWT) of MVO zone was similar to that of infarct zone (P = 0.762). Histopathology revealed transmural deposition of collagen, with microvessels obstructed by microspheres. The fibrotic fraction of infarct with MVO segments was similar to that of infarct without MVO segments (P = 0.954). The fraction of iron deposit in infarct with MVO segments was higher than that of infarct without MVO segments (P < 0.05), but the fraction of macrophage infiltration between these two segments did not show statistical difference (P = 0.723). Large animal model of coronary microvascular embolism could mimic most clinical imaging phenotypes of myocardial hypoperfusion in patients with STEMI, demonstrated by serial CMR and histopathology.
Subject(s)
Coronary Artery Disease , Embolism , Percutaneous Coronary Intervention , ST Elevation Myocardial Infarction , Humans , Animals , Swine , ST Elevation Myocardial Infarction/therapy , ST Elevation Myocardial Infarction/surgery , Contrast Media , Swine, Miniature , Coronary Circulation , Predictive Value of Tests , Gadolinium , Magnetic Resonance Imaging , Magnetic Resonance Spectroscopy , Models, Animal , Embolism/diagnostic imaging , Embolism/etiology , MicrocirculationABSTRACT
ATP-binding cassette transporter A1 (ABCA1) plays a crucial role in atherosclerotic formation through mediated cholesterol efflux in macrophage-derived foam cells. In this study, a scavenger receptors AI (SR-AI) targeted theranostic nanoparticles was constructed for atherosclerosis regression via ABCA1 activation in foam cells. ABCA1-upregulator 5242331 and IR780 were encapsulated in PLGA-PEG micelles which were conjugated with SR-AI targeting peptide (PP1) to formulate the nanoparticles (SAU-NPs). Immunostaining revealed that SR-AI was highly expressed both in macrophage foam cells and in atherosclerotic plaque of ApoE-/- mice. The SAU-NPs have shown more active targeting to plaque lesion with higher stability compared with non-SR-AI targeted nanoparticles. The transformation from macrophage to foam cells was inhibited by SAU-NPs carried 5242331. Cholesterol deposition was effectively reduced in foam cells by SAU-NPs through activating the LXRα-ABCA1/ABCG1/SR-BI pathway. In conclusion, theranostic SAU-NPs which carried ABCA1-upregulator 5242331 exert beneficial effects on atherosclerosis regression via LXRα activation.
Subject(s)
Atherosclerosis , Plaque, Atherosclerotic , Animals , Mice , Atherosclerosis/pathology , ATP Binding Cassette Transporter 1/metabolism , Cholesterol/metabolism , Plaque, Atherosclerotic/drug therapy , Precision Medicine , Scavenger Receptors, Class B/metabolismABSTRACT
Resveratrol (Res) is a common natural polyphenol that inhibits inflammation and oxidative stress in Alzheimer's disease (AD). However, the absorption efficiency and in vivo bioactivity of Res are poor. High fat diet-induced metabolic disorders, including obesity and insulin resistance, can promote AD-related ß-amyloid (Aß) aggregation, Tau protein phosphorylation and neurotoxicity. Gut microbiota play a role in modulating metabolic syndrome and cognitive impairment. Herein, flower-like Res-loaded selenium nanoparticles/chitosan nanoparticles (Res@SeNPs@Res-CS-NPs) with higher loading capacity (64 %) were prepared to regulate gut microbiota in cases of AD with metabolic disorder. The nano-flowers could restore gut microbiota homeostasis to reduce lipopolysaccharide (LPS) formation and LPS-induced neuroinflammation. Additionally, Res@SeNPs@Res-CS-NPs can prevent lipid deposition and insulin resistance by decreasing Firmicutes levels and increasing Bacteroidetes levels in the gut, further inhibiting Aß aggregation and Tau protein phosphorylation through the JNK/AKT/GSK3ß signaling pathway. Moreover, Res@SeNPs@Res-CS-NPs treatment was able to regulate the relative levels of gut microbiota associated with oxidative stress, inflammation and lipid deposition, including Entercoccus, Colidextribacter, Rikenella, Ruminococcus, Candidatus_Saccharimonas, Alloprevotella and Lachnospiraceae_UCG-006. Overall, Res@SeNPs@Res-CS-NPs significantly enhances cognitive ability in AD mice with metabolic disorder, highlighting their potential for preventing cognitive impairments in AD.
Subject(s)
Alzheimer Disease , Chitosan , Cognitive Dysfunction , Insulin Resistance , Selenium , Mice , Animals , Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Resveratrol/pharmacology , Resveratrol/therapeutic use , Selenium/pharmacology , tau Proteins , Lipopolysaccharides , Cognitive Dysfunction/drug therapy , Cognitive Dysfunction/etiologyABSTRACT
The pathology of Alzheimer's disease (AD) is highly correlated with obesity-induced insulin resistance. Resveratrol (Res) is a natural phenol that demonstrates a neuroprotective effect, but the bioactivity of Res is low in vivo. Here, chitosan (CS) was cross-linked with sodium tripolyphosphate (TPP) to encapsulate low water solubility Res. Next, a brain-targeted peptide (TG: TGNYKALHPHNG) was modified on the surface of Res-loaded CS/TPP nanoparticles (TG-Res-CS/TPP-NPs) to specifically deliver Res to the brain. Morris water maze results indicated that cognitive impairments were ameliorated by TG-Res-CS/TPP-NPs in obesity-related AD mice. Obesity-related insulin resistance promotes Tau phosphorylation and Aß aggregation in the brain. Administration of TG-Res-CS/TPP-NPs alleviated lipid deposition-induced insulin resistance and decreased the level of phosphorylated Tau and Aß aggregation via the JNK/AKT/GSK3ß pathway. Additionally, TG-Res-CS/TPP-NPs transported across blood-brain barrier which in turn increased glucose transporter expression levels, antioxidant enzyme activity and inhibited microglial cell activation. Thus, TG-Res-CS/TPP-NPs were more effective than Res-CS/TPP-NPs at regulating glucose homeostasis, oxidative stress and neuroinflammation in the brain. Moreover, inflammatory, lipid metabolism and oxidative stress-related gut microbiota including Helicobacter, Colidextribacter, Anaerotruncus, Parasutterella, Allobaculum, Alloprevotella, Alistipes, Bifidobacterium and Candidatus_Saccharimonas were also regulated by TG-Res-CS/TPP-NPs. This work indicates the potential use of TG-Res-CS/TPP-NPs for the delivery of Res.
Subject(s)
Alzheimer Disease , Chitosan , Gastrointestinal Microbiome , Insulin Resistance , Nanoparticles , Mice , Animals , Resveratrol/pharmacology , Resveratrol/therapeutic use , Alzheimer Disease/drug therapy , Antioxidants/pharmacology , Blood-Brain Barrier , PeptidesABSTRACT
Background: Clear cell renal cell carcinoma's (ccRCC) occurrence and development are strongly linked to the metabolic reprogramming of tumors, and thus far, neither its prognosis nor treatment has achieved satisfying clinical outcomes. Methods: The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, respectively, provided us with information on the RNA expression of ccRCC patients and their clinical data. Cuproptosis-related genes (CRGS) were discovered in recent massive research. With the help of log-rank testing and univariate Cox analysis, the prognostic significance of CRGS was examined. Different cuproptosis subtypes were identified using consensus clustering analysis, and GSVA was used to further investigate the likely signaling pathways between various subtypes. Univariate Cox, least absolute shrinkage and selection operator (Lasso), random forest (RF), and multivariate stepwise Cox regression analysis were used to build prognostic models. After that, the models were verified by means of the C index, Kaplan-Meier (K-M) survival curves, and time-dependent receiver operating characteristic (ROC) curves. The association between prognostic models and the tumor immune microenvironment as well as the relationship between prognostic models and immunotherapy were next examined using ssGSEA and TIDE analysis. Four online prediction websites-Mircode, MiRDB, MiRTarBase, and TargetScan-were used to build a lncRNA-miRNA-mRNA ceRNA network. Results: By consensus clustering, two subgroups of cuproptosis were identified that represented distinct prognostic and immunological microenvironments. Conclusion: A prognostic risk model with 13 CR-lncRNAs was developed. The immune microenvironment and responsiveness to immunotherapy are substantially connected with the model, which may reliably predict the prognosis of patients with ccRCC.
ABSTRACT
Aß aggregation-related neuroinflammation and imbalance of brain glucose homeostasis play important roles in the pathological process of Alzheimer's disease (AD). Chlorogenic acid (CGA) is one of the most common dietary polyphenols with neuroprotective effects. However, due to the low bioavailability of CGA, its application dose is usually high in vivo. In our previous study, the spherical selenium nanoparticles act as drug carriers to improve the bioactivity of resveratrol. Here, the brain-targeting peptide (TGN peptide) and CGA were used to prepare a new flowerlike selenium nanocluster (TGN-CGA@SeNCs) for enhancing the bioavailability of CGA. After decoration on selenium nanoclusters, the solubility and stability of CGA was obviously increased. Oral administration of a low dose of CGA (80 mg/kg/body weight) only slightly inhibited Aß aggregate-related neuroinflammation and glucose homeostasis disorder in the brain. Moreover, CGA showed less effect on increasing the diversity and richness of gut microbiota. At the same concentration, the CGA-modified selenium nanocluster (CGA@SeNCs) and TGN-CGA@SeNCs showed better function in ameliorating the gut microbiota disorder. Especially, TGN-CGA@SeNCs significantly increased the relative abundance of Turicibacter, Colidextribacter, Ruminococcus, Alloprevotella, and Alistipes against oxidative stress, inflammation, and glucose homeostasis imbalance. Notably, only TGN-CGA@SeNCs can transport through the blood-brain barrier (BBB), and TGN-CGA@SeNCs showed better effects than CGA@SeNCs in regulating Aß aggregation and improving brain glucose homeostasis. These results broadened the application of TGN-CGA@SeNCs, effectively improving the bioactivity of CGA, which also lowers the CGA dose for preventing AD progression.
Subject(s)
Alzheimer Disease , Cognitive Dysfunction , Selenium , Mice , Animals , Chlorogenic Acid , Neuroinflammatory Diseases , Peptides/pharmacology , Alzheimer Disease/drug therapy , Cognitive Dysfunction/drug therapy , Blood-Brain Barrier , GlucoseABSTRACT
Objective: This study aims to investigate novel clinical risk factors for cognitive impairment (CI) in elderly. Methods: A total of 3221 patients (259 patients with CI and 2,962 subjects without CI) were recruited into this nested case-control study who underwent cerebral magnetic resonance angiography (MRA) from 2007 to 2021. All of the clinical data with MRA imaging were recorded followed by standardization processing blindly. The maximum stenosis score of the posterior circulatory artery, including the basilar artery, and bilateral posterior cerebral artery (PCA), was calculated by the cerebral MRA automatic quantitative analysis method. Logistic regression (LR) analysis was used to evaluate the relationship between risk factors and CI. Four machine learning approaches, including LR, decision tree (DT), random forest (RF), and support vector machine (SVM), employing 5-fold cross-validation were used to establish CI predictive models. Results: After matching with age and gender, 208 CI patients and 208 control subjects were finalized the follow-up (3.46 ± 3.19 years) with mean age at 84.47 ± 6.50 years old. Pulse pressure (PP) in first tertile (<58 mmHg) (OR 0.588, 95% confidence interval (CI): 0.362-0.955) was associated with a decreased risk for CI, and ≥50% stenosis of the left PCA (OR 2.854, 95% CI: 1.387-5.872) was associated with an increased risk for CI after adjusting for body mass index, myocardial infarction, and stroke history. Based on the means of various blood pressure (BP) parameters, the performance of the LR, DT, RF and SVM models accurately predicted CI (AUC 0.740, 0.786, 0.762, and 0.753, respectively) after adding the stenosis score of posterior circulatory artery. Conclusion: Elderly with low pulse differential pressure may have lower risk for cognitive impairment. The hybrid model combined with the stenosis score of posterior circulatory artery, clinical indicators, and the means of various BP parameters can effectively predict the risk of CI in elderly individuals.