SUMMARY
Background and purpose: Elevated plasma C‐reactive protein (CRP) has been suggested as a risk factor for ischemic stroke (IS) and coronary ischemic disease. Evidence has shown that ...high‐sensitivity CRP (hs‐CRP) is related to a worsening prognosis after IS, but hs‐CRP was rare in a large‐sample study in a Chinese population. We investigated the associations between hs‐CRP and outcome of Chinese patients after acute IS. Methods: Seven hundred and forty‐one consecutive acute IS patients (74.9% male, mean age 60.9 years), with baseline characteristics and hs‐CRP measured within 24 h after hospitalization, were admitted in this study. We also prospectively followed up for clinical outcome and death 3 months after disease onset. hs‐CRP was divided into two categories: hs‐CRP >3 mg/L and hs‐CRP ≤3 mg/L. Survival analysis using multivariable Cox regression was performed to analyze the association between hs‐CRP and stroke outcomes after adjusting for potential confounding factors. Results: Compared with low hs‐CRP, patients with high hs‐CRP (>3 mg/L) had a significantly higher rate of all‐cause death (0.71% vs. 10.00%; P < 0.001) at 3 months after stroke onset. High hs‐CRP was an independent risk factor for all‐cause death (HR, 6.48; 95% CI, 1.41 to 29.8; P= 0.016), as well as history of atrial fibrillation (HR, 5.24; 95% CI, 1.83 to 15.0; P= 0.002), no statin therapy during hospitalization (HR, 4.56; 95% CI, 2.18 to 9.55; P < 0.001), high homocysteine (>15.1 mmol/L) (HR, 2.66; 95% CI, 1.26 to 5.60; P= 0.01); fasting glucose (>6.1 mmol/L) (HR, 9.14; 95% CI, 3.34 to 25.0; P < 0.001), NIHSS at admission (HR, 2.35; 95% CI, 1.35 to 4.09; P= 0.003) and history of coronary heart disease (CHD) (HR, 2.34; 95% CI, 1.06 to 5.17; P= 0.035). Kaplan–Meier survival curves showed a higher risk of death for patients with hs‐CRP >3 mg/L (P= 0.016). Conclusion: Elevated plasma hs‐CRP independently predicted risk of all‐cause death within 3 months after acute IS in Chinese patients.
Oxygen is a necessary substance for life activities, but reduced oxygen utilization due to high altitude exposure and respiratory dysfunction diseases could lead to pathological changes in the ...organisms. Herein gypenosides, the active ingredients in the food and medicine resource plant Gynostemma pentaphyllum (Thunb.) Makino were found to alleviate hypoxia-induced injury in PC12 cells. Moreover, hypoxia induced an increase in Ca
and reactive oxygen species content, and such patterns were both significantly reduced by gypenosides treatment. At the same time, gypenosides significantly blocked the decrease of both NO content and mitochondrial membrane potential caused by hypoxia. Furthermore, gypenosides gavage treatment significantly prolonged the survival time of C57BL/6 mice in confinement up to 24.3% and enhanced the locomotor ability of mice. Therefore, gypenosides have good neuroprotective effects and hypoxia tolerance activity and have the prospect of being developed as a preventive and therapeutic drug for hypoxia-related diseases. PRACTICAL APPLICATIONS: Gypenosides can enhance tolerance of cells and mice to hypoxia and have the potential to be developed into hypoxia-resistant health food and drugs.
Extracellular matrix (ECM) assembly/disassembly is a critical regulator for airway epithelial development and remodeling. Airway organoid is widely used in respiratory research, yet there is limited ...study to indicate the roles and mechanisms of ECM organization in epithelial growth and differentiation by using in vitro organoid system. Moreover, most of current Matrigel-based airway organoids are in basal-out orientation where accessing the apical surface is challenging. We present a human apical-out airway organoid using a biochemically defined hybrid hydrogel system. During human nasal epithelial progenitor cells (hNEPCs) differentiation, the gel gradually degrade, leading to the organoid apical surfaces facing outward. The expression and activity of ECM-degrading enzymes, matrix metalloproteinases (MMP7, MMP9, MMP10 and MMP13) increases during organoid differentiation, where inhibition of MMPs significantly suppresses the normal ciliation, resulting in increased goblet cell proportion. Moreover, a decrease of MMPs is found in goblet cell hyperplastic epithelium in inflammatory mucosa. This system reveals essential roles of epithelial-derived MMPs on epithelial cell fate determination, and provides an applicable platform enabling further study for ECM in regulating airway development in health and diseases.
Metapopulation structure generated by recurrent extinctions and recolonizations plays an important role in the evolution of species but is rarely considered in agricultural systems. In this study, ...generation and mechanism of metapopulation structure were investigated by microsatellite assaying 725 isolates of
sampled from potato hosts at 16 locations across China. We found a single major cluster, no isolate-geography associations and no bottlenecks in the
isolates, suggesting a metapopulation genetic structure of the pathogen. We also found weak isolation-by-distance, lower among than within cropping region population differentiation, concordant moving directions of potato products and net gene flow and the highest gene diversity in the region with the most potato imports. These results indicate that in addition to natural dispersal, human-mediated gene flow also contributes to the generation and dynamics of the metapopulation genetic structure of
in China. Metapopulation structure increases the adaptive capacity of the plant pathogen as a result of enhanced genetic variation and reduced population fragmentation. Consequently, rigid quarantine regulations may be required to reduce population connectivity and the evolutionary potential of
and other pathogens with a similar population dynamics for a sustainable plant disease management.
To evaluate signal enhancement ratio (SER) for tissue characterization and prognosis stratification in pancreatic adenocarcinoma (PDAC), with quantitative histopathological analysis (QHA) as the ...reference standard.
This retrospective study included 277 PDAC patients who underwent multi-phase contrast-enhanced (CE) MRI and whole-slide imaging (WSI) from three centers (2015-2021). SER is defined as (SI
- SI
)/(SI
- SI
), where SI
, SI
and SI
represent the signal intensity of the tumor in pre-contrast, early-, and late post-contrast images, respectively. Deep-learning algorithms were implemented to quantify the stroma, epithelium, and lumen of PDAC on WSIs. Correlation, regression, and Bland-Altman analyses were utilized to investigate the associations between SER and QHA. The prognostic significance of SER on overall survival (OS) was evaluated using Cox regression analysis and Kaplan-Meier curves.
The internal dataset comprised 159 patients, which was further divided into training, validation, and internal test datasets (n = 60, 41, and 58, respectively). Sixty-five and 53 patients were included in two external test datasets. Excluding lumen, SER demonstrated significant correlations with stroma (r = 0.29-0.74, all p < 0.001) and epithelium (r = -0.23 to -0.71, all p < 0.001) across a wide post-injection time window (range, 25-300 s). Bland-Altman analysis revealed a small bias between SER and QHA for quantifying stroma/epithelium in individual training, validation (all within ± 2%), and three test datasets (all within ± 4%). Moreover, SER-predicted low stromal proportion was independently associated with worse OS (HR = 1.84 (1.17-2.91), p = 0.009) in training and validation datasets, which remained significant across three combined test datasets (HR = 1.73 (1.25-2.41), p = 0.001).
SER of multi-phase CE-MRI allows for tissue characterization and prognosis stratification in PDAC.
The signal enhancement ratio of multi-phase CE-MRI can serve as a novel imaging biomarker for characterizing tissue composition and holds the potential for improving patient stratification and therapy in PDAC.
Imaging biomarkers are needed to better characterize tumor tissue in pancreatic adenocarcinoma. Signal enhancement ratio (SER)-predicted stromal/epithelial proportion showed good agreement with histopathology measurements across three distinct centers. Signal enhancement ratio (SER)-predicted stromal proportion was demonstrated to be an independent prognostic factor for OS in PDAC.
The formation of fat-laden foam cells, contributing to the fatty streaks of the plaques of atheroma, is the critical early process in atherosclerosis. The previous study demonstrated that vascular ...smooth muscle cells (VSMCs) contain a much larger burden of the excess cholesterol in comparison with monocyte-derived macrophages in human coronary atherosclerosis, as the main origin of foam cells. It is noteworthy that VSMC-derived foam cells are deposited in subintima but not media, where VSMCs normally deposit in. Therefore, migration from media to intima is an indispensable step for a VSMC to accrue neutral lipids and form foam cell. Whether this migration occurs paralleled with or prior to the formation of foam cell is still unclear. Herein, the present study was designed to test the VSMC migratory capability in the process of foam cell formation induced by oxidized low-density lipoprotein (oxLDL). In conclusion, we provide evidence that oxLDL induces the VSMC-derived foam cells formation with increased migration ability and MMP-9 expression, which were partly attributed to the impaired SIRT1 and enhanced nuclear factor-kappa B (NF-κB) activity. As activation of transient receptor potential vanilloid type 1 (TRPV1) has been reported to have anti-atherosclerotic effects, we investigated its role in oxLDL-treated VSMC migration. It is found that activating TRPV1 by capsaicin inhibits VSMC foam cell formation and the accompanied migration through rescuing the SIRT1 and suppressing NF-κB signaling. The present study provides evidence that SIRT1 may be a promising intervention target of atherosclerosis, and raises the prospect of TRPV1 in prevention and treatment of atherosclerosis.
► A novel green MAAEE technique is developed for the I. indigotica seed oil extraction. ► MAAEE process with enzyme cocktail is optimized by response contour methodology. ► MAAEE-oil reveals better ...oxidation stability as against Soxhlet extraction-oil. ► MAAEE-oil has more PUFA, tocopherols and phenolics than Soxhlet extraction-oil. ► MAAEE-oil exhibits stronger antioxidant activity than Soxhlet extraction-oil.
A novel and green microwave-assisted aqueous enzymatic extraction (MAAEE) of oil from Isatis indigotica seeds was investigated in the present study. Enzyme cocktail (cellulase/proteinase/pectinase=1/1/1, w/w/w) was found to be the most effective in releasing the oil. Under the optimal conditions as enzyme concentration 1.82% (w/w), temperature 43°C, time 83min and irradiation power 375W, the highest oil recovery of 59.27% was obtained using the emerging technique. As compared to conventional Soxhlet extraction-derived oil (SEO), MAAEE-derived oil (MAAEEO) revealed the similar physicochemical properties but exhibited better oxidation stability. In addition, MAAEEO had higher contents of valuable polyunsaturated fatty acids, tocopherols and phenolics as against SEO, and it exhibited considerable antioxidant activities with IC50 values 9.58 and 15.03mg/mL, according to DPPH radical scavenging assay and β-carotene/linoleic acid bleaching test, respectively. Scanning electron micrographs illustrated the severely structural disruptions of sample cell walls and membranes by MAAEE.
Terminal differentiation failure is an important cause of rhabdomyosarcoma genesis, however, little is known about the epigenetic regulation of aberrant myogenic differentiation. Here, we show that ...GATA-4 recruits polycomb group proteins such as EZH2 to negatively regulate miR-29a in undifferentiated C2C12 myoblast cells, whereas recruitment of GRIP-1 to GATA-4 proteins displaces EZH2, resulting in the activation of miR-29a during myogenic differentiation of C2C12 cells. Moreover, in poorly differentiated rhabdomyosarcoma cells, EZH2 still binds to the miR-29a promoter with GATA-4 to mediate transcriptional repression of miR-29a. Interestingly, once re-differentiation of rhabdomyosarcoma cells toward skeletal muscle, EZH2 was dispelled from miR-29a promoter which is similar to that in myogenic differentiation of C2C12 cells. Eventually, this expression of miR-29a results in limited rhabdomyosarcoma cell proliferation and promotes myogenic differentiation. We thus establish that GATA-4 can function as a molecular switch in the up- and downregulation of miR-29a expression. We also demonstrate that GATA-4 acts as a tumor suppressor in rhabdomyosarcoma partly via miR-29a, which thus provides a potential therapeutic target for rhabdomyosarcoma.
Abstract Zero‐dimensional (0D) hybrid manganese halides have gained wide attention for the various crystal structures, excellent optical performance and scintillation properties compared with 3D lead ...halide perovskite nanocrystals. In this work, a new family of 0D hybrid manganese halides of A 2 MnBr 4 (A = BzTPP, Br‐BzTPP, and F‐BzTPP) based on discrete MnBr 4 2− tetrahedral units is reported as highly efficient lead‐free scintillators. Excited by UV or blue light, these hybrids emit bright green light originating from the d – d transition of Mn 2+ with near‐unity PLQY (99.5%). Significantly, high PLQY and low self‐absorption render extraordinary radioluminescence properties with the highest light yield of 80,100 photons MeV −1 , which reached the climax of present hybrid manganese halides and surpassed most commercial scintillators. The radioluminescence intensity features a linear response to X‐ray doses with a detection limit of 30 nGy air s −1 , far lower than the requirement of medical diagnostic (5.5 µGy air s −1 ). X‐ray imaging demonstrates ultrahigh spatial resolution of 14.06 lp mm −1 and short afterglow of 0.3 ms showcasing promising application prospects in radiography. Overall, we demonstrated new hybrid manganese halides as promising scintillators for advanced applications in X‐ray imaging with multiple superiorities of nontoxicity, facile‐assembly process, high irradiation light yield, excellent resolution, and stability.
Since Alzheimer's disease (AD) is a complex and multifactorial neuropathology, the discovery of multi-targeted inhibitors has gradually demonstrated greater therapeutic potential. Neurofibrillary ...tangles (NFTs), the main neuropathologic hallmarks of AD, are mainly associated with hyperphosphorylation of the microtubule-associated protein Tau. The overexpression of GSK3β and DYRK1A has been recognized as an important contributor to hyperphosphorylation of Tau, leading to the strategy of using dual-targets inhibitors for the treatment of this disorder. ZDWX-12 and ZDWX-25, as harmine derivatives, were found good inhibition on dual targets in our previous study. Here, we firstly evaluated the inhibition effect of Tau hyperphosphorylation using two compounds by HEK293-Tau P301L cell-based model and okadaic acid (OKA)-induced mouse model. We found that ZDWX-25 was more effective than ZDWX-12. Then, based on comprehensively investigations on ZDWX-25 in vitro and in vivo, 1) the capability of ZDWX-25 to show a reduction in phosphorylation of multiple Tau epitopes in OKA-induced neurodegeneration cell models, and 2) the effect of reduction on NFTs by 3xTg-AD mouse model under administration of ZDWX-25, an orally bioavailable, brain-penetrant dual-targets inhibitor with low toxicity. Our data highlight that ZDWX-25 is a promising drug for treating AD.
•The effects of ZDWX-25 had been investigated for the first time in several models of Tau hyperphosphorylation.•ZDWX-25 reduced the formation of NFTs in 3×Tg AD mice and thus improving cognitive function in model AD mice.•ZDWX-25 had good BBB permeability, good PK properties and low toxic effects, and it was a promising anti-AD drug.
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