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1.
Environ Res ; 259: 119549, 2024 Jul 02.
Artículo en Inglés | MEDLINE | ID: mdl-38964576

RESUMEN

Methane (CH4) is the second most abundant greenhouse gas. China is the largest CH4 emitter in the world, with coal mine methane (CMM) being one of the main anthropogenic contributions. Thus, there is an urgent need for comprehensive estimates and strategies for reducing CMM emissions in China. However, the development of effective strategies is currently challenged by a lack of information on temporal variations in the contributions of different CMM sources and the absence of provincial spatial analysis. Here, considering five sources and utilization, we build a comprehensive inventory of China's CMM emissions from 1980 to 2022 and quantify the contributions of individual sources to the overall CMM emissions at the national and provincial levels. Our results highlight a significant shift in the source contributions of CMM emissions, with the largest contributor, underground mining, decreasing from 89% in 1980 to 69% in 2022. Underground abandoned coal mines, which were ignored or underestimated in past inventories, have become the second source of CMM emissions since 1999. From 2011 to 2022, we identified Shanxi, Guizhou, and Shaanxi as the three largest CMM-emitting provinces, while the Emissions Database for Global Atmospheric Research (EDGAR) v8 overestimated emissions from Inner Mongolia, ranking it third. Notably, we observed a substantial decrease (exceeding 1 Mt) in CMM emissions in Sichuan, Henan, Liaoning, and Hunan between 2011 and 2022, which was not captured by EDGAR v8. To develop targeted CMM emission reduction strategies at the provincial level, we classified 31 provinces into four groups based on their CMM emission structures. In 2022, the number of provinces with CMM emissions mainly from abandoned coal mines has exceeded that of provinces with mainly underground mines, which requires attention. This study reveals the characteristics of the source of CMM emissions in China and provides emission reduction directions for four groups of provinces.

2.
Nutrients ; 16(12)2024 Jun 19.
Artículo en Inglés | MEDLINE | ID: mdl-38931311

RESUMEN

Post-traumatic stress disorder (PTSD) is a persistent psychiatric condition that arises following exposure to traumatic events such as warfare, natural disasters, or other catastrophic incidents, typically characterized by heightened anxiety, depressive symptoms, and cognitive dysfunction. In this study, animals subjected to single prolonged stress (SPS) were administered evodiamine (EVO) and compared to a positive control group receiving sertraline. The animals were then assessed for alterations in anxiety, depression, and cognitive function. Histological analysis was conducted to examine neuronal changes in the hippocampus. In order to predict the core targets and related mechanisms of evodiamine intervention in PTSD, network pharmacology was used. The metabolic markers pre- and post-drug administration were identified using nontargeted serum metabolomics techniques, and the intersecting Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were screened. Finally, the core targets were validated through molecular docking, enzyme-linked immunosorbent assays, and immunofluorescence staining to confirm the anti-PTSD effects and mechanisms of these targets. As well as improving cognitive impairment, evodiamine reversed anxiety- and depression-like behaviors. It also inhibited the reduction in the number of hippocampal neuronal cells and Nissl bodies in SPS mice inhibited angiotensin converting enzyme (ACE) levels in the hippocampus of SPS mice, and modulated the renin angiotensin pathway and its associated serum metabolites in brain tissue. Evodiamine shows promise as a potential candidate for alleviating the symptoms of post-traumatic stress disorder.


Asunto(s)
Modelos Animales de Enfermedad , Hipocampo , Neuronas , Quinazolinas , Sistema Renina-Angiotensina , Trastornos por Estrés Postraumático , Animales , Trastornos por Estrés Postraumático/tratamiento farmacológico , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Quinazolinas/farmacología , Ratones , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Masculino , Sistema Renina-Angiotensina/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Depresión/tratamiento farmacológico , Simulación del Acoplamiento Molecular , Ansiedad/tratamiento farmacológico , Ratones Endogámicos C57BL , Farmacología en Red
4.
Ecotoxicol Environ Saf ; 281: 116563, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38878560

RESUMEN

Evodiamine (EVO), the main active alkaloid in Evodia rutaecarpa, was shown to exert various pharmacological activities, especially anti-tumor. Currently, it is considered a potential anti-cancer drug due to its excellent anti-tumor activity, which unfortunately has adverse reactions, such as the risk of liver and kidney injury, when Evodia rutaecarpa containing EVO is used clinically. In the present study, we aim to clarify the potential toxic target organs and toxicity mechanism of EVO, an active monomer in Evodia rutaecarpa, and to develop mitigation strategies for its toxicity mechanism. Transcriptome analysis and related experiments showed that the PI3K/Akt pathway induced by calcium overload was an important step in EVO-induced apoptosis of renal cells. Specifically, intracellular calcium ions were increased, and mitochondrial calcium ions were decreased. In addition, EVO-induced calcium overload was associated with TRPV1 receptor activation. In vivo TRPV1 antagonist and calcium chelator effects were observed to significantly reduce body weight loss and renal damage in mice due to EVO toxicity. The potential nephrotoxicity of EVO was further confirmed by an in vivo test. In conclusion, TRPV1-mediated calcium overload-induced apoptosis is one of the mechanisms contributing to the nephrotoxicity of EVO due to its toxicity, whereas maintaining body calcium homeostasis is an effective measure to reduce toxicity. These studies suggest that the clinical use of EVO-containing herbal medicines should pay due attention to the changes in renal function of patients as well as the off-target effects of the drugs.


Asunto(s)
Apoptosis , Calcio , Evodia , Homeostasis , Riñón , Quinazolinas , Quinazolinas/toxicidad , Quinazolinas/farmacología , Animales , Homeostasis/efectos de los fármacos , Calcio/metabolismo , Ratones , Apoptosis/efectos de los fármacos , Riñón/efectos de los fármacos , Riñón/patología , Evodia/química , Masculino , Canales Catiónicos TRPV/metabolismo , Quelantes del Calcio/farmacología
5.
Comput Biol Med ; 178: 108747, 2024 Jun 18.
Artículo en Inglés | MEDLINE | ID: mdl-38897150

RESUMEN

BACKGROUND: Ovarian cancer (OV) is a common malignant tumor of the female reproductive system with a 5-year survival rate of ∼30 %. Inefficient early diagnosis and prognosis leads to poor survival in most patients. G protein-coupled receptors (GPCRs, the largest family of human cell surface receptors) are associated with OV. We aimed to identify GPCR-related gene (GPCRRG) signatures and develop a novel model to predict OV prognosis. METHOD: We downloaded data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Prognostic GPCRRGs were screened using least absolute shrinkage and selection operator (LASSO) Cox regression analysis, and a prognostic model was constructed. The predictive ability of the model was evaluated by Kaplan-Meier (K-M) survival analysis. The levels of GPCRRGs were examined in normal and OV cell lines using quantitative reverse-Etranscription polymerase chain reaction. The immunological characteristics of the high- and low-risk groups were analyzed using single-sample gene set enrichment analysis (ssGSEA) and CIBERSORT. RESULTS: Based on the risks scores, 17 GPCRRGs were associated with OV prognosis. CXCR4, GPR34, LGR6, LPAR3, and RGS2 were significantly expressed in three OV datasets and enabled accurate OV diagnosis. K-M analysis of the prognostic model showed that it could differentiate high- and low-risk patients, which correspond to poorer and better prognoses, respectively. GPCRRG expression was correlated with immune infiltration rates. CONCLUSIONS: Our prognostic model elaborates on the roles of GPCRRGs in OV and provides a new tool for prognosis and immune response prediction in patients with OV.

6.
Sci Rep ; 14(1): 12134, 2024 May 27.
Artículo en Inglés | MEDLINE | ID: mdl-38802431

RESUMEN

Online rumors are widespread and difficult to identify, which bring serious harm to society and individuals. To effectively detect and govern online rumors, it is necessary to conduct in-depth semantic analysis and understand the content features of rumors. This paper proposes a TFI domain ontology construction method, which aims to achieve semantic parsing and reasoning of the rumor text content. This paper starts from the term layer, the frame layer, and the instance layer, and based on the reuse of the top-level ontology, the extraction of core literature content features, and the discovery of new concepts in the real corpus, obtains the core classes (five parent classes and 88 subclasses) of the rumor domain ontology and defines their concept hierarchy. Object properties and data properties are designed to describe relationships between entities or their features, and the instance layer is created according to the real rumor datasets. OWL language is used to encode the ontology, Protégé is used to visualize it, and SWRL rules and pellet reasoner are used to mine and verify implicit knowledge of the ontology, and judge the category of rumor text. This paper constructs a rumor domain ontology with high consistency and reliability.

7.
J Hazard Mater ; 470: 134218, 2024 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-38581878

RESUMEN

The development of high-performance sensors for doxycycline (DOX) detection is necessary because its residue accumulation will cause serious harm to human health and the environment. Here, a novel tri-emission ratiometric fluorescence sensor was proposed by using "post-mixing" strategy of different emissions fluorescence molecularly imprinted polymers with salicylamide as dummy template (DMIPs). BSA was chosen as assistant functional monomer, and also acted as sensitizers for the aggregation-induced emission (AIE) effect of DOX. The blue-emitting carbon dots and the red-emitting CdTe quantum dots were separately introduced into DMIPs as the response signals. Upon DOX recognition within 2 min, blue and red fluorescence of the tri-emission DMIPs sensor were quenched while green fluorescence of DOX was enhanced, resulting in a wide range of color variations observed over bluish violet-rosered-light pink-orange-yellow-green with a detection limit of 0.061 µM. The sensor possessed highly selective recognition and was successfully applied to detect DOX in complicated real samples. Moreover, with the fluorescent color collection and data processing, the smartphone-assisted visual detection of the sensors showed satisfied sensitivity with low detection limit. This work provides great potential applications for rapid and visual detection of antibiotics in complex substrates.


Asunto(s)
Antibacterianos , Compuestos de Cadmio , Doxiciclina , Impresión Molecular , Puntos Cuánticos , Espectrometría de Fluorescencia , Telurio , Doxiciclina/análisis , Doxiciclina/química , Puntos Cuánticos/química , Telurio/química , Antibacterianos/análisis , Compuestos de Cadmio/química , Límite de Detección , Fluorescencia , Carbono/química , Colorantes Fluorescentes/química , Polímeros Impresos Molecularmente/química , Teléfono Inteligente
8.
Mol Psychiatry ; 2024 Apr 24.
Artículo en Inglés | MEDLINE | ID: mdl-38658772

RESUMEN

Early onset familial Alzheimer's disease (FAD) with APP, PS1/2 (presenilins) mutation accounts for only a small portion of AD cases, and most are late-onset sporadic. However, majority of AD mouse models are developed to mimic the genetic cause of human AD by overexpressing mutated forms of human APP, PS1/2, and/or Tau protein, though there is no Tau mutation in AD, and no single mouse model recapitulates all aspects of AD pathology. Here, we report Thy1-ApoE4/C/EBPß double transgenic mouse model that demonstrates key AD pathologies in an age-dependent manner in absence of any human APP or PS1/2 mutation. Using the clinical diagnosis criteria, we show that this mouse model exhibits tempo-spatial features in AD patient brains, including progressive cognitive decline associated with brain atrophy, which is accompanied with extensive neuronal degeneration. Remarkably, the mice display gradual Aß aggregation and neurofibrillary tangles formation in the brain validated by Aß PET and Tau PET. Moreover, the mice reveal widespread neuroinflammation as shown in AD brains. Hence, Thy1-ApoE4/C/EBPß mouse model acts as a sporadic AD mouse model, reconstituting the major AD pathologies.

9.
Front Psychol ; 15: 1358903, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38558778

RESUMEN

Based on the perspective of combining informal and formal systems, this paper empirically explores the impact of neighborhood effects and policy interventions on the deviation of farmers' willingness and behavior of domestic waste separation (DWS) by using data from the China Land Economy Survey (CLES) and constructing a probit model. It should be explained that the neighborhood effect in this paper refers to the fact that the behavior of farmers is highly susceptible to the behavior of their neighbors in the process of production and living. The results of the study show that neighborhood effects and policy interventions have a significant negative impact on the deviation of farmers' willingness and behavior of DWS, respectively. Comparison of marginal effects shows that neighborhood effects > environmental advocacy > reward and punishment policies. From the interaction effects as a whole, neighborhood effects and policy interventions have complementary effects on the deviation of farmers' willingness and behavior of DWS, with the complementary effects of neighborhood effects and environmental advocacy being more significant. Heterogeneity analysis reveals that neighborhood effects completely replace the inhibitory effect of policy interventions on the deviation of high-income farmers' willingness and behavior of DWS, but have no effect on political elite farmers. The interaction between neighborhood effects and policy interventions has complementary effects on low-income farmers and ordinary farmers, with the complementary effects of neighborhood effects and environmental advocacy being more significant.

10.
Nat Commun ; 15(1): 2245, 2024 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-38472279

RESUMEN

Bifacial perovskite solar cells have shown great promise for increasing power output by capturing light from both sides. However, the suboptimal optical transmittance of back metal electrodes together with the complex fabrication process associated with front transparent conducting oxides have hindered the development of efficient bifacial PSCs. Here, we present a novel approach for bifacial perovskite devices using single-walled carbon nanotubes as both front and back electrodes. single-walled carbon nanotubes offer high transparency, conductivity, and stability, enabling bifacial PSCs with a bifaciality factor of over 98% and a power generation density of over 36%. We also fabricate flexible, all-carbon-electrode-based devices with a high power-per-weight value of 73.75 W g-1 and excellent mechanical durability. Furthermore, we show that our bifacial devices have a much lower material cost than conventional monofacial PSCs. Our work demonstrates the potential of SWCNT electrodes for efficient, stable, and low-cost bifacial perovskite photovoltaics.

11.
Environ Sci Technol ; 58(13): 5750-5759, 2024 Apr 02.
Artículo en Inglés | MEDLINE | ID: mdl-38506744

RESUMEN

1,1-Difluoroethane (HFC-152a) is a hydrofluorocarbon regulated by the Montreal Protocol, and its emissions in China are of concern as China will regulate HFC-152a in 2024. However, no observation-inferred top-down estimates were undertaken after 2017, and substantial gaps existed among previous estimates of China's HFC-152a emissions. Using the atmospheric observations and inverse modeling, this study reveals China's HFC-152a emissions of 9.4 ± 1.7 Gg/yr (gigagrams per year), 10.6 ± 1.8 Gg/yr, and 9.7 ± 1.5 Gg/yr in 2018, 2019, and 2020, respectively. In addition, we display an overall increasing trend during 2011-2020, which is in contrast to the decreasing and steady trend reported by the Emission Database for Global Atmospheric Research (EDGAR) and the Chinese government, respectively. Subsequently, we establish a comprehensive bottom-up emission inventory matching with top-down estimates and thus succeed in explaining the gaps among previous estimates. Furthermore, the contribution of China's emissions to global HFC-152a emission growth increased from 15% during 2001-2010 to >100% during 2011-2020. An emission projection based on our improved inventory shows that the Kigali Amendment (KA) would assist in avoiding 1535.6-4710.6 Gg (251.8-772.5 Tg CO2-eq) HFC-152a emissions during 2024-2100. Our findings indicate relatively accurate China's HFC-152a emissions and provide scientific support for addressing climate change and implementing the KA.


Asunto(s)
Gases de Efecto Invernadero , Rwanda , China , Cambio Climático
12.
J Hazard Mater ; 469: 133969, 2024 May 05.
Artículo en Inglés | MEDLINE | ID: mdl-38460257

RESUMEN

Marine algal toxin contamination is a major threat to human health. Thus, it is crucial to develop rapid and on-site techniques for detecting algal toxins. In this work, we developed colorimetric cloth and paper hybrid microfluidic devices (µCPADs) for rapid detection of gonyautoxin (GTX1/4) combined with molecularly imprinted polymers. In addition, the metal-organic frameworks (MOFs) composites were applied for this approach by their unique features. Guanosine serves as a dummy template for surface imprinting and has certain structural advantages in recognizing gonyautoxin. MOF@MIPs composites were able to perform a catalytic color reaction using hydrogen peroxide-tetramethylbenzidine for the detection of GTX1/4. The cloth-based sensing substrates were assembled on origami µPADs to form user-friendly, miniaturized colorimetric µCPADs. Combined with a smartphone, the proposed colorimetric µCPADs successfully achieved a low limit of detection of 0.65 µg/L within the range of 1-200 µg/L for rapid visual detection of GTX1/4. Moreover, the GTX1/4 of real shellfish and seawater samples were satisfactorily detected to indicate the application prospect of the µCPADs. The proposed method shows good potential in the low-cost, stable establishment of assays for the rapid detection of environmental biotoxins.


Asunto(s)
Estructuras Metalorgánicas , Impresión Molecular , Saxitoxina/análogos & derivados , Humanos , Estructuras Metalorgánicas/química , Impresión Molecular/métodos , Límite de Detección
13.
Sci Rep ; 14(1): 5827, 2024 Mar 09.
Artículo en Inglés | MEDLINE | ID: mdl-38461303

RESUMEN

Danmakus are user-generated comments that overlay on videos, enabling real-time interactions between viewers and video content. The emotional orientation of danmakus can reflect the attitudes and opinions of viewers on video segments, which can help video platforms optimize video content recommendation and evaluate users' abnormal emotion levels. Aiming at the problems of low transferability of traditional sentiment analysis methods in the danmaku domain, low accuracy of danmaku text segmentation, poor consistency of sentiment annotation, and insufficient semantic feature extraction, this paper proposes a video danmaku sentiment analysis method based on MIBE-RoBERTa-FF-BiLSTM. This paper constructs a "Bilibili Must-Watch List and Top Video Danmaku Sentiment Dataset" by ourselves, covering 10,000 positive and negative sentiment danmaku texts of 18 themes. A new word recognition algorithm based on mutual information (MI) and branch entropy (BE) is used to discover 2610 irregular network popular new words from trigrams to heptagrams in the dataset, forming a domain lexicon. The Maslow's hierarchy of needs theory is applied to guide the consistent sentiment annotation. The domain lexicon is integrated into the feature fusion layer of the RoBERTa-FF-BiLSTM model to fully learn the semantic features of word information, character information, and context information of danmaku texts and perform sentiment classification. Comparative experiments on the dataset show that the model proposed in this paper has the best comprehensive performance among the mainstream models for video danmaku text sentiment classification, with an F1 value of 94.06%, and its accuracy and robustness are also better than other models. The limitations of this paper are that the construction of the domain lexicon still requires manual participation and review, the semantic information of danmaku video content and the positive case preference are ignored.

14.
Biomater Sci ; 12(6): 1465-1476, 2024 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-38318975

RESUMEN

Sono-photodynamic therapy (SPDT) has emerged as a promising treatment modality for triple negative breast cancer (TNBC). However, the hypoxic tumor microenvironment hinders the application of SPDT. Herein, in this study, a multifunctional platform (MnO2/Ce6@MBs) was designed to address this issue. A sono-photosensitizer (Ce6) and a hypoxia modulator (MnO2) were loaded into microbubbles and precisely released within tumor tissues under ultrasound irradiation. MnO2in situ reacted with the excess H2O2 and H+ and produced O2 within the TNBC tumor, which alleviated hypoxia and augmented SPDT by increasing ROS generation. Meanwhile, the reaction product Mn2+ was able to achieve T1-weighted MRI for enhanced tumor imaging. Additionally, Ce6 and microbubbles served as a fluorescence imaging contrast agent and a contrast-enhanced ultrasound imaging agent, respectively. In in vivo anti-tumor studies, under the FL/US/MR imaging guidance, MnO2/Ce6@MBs combined with SPDT significantly reversed tumor hypoxia and inhibited tumor growth in 4T1-tumor bearing mice. This work presents a theragnostic system for reversing tumor hypoxia and enhancing TNBC treatment.


Asunto(s)
Fotoquimioterapia , Porfirinas , Neoplasias de la Mama Triple Negativas , Humanos , Animales , Ratones , Neoplasias de la Mama Triple Negativas/diagnóstico por imagen , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Microburbujas , Compuestos de Manganeso , Peróxido de Hidrógeno , Línea Celular Tumoral , Óxidos , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/uso terapéutico , Hipoxia , Porfirinas/farmacología , Microambiente Tumoral
15.
Biomater Sci ; 12(6): 1603, 2024 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-38363155

RESUMEN

Correction for 'MnO2/Ce6 microbubble-mediated hypoxia modulation for enhancing sono-photodynamic therapy against triple negative breast cancer' by Ping Li et al., Biomater. Sci., 2024, https://doi.org/10.1039/d3bm00931a.

16.
Nat Commun ; 15(1): 1725, 2024 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-38409087

RESUMEN

According to the Montreal Protocol, the production and consumption of ozone-layer-depleting CCl4 for dispersive applications was globally phased out by 2010, including China. However, continued CCl4 emissions were disclosed, with the latest CCl4 emissions unknown in eastern China. In the current study, based on the atmospheric measurements of ~12,000 air samples taken at two sites in eastern China, the 2021-2022 CCl4 emissions are quantified as 7.6 ± 1.7 gigagrams per year. This finding indicates that CCl4 emissions continued after being phased out for dispersive uses in 2010. Subsequently, our study identifies potential industrial sources (manufacture of general purpose machinery and manufacture of raw chemical materials, and chemical products) of CCl4 emissions.

17.
Small Methods ; 8(2): e2300564, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37462256

RESUMEN

Incontrovertibly there is an increasing demand for the development of benign inks suitable for fabrication of high-performing perovskite-based thin film functional layers. Nevertheless, most reported perovskite precursors rely on the use of highly toxic solvents such as acetonitrile, 2-methoxyethanol, dimethylformamide, and many others. Hence, there is a strong imperative for the development of novel and greener inks, which will facilitate smoother commercialization of technologies based on functional perovskite films. Therefore, four perovskite precursors are studied, some of which consist of up to 90% ethanol. All inks are developed to fulfill the requirements of a high-throughput deposition compatible with roll-to-roll techniques at room temperature, assisted by an air knife for instant solvent removal. Two of the inks are particularly suitable for the fabrication of high-quality and densely packed multi-crystalline (CH3 NH3 )PbI3 layers, as confirmed by numerous nanoscale spectroscopic and material characterization techniques. Additionally, large-area photoluminescence (PL) imaging is demonstrated to improve the quality of the deposited perovskite films, with a route to enhance deposition uniformity when upscaling for manufacture. The genuine potential of the developed greener perovskite inks is demonstrated with the fabrication of solar cells with power conversion efficiencies above 19.5%.

18.
Small Methods ; 8(2): e2300223, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37330642

RESUMEN

Perovskite solar cells (PSCs) have shown rapid development recently, whereas nonideal stability remains the chief obstacle toward commercialization. Thus, it is of utmost importance to probe the degradation pathway for the entire device. Here, the extrinsic stability of inverted PSCs (IPSCs) is investigated by using standard shelf-life testing based on the International Summit on Organic Photovoltaic Stability protocols (ISOS-D-1). During the long-term assessment of 1700 h, the degraded power conversion efficiency is mainly caused by the fill factor (53% retention) and short-circuit current density (71% retention), while the open-circuit voltage still maintains 97% of the initial values. Further absorbance evolution and density functional theory calculations disclose that the perovskite rear-contact side, in particular for the perovskite/fullerene interface, is the predominant degradation pathway. This study contributes to understanding the aging mechanism and enhancing the durability of IPSCs for future applications.

19.
Neuropsychopharmacology ; 49(3): 620-630, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38030711

RESUMEN

Alzheimer's disease (AD) is a progressive neurodegenerative disease with cognitive dysfunction as its major clinical symptom. However, there is no disease-modifying small molecular medicine to effectively slow down progression of the disease. Here, we show an optimized asparagine endopeptidase (AEP, also known as δ-secretase) inhibitor, #11 A, that displays an orderly in vivo pharmacokinetics/pharmacodynamics (PK/PD) relationship and robustly attenuates AD pathologies in a sporadic AD mouse model. #11 A is brain permeable with great oral bioavailability. It blocks AEP cleavage of APP and Tau dose-dependently, and significantly decreases Aß40 and Aß42 and p-Tau levels in APP/PS1 and Tau P301S mice after oral administration. Notably, #11 A strongly inhibits AEP and prevents mouse APP and Tau fragmentation by AEP, leading to reduction of mouse Aß42 (mAß42), mAß40 and mouse p-Tau181 levels in Thy1-ApoE4/C/EBPß transgenic mice in a dose-dependent manner. Repeated oral administration of #11 A substantially decreases mAß aggregation as validated by Aß PET assay, Tau pathology, neurodegeneration and brain volume reduction, resulting in alleviation of cognitive impairment. Therefore, our results support that #11 A is a disease-modifying preclinical candidate for pharmacologically treating AD.


Asunto(s)
Enfermedad de Alzheimer , Cisteína Endopeptidasas , Enfermedades Neurodegenerativas , Ratones , Animales , Enfermedad de Alzheimer/patología , Proteínas tau , Ratones Transgénicos , Péptidos beta-Amiloides , Modelos Animales de Enfermedad
20.
Regen Ther ; 25: 77-84, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38111468

RESUMEN

Introduction: Angiogenesis plays an important role in the repair of urethral injury, and stem cells and their secretomes can promote angiogenesis. We obtained pediatric urethral mesenchymal stem-like cells (PU-MSLCs) in an earlier study. This project studied the pro-angiogenic effect of PU-MSLC-derived small extracellular vesicles (PUMSLC-sEVs) and the underlying mechanisms. Materials and methods: PUMSLCs and PUMSLC-sEVs were cultivated and identified. Then, biological methods such as the ethynyl deoxyuridine (EdU) incorporation assay, Cell Counting Kit-8 (CCK-8) assay, scratch wound assay, Transwell assay, and tube formation assay were used to study the effect of PUMSLC-sEVs on the proliferation, migration, and tube formation of human umbilical vein endothelial cells (HUVECs). We explored whether the proangiogenic effect of PUMSLC-sEVs is related to CD73 and whether adenosine (ADO, a CD73 metabolite) promoted angiogenesis. GraphPad Prism 8 software was used for data analysis. Results: We observed that PUMSLC-sEVs significantly promoted the proliferation, migration, and tube-forming abilities of HUVECs. PUMSLC-sEVs delivered CD73 molecules to HUVECs to promote angiogenesis. The angiogenic ability of HUVECs was enhanced after treatment with extracellular ADO produced by CD73, and PUMSLC-sEVs further promoted angiogenesis by activating Adenosine Receptor A2A (A2AR). Conclusions: These observations suggest that PUMSLC-sEVs promote angiogenesis, possibly through activation of the CD73/ADO/A2AR signaling axis.

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