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2.
Artigo em Inglês | MEDLINE | ID: mdl-34501802

RESUMO

In China, organophosphate esters (OPEs) are widely used in indoor environments. However, there is little information regarding the internal and external exposure of university students to OPEs. Therefore, in this study, nine OPEs and eight OPE metabolites (mOPEs) were measured in indoor dust and atmospheric PM2.5 samples from a university campus in Shanghai, as well as in urine samples collected from the university students. The total concentration of OPEs in the indoor dust in female dormitories (1420 ng/g) was approximately twice that in male dormitories (645 ng/g). In terms of indoor PM2.5, the highest OPE concentration was found in meeting rooms (105 ng/m3, on average), followed by chemical laboratories (51.2 ng/m3), dormitories (44.9 ng/m3), and offices (34.9 ng/m3). The total concentrations of the eight mOPEs ranged from 279 pg/mL to 14,000 pg/mL, with a geometric mean value of 1590 pg/mL. The estimated daily intake values based on the indoor dust and PM2.5 OPE samples (external exposure) were 1-2 orders of magnitude lower than that deduced from the concentration of urinary mOPEs (internal exposure), indicating that dermal contact, dust ingestion, and inhalation do not contribute significantly to OPE exposure in the general population. Moreover, additional exposure routes lead to the accumulation of OPEs in the human body.

3.
Hepatology ; 2021 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-34510484

RESUMO

OBJECTIVES: Aging exacerbates liver neutrophil infiltration and alcohol-associated liver disease (ALD) in mice and humans, but the underlying mechanisms remain obscure. This study aimed to examine the effect of aging and alcohol consumption on neutrophilic Sirtuin 1 (SIRT1) and microRNA-223 (miR-223), and their contribution to ALD pathogeneses. DESIGN: Young and aged mice, myeloid-specific Sirt1 knockout mice were subjected to chronic-plus-binge ethanol feeding. Blood samples from healthy controls and patients with chronic alcohol drinking presented with acute intoxication were analyzed. RESULTS: Neutrophilic Sirt1 and miR-223 expression were downregulated in aged mice compared to young mice. Deletion of the Sirt1 gene in myeloid cells including neutrophils exacerbated chronic-plus-binge ethanol-induced liver injury and inflammation and downregulated neutrophilic miR-223 expression. Immunoprecipitation experiments revealed that SIRT1 promoted C/EBPα deacetylation by directly interacting with C/EBPα, a key transcription factor that controls miR-223 biogenesis, and subsequently elevated miR-223 expression in neutrophils. Importantly, downregulation of SIRT1 and miR-223 expression was also observed in circulating neutrophils from middle-aged and elderly subjects compared to those from young individuals. Chronic alcohol users with acute intoxication had a reduction in neutrophilic SIRT1 expression in young and middle-aged patients, with a greater reduction in the latter group. The neutrophilic SIRT1 expression correlated with neutrophilic miR-223 and serum alanine transaminase levels in those patients. CONCLUSIONS: Aging increases the susceptibility of alcohol-induced liver injury in mice and humans via the downregulation of the neutrophilic SIRT1-C/EBPα-miR-223 axis, which could be a novel therapeutic target for the prevention and/or treatment of ALD.

4.
Pathol Res Pract ; 226: 153603, 2021 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-34500374

RESUMO

BACKGROUND: Triple-negative breast cancer (TNBC) has a high probability of relapse and poor overall survival. Neoadjuvant chemotherapy (NACT) is currently a routine treatment strategy for TNBC, but some patients do not respond well. T-LAK cell-originated protein kinase (TOPK) is highly expressed in breast cancer cells and contributes to cancer cell proliferation. The present study aimed to investigate the correlation of TOPK expression with NACT treatment response and prognosis in TNBC. METHODS: We collected 66 pairs of TNBC samples before and after NACT with docetaxel+ epirubicin+ cyclophosphamide (TEC). The Miller-Payne (MP) system was used to assess the therapeutic response to NACT in TNBC patients. RESULTS: Immunohistochemistry analysis showed that TNBC patients with high TOPK expression before NACT had a poor treatment response and a poor prognosis. The expression of TOPK after NACT was significantly higher than that before NACT in patients with MP grade 1-3. In contrast, patients with MP grade 4-5 had significantly lower TOPK expression after NACT than before NACT, and the expression change in Ki-67 in patients with MP grade 4-5 exhibited the same trend. Survival analysis revealed that patients with TNBC accompanied by elevated TOPK expression before NACT had a worse prognosis than those with lower TOPK expression. CONCLUSION: TOPK may be a novel predictor for the therapeutic response to NACT and prognosis for patients with TNBC.

5.
Mol Med ; 27(1): 113, 2021 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-34535085

RESUMO

BACKGROUND: Increasing evidence has indicated that circular RNAs (circRNAs) play a role in various diseases. However, the influence of circRNAs in nephritis remains unknown. METHODS: Microarray analysis and RT-qPCR were used to detect the expression of circRNA. Type I IFN were administrated to RMC and HEK293 cells to establish a nephritis cell model. CCK-8, MTT assay, and flow cytometry were used to assess cell proliferation, viability, and apoptosis of cells. Bioinformatics analysis and dual luciferase reporter assay detect the interaction of circ_0007059, miRNA-1278, and SHP-1. Glomerulonephritis was performed in a mouse model by administration of IFNα-expressing adenovirus. IHC staining showed the pathogenic changes. RESULTS: In the present study, the expression of circ_0007059 in type I interferon (IFN)-treated renal mesangial cells (RMCs), lupus nephritis (LN) specimens, and HEK293 cells was downregulated compared with that in normal healthy samples and untreated cells. Circ_0007059 overexpression resulted in increased cell proliferation, cell viability, apoptosis, and inflammation-associated factors (CXCL10, IFIT1, ISG15, and MX1) in RMCs and HEK293 cells. In addition, circ_0007059 overexpression significantly restored cell proliferation and viability and inhibited IFN-induced apoptosis. Further, the increased expression resulted in reduced inflammation and the downregulation of CXCL10, IFIT1, ISG15, and MX1 in RMCs and HEK293 cells. Circ_0007059 serves as a sponge for miR-1278 so that the latter can target the 3'-untranslated region of SHP-1. Overexpressed circ_0007059 inhibited miR-1278 expression and elevated SHP-1 expression, subsequently reducing STAT3 phosphorylation. Meanwhile, miR-1278 was upregulated and SHP-1 was downregulated in LN samples and IFN-treated cells. The restoration of miR-1278 counteracted the effect of circ_0007059 on viability, apoptosis, and inflammation as well as on SHP-1/STAT3 signaling in RMCs and HEK293 cells. We also investigated the role of SHP-1 overexpression in IFN-treated RMCs and HEK293 cells; SHP-1 overexpression resulted in a similar phenotype as that observed with circ_0007059 expression. CONCLUSIONS: The study indicates that circ_0007059 protects RMCs against apoptosis and inflammation during nephritis by attenuating miR-1278/SHP-1/STAT3 signaling.

6.
Artigo em Inglês | MEDLINE | ID: mdl-34536214

RESUMO

In December 2019, the COVID-19 pandemic quickly spread throughout China and beyond, posing enormous global challenges. With prompt, vigorous, and coordinated control measures, mainland China contained the spread of the epidemic within two months and halted the epidemic in three months. Aggressive containment strategy, hierarchical management, rational reallocation of resources, efficient contact tracing, and voluntary cooperation of Chinese citizens contributed to the rapid and efficient control of the epidemic, thus promoting the rapid recovery of the Chinese economy. This review summarizes China's prevention and control strategies and other public health measures, which may provide a reference for the epidemic control in other countries.

7.
Clin Exp Hypertens ; : 1-6, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34523366

RESUMO

BACKGROUND: Primary hypertension is one of the most well-known risk factors for cardiovascular disease. Currently, there is still no ideal indicator for left ventricular end-diastolic pressure. METHODS: 73 hypertension patients and 37 healthy people were enrolled in this study. Each member was examined with conventional echocardiography including multiple indicators such as Peak mitral valve flow velocity (E, A), E/A, left atrial volume index (LAVl), tissue Doppler (PW-TDI) peak velocities during early and late diastolic mitral valve flow (e '), E/e ', and GLS. We have collected clinical data from all enrolled members. The above cardiac ultrasound indicators were obtained before the antihypertensive treatment, one month and three months after treatment. RESULTS: Left ventricular end-diastolic pressure (LVEDP) was positively correlated and negatively correlated with GLS (r = 0.638, P < .01) and E/e' (r = -0.578, P < .05), respectively. The hypertensives had lower e' value and higher values of GLS, E/e', and LAVI than the control group (P < .05). GLS and E/e' were significantly lower in hypertension group than those in the Control group after one month and three months of treatment (P < .05). The improvement rate of GLS was significantly higher than those in the improvement rate of e', E/e', LAVI after treatment (p < .05). CONCLUSION: The GLS improvement rate was significantly higher than those of e', E/e' after one and three-month treatment. Therefore, GLS might be a potential ideal index for patients with anti-hypertension treatment. The results obtained in this study provide useful information for further study.

8.
Oncoimmunology ; 10(1): e1964189, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34513318

RESUMO

Although the vast majority of patients with papillary thyroid cancer (PTC) have a favorable prognosis when conventional treatments are implemented, local recurrence and distant metastasis of advanced PTCs still hamper the survival and clinical management in certain patients. As immune checkpoint blockade (ICB) therapy achieves a great success in some advanced cancers, we aimed to investigate the immune landscape in PTC and its potential implications for prognosis and immunotherapy. In this study, different algorithms were conducted to estimate immune infiltration in PTC samples. A series of bioinformatic and machine learning approaches were performed to identify PTC-specific immune-related genes (IRGs) and distinct immune clusters. Differences in intrinsic tumor immunogenicity and potential immunotherapy response were observed between distinct immune clusters. A prognostic immune-related signature (IRS) was established to predict progression-free survival (PFS). IRS exhibited more powerful prognostic capacity and accurate survival prediction compared to conventional clinicopathological features. Furthermore, an integrated survival decision tree and a scoring nomogram were constructed to improve prognostic stratification and predictive accuracy for individual patients. In addition, altered pathways, mutational patterns, and potential applicable drugs were analyzed in different immune-related risk groups. Our study gained some insight into the immune landscape of PTC, and provided some useful clues for introducing immune-based molecular classification into risk stratification and guiding ICB decision-making.

9.
Virus Genes ; 2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34519961

RESUMO

H9N2 subtype avian influenza virus has dramatically evolved and undergone extensive reassortment since its emergence in early 1990s in China. The genotype S (G57), emerging in 2007 with the substitution of F98-like PB2 and M gene by G1-like ones, has become the overwhelming predominant genotype for the past 11 years since 2010. Here, we found that virus with G1-like PB2 were more efficient in protein expression and in infectious virus production than that with F98-like PB2 gene. By coinfected MDCK cells with the reassortant virus, more survival opportunity for viruses with G1-like PB2 than that of F/98-like was observed. Besides, in animal experiments, we found that the G1-like PB2 increases virus infectivity, replication, and virus shedding of H9N2 in chickens. Our results suggested that the substitution of G1-like PB2 play important role in promoting the fitness of genotype S H9N2 virus in China.

10.
BMJ Open ; 11(9): e045454, 2021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34493502

RESUMO

OBJECTIVES: This phenomenological study aimed to examine intensive care unit (ICU) nurses' experiences of caring for patients with COVID-19, and understand better their everyday experiences of patient' management in the ICU. DESIGN: A descriptive phenomenological research design was used. Individual interviews were conducted. The data were transcribed verbatim and analysed using Colaizzi's seven-step framework. SETTING: An ICU with 16 beds in a tertiary hospital in Wuhan, China. PARTICIPANTS: Nurses who had more than 1 year of experience and had provided care to patients with COVID-19 in ICU for more than 1 week were identified as participants. A total of 13 nurses were interviewed. RESULTS: An analysis of these significant statements yielded four distinct stages of feelings, thereby revealing the essence of this phenomenon. Worry about being infected and infecting family members was present across in all four stages. The themes associated with the four stages were as follows: initial contradictory feelings, quick adaption to the 'new working environment' in the first 1-2 weeks in the ICU, desperation after adaption, holding on and survive. CONCLUSIONS: The nurses reported distinct experiences of providing care to patients with COVID-19 in ICUs. Interventions, such as providing information about the disease, simulation training, emotional support and follow-up care, are needed to help nurses manage patients with COVID-19 and maintain nurses' health.


Assuntos
COVID-19 , Enfermeiras e Enfermeiros , Recursos Humanos de Enfermagem no Hospital , Humanos , Unidades de Terapia Intensiva , Pesquisa Qualitativa , SARS-CoV-2
11.
J Am Chem Soc ; 2021 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-34491047

RESUMO

Zn-organic batteries are attracting extensive attention, but their energy density is limited by the low capacity (<400 mAh g-1) and potential (<1 V vs Zn/Zn2+) of organic cathodes. Herein, we propose a long-life and high-rate Zn-organic battery that includes a poly(1,5-naphthalenediamine) cathode and a Zn anode in an alkaline electrolyte, where the cathode reaction is based on the coordination reaction between K+ and the C═N group (i.e., C═N/C-N-K conversion). Interestingly, we find that the discharged Zn-organic battery can recover to its initial state quickly with the presence of O2, and the theoretical calculation demonstrates that the K-N bond in the discharged cathode can be easily broken by O2 via redox reaction. Accordingly, we design a chemically self-charging aqueous Zn-organic battery. Benefiting from the excellent self-rechargeability, the organic cathode exhibits an accumulated capacity of 16264 mAh g-1, which enables the Zn-organic battery to show a record high energy density of 625.5 Wh kg-1.

12.
Zhongguo Zhong Yao Za Zhi ; 46(15): 3970-3979, 2021 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-34472274

RESUMO

The traditional Chinese medicines(TCM) for activating blood circulation and the TCM for regulating Qi are often used in combination in clinical practice. However, their mechanisms are still unclear. The activity spectrum of targets can fuse the active components, targets and intensity of action, which provides support for the discussion of efficacy targets. The chemical components of common TCM sets for activating blood circulation and regulating Qi, as well as the negative sets not for activating blood circulation and re-gulating Qi were obtained from the database of TCM. By the similarity analysis of chemical components in TCM for activating blood circulation and DrugBank database, the predicted targets of chemical components in TCM for activating blood circulation were obtained, and the similarity value of the two was taken as the activity value of the active components and predicted targets. Then, the component-target activity value was weighted. The activity values of herb acting on the same target were fused to construct activity spectra of targets of the herbs for activating blood circulation, herbs for regulating Qi and negative herbs. The targets whose activity values of activating blood circulation and regulating Qi were higher than those of negative herbs were selected as potential targets of efficacy. Protein-protein interaction networks were constructed for topological, GO and KEGG enrichment analysis to determine the key targets of efficacy of activating blood circulation and regulating Qi. The component-target activity information collected from DrugBank database contained 4 499 compounds, 627 targets and 11 295 action relationships. The activating blood function protein-protein interaction network contained 206 nodes and 1 728 edges, while the regulating Qi function protein-protein interaction network contained 230 nodes and 986 edges. The enrichment analysis of topology, GO and KEGG showed that TCM for activating blood circulation mainly exerted its anti-inflammatory, neuroprotective and angiogenic effects on signaling cascade pathway mediated by VEGF/VEGFR2, ERK signaling pathway, calcium signaling pathway and PI3 K-AKT signaling pathway, and the key targets included mitogen activated protein kinases 3(MAPK3), proto-oncogene tyrosine-protein kinase Src(SRC), mitogen activated protein kinases 1(MAPK1), epidermal growth factor receptor(EGFR), phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform(PIK3 CA), peroxisome proliferators-activated receptor gamma(PPARG), nitric oxide synthase 3(NOS3), prostaglandin G/H synthetase 2(PTGS2), matrix metalloproteinase-9(MMP9), and vascular endothelial growth factor A(VEGFA). TCM for regulating Qi mainly exerted anti-inflammatory and neuroprotective effects by acting on MAPK signaling pathway and PI3 K-AKT signaling pathway, and the key targets included mitogen activated protein kinases 8(MAPK8), SRC, mitogen activated protein kinases 14(MAPK14), and RAC-alpha serine/threonine-protein kinase(AKT1), mitogen activated protein kinases 3(MAPK3). Based on the activity spectrum of targets, the targets of the TCM for activating blood and the targets of the TCM for regulating Qi were analyzed to provide reference for the study of efficacy targets of TCM, and also provide some scientific basis for clinical application.


Assuntos
Medicamentos de Ervas Chinesas , Medicamentos de Ervas Chinesas/farmacologia , Medicina Tradicional Chinesa , Mapas de Interação de Proteínas , Qi , Fator A de Crescimento do Endotélio Vascular
13.
Phytother Res ; 2021 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-34494323

RESUMO

The aim of this study was to examine the effect of whole soy and purified daidzein on markers of thyroid function in Chinese postmenopausal women who were equol-producers. Total 270 eligible women were randomized to either one of the three isocaloric supplements: 40 g soy flour (whole soy group), 40 g low-fat milk powder +63 mg daidzein (daidzein group) or 40 g low-fat milk powder (placebo) daily for 6 months. Serum thyroid markers were tested at baseline and 6 months for thyroid stimulating hormone, free triiodothyronine, reverse triiodothyronine and free thyroxine (FT4). There was no significant difference in the 6-month changes of thyroid markers among the three groups. Subgroup analysis among women with lowered thyroid function suggested a modest decrease of FT4. This randomized controlled trial among Chinese equol-producing postmenopausal women indicates the consumption of whole soy and purified daidzein at the provided dosages are safe and have no detrimental effect on thyroid function.

14.
BMC Gastroenterol ; 21(1): 339, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34470610

RESUMO

AIM: To discover the novel ATP7B mutations in 103 southern Chinese patients with Wilson disease (WD), and to determine the spectrum and frequency of mutations in the ATP7B gene and genotype-phenotype correlation in a large-scale sample of Chinese WD patients. METHODS: One hundred three WD patients from 101 unrelated families in southern China were enrolled in this study. Genomic DNA was extracted from the peripheral blood. Direct sequencing of all 21 exons within ATP7B was performed. Subsequently, an extensive study of the overall spectrum and frequency of ATP7B mutations and genotype-phenotype correlation was performed in all Chinese patients eligible from the literature, combined with the current southern group. RESULTS: In 103 patients with WD, we identified 48 different mutations (42 missense mutations, 4 nonsense mutations and 2 frameshifts). Of these, 3 mutations had not been previously reported: c.1510_1511insA, c.2233C>A (p.Leu745Met) and c.3824T>C (p.Leu1275Ser). The c.2333G>T (p.Arg778 Leu) at exon 8, was the most common mutation with an allelic frequency of 18.8%, followed by c.2975C>T (p.Pro992Leu) at exon 13, with an allelic frequency of 13.4%. In the comprehensive study, 233 distinct mutations were identified, including 154 missense mutations, 23 nonsense mutations and 56 frameshifts. Eighty-five variants were identified as novel mutations. The c.2333G>T (p.Arg778 Leu) and c.2975C>T (p.Pro992Leu) were the most common mutations, with allelic frequencies of 28.6% and 13.0%, respectively. Exons 8, 12, 13, 16 and 18 were recognised as hotspot exons. Phenotype-genotype correlation analysis suggested that c.2333G>T (p.Arg778 Leu) was significantly associated with lower levels of serum ceruloplasmin (P = 0.034). c.2975C>T (p.Pro992Leu) was correlated with earlier age of disease onset (P = 0.002). Additionally, we found that the c.3809A>G (p.Asn1270Ser) mutation significantly indicated younger onset age (P = 0.012), and the c.3884C>T (p.Ala1295Val) mutation at exon 18 was significantly associated with hepatic presentation (P = 0.048). Moreover, the patients with mixed presentation displayed the initial WD features at an older onset age than the groups with either liver disease or neurological presentation (P = 0.039, P = 0.015, respectively). No significant difference was observed in the presence of KF rings among the three groups with different clinical manifestations. CONCLUSION: In this study, we identified three novel mutations in 103 WD patients from the southern part of China, which could enrich the previously established mutational spectrum of the ATP7B gene. Moreover, we tapped into a large-scale study of a Chinese WD cohort to characterise the overall phenotypic and genotypic spectra and assess the association between genotype and phenotype, which enhances the current knowledge about the population genetics of WD in China.


Assuntos
Proteínas de Transporte de Cátions , ATPases Transportadoras de Cobre , Degeneração Hepatolenticular , Adenosina Trifosfatases/genética , Adenosina Trifosfatases/metabolismo , Proteínas de Transporte de Cátions/genética , China , ATPases Transportadoras de Cobre/genética , Análise Mutacional de DNA , Estudos de Associação Genética , Genótipo , Degeneração Hepatolenticular/genética , Humanos , Mutação
15.
ACS Chem Neurosci ; 2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34505505

RESUMO

Protein kinase C (PKC) isozymes play essential roles in biological processes, and activation of PKC is proposed to alleviate the symptoms of a variety of diseases. It would be of great significance to find effective pharmacological modulators of PKC isozymes that can be translated for clinical use. Here, using in vitro activity assay, we demonstrated that green tea extract (-)-epigallocatechin-3-gallate (EGCG) dose-dependently activated PKCα with a half effective concentration (EC50) of 0.49 µM. We also performed surface plasmon resonance analysis and found that EGCG binds PKCα with an equilibrium dissociation constant (KD) value of 4.11 × 10-6 mol/L. Further computational flexible docking analysis revealed that EGCG interacted with the catalytic C3-C4 domain of PKCα (PDB: 4RA4) through establishing polar hydrogen bonds with V420, T401, E387, and K368 of PKCα, and the benzene ring group of EGCG hydrophobically interacted with the hydrophobic pocket formed by L345, M470, I479, and V353 of PKCα. Interestingly, the PKCα-selective blocker Ro-32-0432 could compete with EGCG for the same substrate-binding pocket of PKCα. Moreover, we found that EGCG dose-dependently improved the spatial memory, object recognition ability, and hippocampal long-term potentiation of ovariectomized mice, which was offset by Ro-32-0432. Collectively, our findings reveal a novel PKCα agonist and open the way to a new perspective on PKCα pharmacology and the treatment of PKCα-related diseases, including cognitive impairment.

16.
Bioengineered ; 12(1): 5916-5931, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34488541

RESUMO

Invasion is a critical pathway leading to tumor metastasis. This study constructed an invasion-related polygenic signature to predict osteosarcoma prognosis. We initially determined two molecular subtypes of osteosarcoma, Cluster1 (C1) and Cluster2 (C2).. A 3 invasive-gene signature was established by univariate Cox analysis and least absolute shrinkage and selection operator (LASSO) Cox regression analysis of the differentially expressed genes (DEGs) between the two subtypes, and was validated in internal and two external data sets (GSE21257 and GSE39058). Patients were divided into high- and low-risk groups by their signature, and the prognosis of osteosarcoma patients in the high-risk group was poor. Based on the time-independent receiver operating characteristic (ROC) curve, the area under the curve (AUC) for 1-year and 2-year OS were higher than 0.75 in internal and external cohorts. This signature also showed a high accuracy and independence in predicting osteosarcoma prognosis and a higher AUC in predicting 1-year osteosarcoma survival than other four existing models. In a word, a 3 invasive gene-based signature was developed, showing a high performance in predicting osteosarcoma prognosis. This signature could facilitate clinical prognostic analysis of osteosarcoma.

17.
Curr Alzheimer Res ; 2021 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-34488598

RESUMO

BACKGROUND: High cholesterol aggravates the risk development of Alzheimer's disease (AD). AD is closely related to the transport impairment of amyloid-ß (Aß) in the blood-brain barrier. It is unclear whether high cholesterol affects the risk of cognitive impairment in AD by affecting Aß transport. The purpose of the study is to investigate whether high cholesterol regulates Aß transport through low-density lipoprotein receptor-related protein 1 (LRP1) and receptor for advanced glycation end products (RAGE) in the risk development of AD. METHODS: We established high cholesterol AD mice model. The learning and memory functions were evaluated by Morris water maze (MWM). Cerebral microvascular endothelial cells were isolated, cultured, and observed. The expression levels of LRP1 and RAGE of endothelial cells and their effect on Aß transport in vivo were observed. The expression level of LRP1 and RAGE was detected in cultured microvessels after using Wnt inhibitor DKK-1 and ß-catenin inhibitor XAV-939. RESULTS: Hypercholesterolemia exacerbated spatial learning and memory impairment. Hypercholes- terolemia increased serum Aß40 level, while serum Aß42 level did not change significantly. Hyper- cholesterolemia decreased LRP1 expression and increased RAGE expression in cerebral microvascular endothelial cells. Hypercholesterolemia increased brain apoptosis in AD mice. In in vitro experiment, high cholesterol decreased LRP1 expression and increased RAGE expression, increased Aß40 expression in cerebral microvascular endothelial cells. High cholesterol regulated the expressions of LRP1 and RAGE and transcriptional activity of LRP1 and RAGE promoters by the Wnt/ß-catenin signaling pathway. CONCLUSION: High cholesterol decreased LRP1 expression and increased RAGE expression in cerebral microvascular endothelial cells, which led to Aß transport disorder in the blood-brain barrier. Increased Aß deposition in the brain aggravated apoptosis in the brain, resulting to cognitive impairment of AD mice.

18.
Zhongguo Zhong Yao Za Zhi ; 46(16): 4238-4243, 2021 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-34467738

RESUMO

Wuwei Ganlu, a formula for medicated bath, consists of medicinal materials of Ephedra sinica, Platycladus orientalis, Myricaria squamosa, Artemisia carvifolia, and Rhododendron anthopogonoides, which is effective in inducing perspiration, resisting inflammation, relieving pain, regulating yellow water disease, and activating blood circulation. On this basis, a variety of formulas for Tibetan medicated bath have been derived for the treatment of diseases in internal organs, joints, nerves, etc. Modern studies have confirmed that Wuwei Ganlu has a good therapeutic efficacy on knee osteoarthritis(KOA). The present study explored the mechanism of Wuwei Ganlu in treating KOA based on network pharmacology and molecular docking. Firstly, the chemical components of Wuwei Ganlu were obtained through literature mining and database retrieval, and corresponding potential targets were predicted according to the BATMAN-TCM database. The protein-protein interaction(PPI) network was obtained after the potential targets were input into the STRING database. The network function modules were analyzed by the Molecular Complex Detection(MCODE) algorithm, and the functions of the modules were annotated to analyze the action mode of Wuwei Ganlu. Secondly, the related targets of KOA were collected through the DisGeNET database, and the overlapping targets were confirmed to analyze the mechanism of Wuwei Ganlu in treating KOA. Finally, the key targets were selected for molecular docking with the main components of Wuwei Ganlu to verify the component-target interaction. A total of 550 chemical components and 1 365 potential targets of Wuwei Ganlu were obtained. PPI analysis indicated that this formula could exert the effects of oxidation-reduction, inflammation resistance, bone absorption, bone mineralization, etc. Nineteen common targets were obtained from the intersection of potential targets of Wuwei Ganlu and KOA disease targets. It was found that the Wuwei Ganlu mainly acts on nuclear factor-κB(NF-κB), interleukin-1 beta(IL1ß), tumor necrosis factor(TNF), IL6, IL1 receptor antagonist(IL1 RN), and prostaglandin-endoperoxide synthase-2(PTGS2) to treat KOA. Among the 550 chemical components of Wuwei Ganlu, 252 potential active components were docked with TNF and 163 with PTGS2, indicating good binding of the components with potential key targets. The study preliminarily explored the mechanism of Wuwei Ganlu in treating KOA to provide a reference for the further development and utilization of Tibetan medicated bath that has been included in the UN Intangible Cultural Heritage.


Assuntos
Medicamentos de Ervas Chinesas , Osteoartrite do Joelho , Bases de Dados Factuais , Humanos , Inflamação , Simulação de Acoplamento Molecular
19.
J Pharmacol Toxicol Methods ; 112: 107108, 2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34363962

RESUMO

INTRODUCTION: Telemetered cynomolgus monkeys are widely used in cardiovascular toxicology research. However, the biological variations in their hemodynamics and electrocardiogram rhythms have not been fully elucidated. METHOD: To determine the potential effects of sex, handling stress, and circadian rhythm on the hemodynamics and electrocardiogram rhythms, data from 23 cynomolgus monkeys, implanted with DSI telemetry devices were examined. RESULTS: Our data showed that males had a longer RR interval (RRi), slower heart rate (HR), shorter QT and corrected QT intervals (QTc), and lower blood pressure than females. During the night time, the animals showed a longer RRi, PRi, QTi, and QTc; slower HR, and lower blood pressure. Handling stress at 0.25- to 1-h post-treatment caused a decrease in RRi and increase in HR and QTi. For RRi, HR, and systolic, diastolic, and mean blood pressure, the coefficients of variation (CVs) between studies of individual animals were less than 30%; for other parameters, the CVs were less than 20%. DISCUSSION: We demonstrated that sex, circadian rhythms, and handling stress all contributed towards variations in telemetry data, albeit to different extents. For each individual animal, the biological variation across different studies was relatively small and acceptable.

20.
Anal Chem ; 93(33): 11626-11633, 2021 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-34387457

RESUMO

This work presents a thorough guide to procedures for absolute electrochemiluminescence (ECL) quantum efficiency (ΦECL) measurements, which if employed effectively should raise the research impact of ECL studies for any luminophore. Absolute measurements are not currently employed in ECL research. Instead, ECL efficiencies have been determined relative to Ru(bpy)32+ under similar conditions, regardless of whether the conditions are favorable for Ru(bpy)32+ emissions or not. In fact, the most cited Ru(bpy)32+ ΦECL is from the pioneering work by the Bard research group in 1973 by means of a rotating ring-disk electrode revolving at 52 rotations per second measured with a silicon photodiode. Our presented technique uses a common disk electrode, spectrometer, and photomultiplier tube to measure the ΦECL. The more common light detection hardware and electrodes combined with an in-depth calculation walkthrough will provide ECL researchers the necessary tools to implement ΦECL measurement procedures in their own laboratories. Following a facile instrument setup and calculation, a systematic study of Ru(bpy)32+ ΦECL finds comparable results to those performed by Bard and co-workers.


Assuntos
Medições Luminescentes , Dióxido de Silício , Eletrodos , Humanos , Silício
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