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1.
Food Chem ; 368: 130832, 2022 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-34474242

RESUMO

Piper nigrum L. is commonly used worldwide and its pericarp, stalks, leaves will be major wastes materials. 42 amide alkaloids were identified in black, white pepper and pericarp by UHPLC-LTQ-Orbitrap HRMS method, followed by 40 constituents in stalks and 36 constituents in leaves. 8 amide alkaloids were reported for the first time in P. nigrum. An ultra-high-performance supercritical fluid chromatography (UHPSFC)-MS method was firstly applied to simultaneously determine 9 characteristic constituents (piperine, piperlonguminine, piperanine, pipercallosine, dehydropipernonaline, pipernonatine, retrofractamide B, pellitorine and guineensine). The most abundant compound in each extract was piperine with a concentration from 0.10 to 12.37 mg/g of dry weight. The fruits, pericarp and leaves extracts could improve cell viability in 6-OHDA-induced SK-N-SH and SH-SY5Y cells. The results showed the characteristics of amide alkaloids of different parts of P. nigrum and evaluated their neuroprotective activities.


Assuntos
Alcaloides , Piper nigrum , Piper , Alcaloides/farmacologia , Benzodioxóis , Frutas , Extratos Vegetais/farmacologia , Folhas de Planta , Alcamidas Poli-Insaturadas/farmacologia
2.
Anal Chem ; 2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34643369

RESUMO

The hydroxyl radical (·OH), one of the reactive oxygen species (ROS) in biosystems, is found to be involved in many physiological and pathological processes. However, specifically detecting endogenous ·OH remains an outstanding challenge owing to the high reactivity and short lifetime of this radical. Herein, inspired by the scavenging mechanism of a neuroprotective drug edaravone toward ·OH, we developed a new ·OH-specific fluorescent probe RH-EDA. RH-EDA is a hybrid of rhodamine and edaravone and exploits a ·OH-specific 3-methyl-pyrazolone moiety to control its fluorescence behavior. RH-EDA itself is almost nonfluorescent in physiological conditions, which was attributed to the formation of a twisted intramolecular charge transfer (TICT) state upon photoexcitation and the acylation of its rhodamine nitrogen at the 3' position. However, upon a treatment with ·OH, its edaravone subunit was converted to the corresponding 2-oxo-3-(phenylhydrazono)-butanoic acid (OPB) derivative (to afford RH-OPB), thus leading to a significant fluorescence increase (ca. 195-fold). RH-EDA shows a high sensitivity and selectivity to ·OH without interference from other ROS. RH-EDA has been utilized for imaging endogenous ·OH production in living cells and zebrafishes under different stimuli. Moreover, RH-EDA allows a high-contrast discrimination of cancer cells from normal ones by monitoring their different ·OH levels upon stimulation with ß-Lapachone (ß-Lap), an effective ROS-generating anticancer therapeutic agent. The present study provides a promising methodology for the construction of probes through a drug-guided approach.

3.
Virol Sin ; 2021 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-34635987

RESUMO

Currently, various porcine reproductive and respiratory syndrome virus (PRRSV) variants emerged worldwide with different genetic characteristics and pathogenicity, increasing the difficulty of PRRS control. In this study, a PRRSV strain named HBap4-2018 was isolated from swine herds suffering severe respiratory disease with high morbidity in Hebei Province of China in 2018. The genome of HBap4-2018 is 15,003 nucleotides in length, and compared with NADC30-like PRRSV, nsp2 of HBap4-2018 has an additional continuous deletion of five amino acids. Phylogenetic analysis based on complete genome and ORF5 showed that HBap4-2018 belonged to lineage 8 of PRRSV-2, which was characterized by highly variable genome. However, HBap4-2018 was classified into lineage 1 based on phylogenetic analysis of nsp2, sharing higher amino acid homology (85.3%-85.5%) with NADC30-like PRRSV. Further analysis suggested that HBap4-2018 was a novel natural recombinant PRRSV with three recombinant fragments in the genome, of which highly pathogenic PRRSV (HP-PRRSV) served as the major parental strains, while NADC30-like PRRSV served as the minor parental strains. Five recombination break points were identified in nsp2, nsp3, nsp5, nsp9 and ORF6, respectively, presenting a novel recombinant pattern in the genome. Piglets inoculated with HBap4-2018 presented typical clinical signs with a mortality rate of 60%. High levels of viremia and obvious macroscopic and histopathological lesions in the lungs were observed, revealing the high pathogenicity of HBap4-2018 in piglets.

4.
Opt Express ; 29(18): 28406-28415, 2021 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-34614972

RESUMO

Deep neural networks (DNNs) have been used as a new method for nanophotonic inverse design. However, DNNs need a huge dataset to train if we need to select materials from the material library for the inverse design. This puts the DNN method into a dilemma of poor performance with a small training dataset or loss of the advantage of short design time, for collecting a large amount of data is time consuming. In this work, we propose a multi-scenario training method for the DNN model using imbalanced datasets. The imbalanced datasets used by our method is nearly four times smaller compared with other training methods. We believe that as the material library increases, the advantages of the imbalanced datasets will become more obvious. Using the high-precision predictive DNN model obtained by this new method, different multilayer nanoparticles and multilayer nanofilms have been designed with a hybrid optimization algorithm combining genetic algorithm and gradient descent optimization algorithm. The advantage of our method is that it can freely select discrete materials from the material library and simultaneously find the inverse design of discrete material type and continuous structural parameters of the nanophotonic devices.

5.
Br J Pharmacol ; 2021 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-34625952

RESUMO

BACKGROUND AND PURPOSE: In chronic kidney disease (CKD), patients inevitably reach end-stage renal disease and require renal replacement therapies. Emerging evidence suggests that CKD is associated with metabolite disorders. However, the molecular pathways targeted by metabolites remain enigmatic. Here, we describe roles of the metabolite 1-hydroxypyrene in mediating renal fibrosis. EXPERIMENTAL APPROACH: We analysed 5406 urine and serum samples from patients with stage 1-5 CKD using metabolomics, and 1-hydroxypyrene was identified and validated using longitudinal and drug intervention cohorts as well as 5/6 nephrectomised and adenine-induced rats. KEY RESULTS: We identified correlations between the urine and serum levels of 1-hydroxypyrene and the estimated glomerular filtration rate in patients with CKD onset and progression. Moreover, increased 1-hydroxypyrene levels in serum and kidney tissues correlated with decreased renal function in two rat models. Upregulated mRNA expression of aryl hydrocarbon receptors (AhR) and its target genes, including CYP1A1, CYP1A2, and CYP1B1, was observed in both patients and rats with progressive CKD. Our study further showed upregulated mRNA expression of AhR and its three target genes and upregulated nuclear AhR protein levels in mice and HK-2 cells treated with 1-hydroxypyrene, which caused accumulation of extracellular matrix components. Furthermore, treatment with AhR short hairpin RNA or flavonoids inhibited mRNA expression of AhR and its target genes in 1-hydroxypyrene-induced HK-2 cells and mice. CONCLUSION AND IMPLICATIONS: Metabolite 1-hydroxypyrene was demonstrated to mediate renal fibrosis through activation of the AhR signalling pathway. Therefore, targeting AhR may be an alternative therapeutic strategy for CKD progression.

6.
Artigo em Inglês | MEDLINE | ID: mdl-34639832

RESUMO

The COVID-19 has caused a serious impact on the global economy, and all countries are in a predicament of fighting the epidemic and recovering their economies. Aiming to discuss the impact of the COVID-19 on the economic resilience of urban agglomerations, the economic data of each quarter from June 2019 to September 2020 of the Beijing-Tianjin-Hebei Urban Agglomeration are selected, and the economic development index (EDI) is calculated based on the entropy method. Combining the fundamental conditions of urban agglomerations and industrial policies during the COVID-19, urban economic resilience is discussed by the changing trend of the economic development index (EDI) and dividing into resistance and restoration. The results show that: (1) The economic development level of the urban agglomeration has been affected by the epidemic and has changed significantly. The change of endogenous power is the main cause of change; (2) During the outbreak of the COVID-19, the economic resilience of the Beijing-Tianjin-Hebei urban agglomeration shows four different development types: high resistance and restoration, high resistance but low restoration, low resistance but high restoration, low resistance and restoration cities; (3) High resistance but low restoration, low resistance but high restoration, and low resistance and restoration cities influence each other, but the relationship between cities is mainly dependent; (4) The economic restoration within the urban agglomeration forms a synergy, which promotes the economic recovery and development of the urban agglomeration during the recovery period of the COVID-19. Urban agglomerations should enhance the combined effect of resistance and increase the impact of high resistance and restoration cities on surrounding cities in the future.


Assuntos
COVID-19 , Epidemias , Pequim/epidemiologia , China/epidemiologia , Cidades , Surtos de Doenças , Humanos , Percepção , SARS-CoV-2
8.
Hum Gene Ther ; 2021 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-34486389

RESUMO

Neutralizing antibodies (NAbs) strongly limit adeno-associated virus (AAV) vector transduction and repeated administration. Previous studies have shown that NAbs induced by AAVs are associated with T and B cell activation and that the B7/CD28 and CD40/CD40L costimulation signaling pathways are involved. CTLA4 and CD40 are vital molecules that participate in the costimulatory pathway. In this study, we evaluated CTLA4-Ig and CD40-Ig immunosuppressive efficacies through AAV and investigated their effects on the feasibility for multiple systemic administrations of AAV vectors. The results showed that a single administration of AAV vector carrying either CTLA4-Ig alone or with CD40-Ig could greatly reduce the level of NAbs. An AAV serotype-specific immune tolerance could be successfully established, which enabled repeated, i.e., second and third, systemic administration of AAV vectors in the same mice. A combination of CTLA4-Ig and CD40-Ig delivered via AAV vectors significantly inhibited T and B cell activations without affecting immune response to the total immunoglobulin G (IgG) production and cytokines. Interestingly, exogenous gene expression significantly improved after multiple administrations of AAV vector in vivo. Our study generates a reliable and effective method for repeated dosing of AAV vectors that is needed on gene therapy.

9.
Theranostics ; 11(18): 8909-8925, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34522218

RESUMO

Rationale: The synergism of new modalities alongside chemodynamic therapy into common chemotherapy has shown promising potential in clinical applications. This paper reports a tumor microenvironment-responsive nanosystem for chemodynamic/chemical synergistic therapy and magnetic resonance imaging (MRI). Methods: The biodegradable nanosystem is synthesized using a surface-modified chain transfer agent for surface-initiated living radical polymerization of the chemotherapeutic drug. Results: In this nanosystem, named CAMNSN@PSN38, the cycling time and solubility of the chemotherapeutic drug are improved. The nanoparticles delivered to tumor tissues gradually release the chemotherapeutic drug and Mn2+ through glutathione (GSH)-triggered biodegradation in the tumor microenvironment. SN38, the released chemotherapeutic drug, not only shows excellent chemical therapy effects but also improves the generation of H2O2. Furthermore, with the Fenton-like agent Mn2+, the generation of reactive oxygen species (ROS) is improved markedly. Finally, CAMNSN@PSN38 shows excellent inhibition of tumor growth in three colorectal cancer tumor models, with an improved accumulation of ROS and controlled release of SN38. Conclusions: The CAMNSN@PSN38-mediated chemodynamic/chemical synergistic therapy provides a promising paradigm for the treatment and MRI-guided therapy of colorectal cancer.

10.
Sci Rep ; 11(1): 17791, 2021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34493750

RESUMO

The purpose of this study is to explore whether uric acid (UA) can independently act as a prognostic factor and critical marker of the 2019 novel corona virus disease (COVID-19). A multicenter, retrospective, and observational study including 540 patients with confirmed COVID-19 was carried out at four designated hospitals in Wuhan. Demographic, clinical, laboratory data were collected and analyzed. The primary end point was in-hospital death of patients with COVID-19. The concentration of admission UA (adUA) and the lowest concentration of uric acid during hospitalization (lowUA) in the dead patients were significantly lower than those in the survivors. Multivariate logistic regression analysis showed the concentration of lowUA (OR 0.986, 95% CI 0.980-0.992, p < 0.001) was able to independently predict the risk of in-hospital death. The mean survival time in the low-level group of lowUA was significantly lower than other groups. When lowUA was ≤ 166 µmol/L, the sensitivity and specificity in predicting hospital short-term mortality were 76.9%, (95% CI 68.5-85.1%) and 74.9% (95% CI 70.3-78.9%). This retrospective study determined that the lowest concentration of UA during hospitalization can be used as a prognostic indicator and a marker of disease severity in severe patients with COVID-19.


Assuntos
COVID-19/mortalidade , Ácido Úrico/sangue , Adulto , Idoso , Biomarcadores/sangue , COVID-19/sangue , COVID-19/diagnóstico , China/epidemiologia , Estudos de Viabilidade , Feminino , Mortalidade Hospitalar , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Medição de Risco/métodos , Fatores de Risco , Sensibilidade e Especificidade , Índice de Gravidade de Doença
11.
Cancer Rep (Hoboken) ; : e1561, 2021 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-34553845

RESUMO

BACKGROUND: Pyroptosis plays a dual role in the development of cancer and malignancy; as such, it may potentially be a new target for cancer treatment. However, the inflammatory response to pyroptosis may have adverse effects on the body. The roles of gasdermin E (GSDME), caspases, and related proteins associated with pyroptosis in cancer remain controversial. AIM: The goal of this study was to determine whether the expression levels of caspase-3 and GSDME affect the clinical stage, pathological grade, or survival prognosis of patients with lung cancer. METHODS: We examined the protein levels of GSDME, caspase-3, caspase-8, and caspase-9 in lung tissue samples from 100 patients with lung cancer by using immunohistochemistry. RESULTS: We found that GSDME, caspase-3, and caspase-8 were more highly expressed in tumor tissues than in adjacent normal tissues. Moreover, we found that GSDME could serve as a prognostic factor as there was a positive correlation between its expression level and the postoperative survival rate of patients with lung cancer. CONCLUSIONS: GSDME may be an independent factor affecting the prognosis of patients with lung cancer. However, the role of GSDME and its related proteins in cancer requires further research.

12.
PLoS One ; 16(9): e0257756, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34559853

RESUMO

This study explored the physiological and molecular mechanisms of yield increase in maize under stable soil water content (SW) conditions. Results of the study showed that under SW conditions, corn yield increased by 38.72 and 44.09% in 2019 and 2020, respectively. Further, it was found that dry matter accumulation, economic coefficient and photosynthetic rate also increased by 31.24 and 25.67%, 5.45 and 15.38% as well as 29.60 and 31.83% in 2019 and 2020 respectively. However, the results showed that both the activity of antioxidant enzymes and content of osmotic adjustment substances decreased in maize under SW conditions. When compared with soil moisture content of dry and wet alternation (DW) conditions, SW could not only significantly promote growth and yield of maize but also increase the economic coefficient. Transcriptome profiles of maize leaves under the two conditions (SW and DW) were also analyzed and compared. It was found that 11 genes were highly up-regulated in the photosynthesis pathway. These genes included photosystem II protein V (PsbE), photosystem II protein VI (PsbF), photosystem II protein D1 (PsbA), photosystem II protein D2 (PsbD) and ATP synthase CF1 beta subunit (atpB). Further, it was found that four genes were up-regulated in the oxidative phosphorylation pathway., These were ATP synthase CF1 epsilon subunit (atpE), ATP synthase CF1 beta subunit (atpB), NADH dehydrogenase subunit 4L (ndhE) and NADH dehydrogenase subunit 6 (ndhG). In conclusion, the physiological mechanism of stable soil water content (SW) to increase corn yield may be the enhancement of photosynthetic capacity and energy metabolism.

13.
BMC Cancer ; 21(1): 994, 2021 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-34488679

RESUMO

BACKGROUND: Many clinical trials have assessed the effect and safety of monoclonal antibodies (MAbs) in combination with proteasome inhibitors or immunomodulators plus dexamethasone/prednisone for the treatment of multiple myeloma (MM). The treatment outcomes of comparing different MAbs in combination with the above-mentioned agents remained unclear. We performed the meta-analysis to indirectly compare the effect and safety of MAbs targeting CD38, SLAMF7, and PD-1/PD-L1 in combination with bortezomib/immunomodulators plus dexamethasone/prednisone for patients with MM. METHODS: We searched thoroughly in the databases for randomised controlled trials (RCTs) in which at least one of the three MAbs were included. We included eleven eligible RCTs with 5367 patients in the meta-analysis. Statistical analysis was carried out using StataMP14 and Indirect Treatment Comparisons software. RESULTS: We calculated hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) and relative risk (RR) for overall response rate, complete response (CR) or better, very good partial response (VGPR) or better, VGPR, partial response, stable disease, and grade 3 or higher adverse events among the three groups. The HRs for PFS of the CD38 group vs SLAMF7 group, CD38 group vs PD-1/PD-L1 group, and SLAMF7 group vs PD-1/PD-L1 group were 0.662 (95%CI 0.543-0.806), 0.317 (95%CI 0.221-0.454), and 0.479 (95%CI 0.328-0.699), respectively. The HR for OS of the CD38 group vs SLAMF7 group was 0.812 (95%CI 0.584-1.127). The RR for CR or better in the CD38 group vs SLAMF7 group was 2.253 (95%CI 1.284-3.955). The RR for neutropenia of the CD38 group vs SLAMF7 group was 1.818 (95%CI 1.41-2.344). CONCLUSIONS: Treatment with the CD38 group had longer PFS and better treatment response than that with the SLAMF7 or PD-1/PD-L1 group. In addition, the SLAMF7 group prolonged PFS compared with the PD-1/PD-L1 group and was associated with a lower incidence of grade 3 or higher neutropenia than the CD38 and PD-1/PD-L1 group. In conclusion, MAbs targeting CD38 are the best, followed by those targeting SLAMF7; MAbs targeting PD-1/PD-L1 are the worst when in combination with bortezomib/immunomodulators plus dexamethasone/prednisone for the treatment of MM.


Assuntos
ADP-Ribosil Ciclase 1/antagonistas & inibidores , Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Glicoproteínas de Membrana/antagonistas & inibidores , Mieloma Múltiplo/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Família de Moléculas de Sinalização da Ativação Linfocitária/antagonistas & inibidores , ADP-Ribosil Ciclase 1/imunologia , Antígeno B7-H1/imunologia , Bortezomib/administração & dosagem , Dexametasona/administração & dosagem , Humanos , Fatores Imunológicos/uso terapêutico , Glicoproteínas de Membrana/imunologia , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Prednisona/administração & dosagem , Prognóstico , Receptor de Morte Celular Programada 1/imunologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Família de Moléculas de Sinalização da Ativação Linfocitária/imunologia
14.
DNA Cell Biol ; 40(10): 1325-1337, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34582699

RESUMO

Psoriasis is a chronic inflammatory skin disease characterized by massive keratinocyte proliferation and immune cell infiltration into the epidermis. However, the specific mechanisms underlying the development of psoriasis remain unclear. Untargeted metabolomics and transcriptomics have been used separately to profile biomarkers and risk genes in the serum of psoriasis patients. However, the integration of metabolomics and transcriptomics to identify dysregulated metabolites and genes in the psoriatic skin is lacking. In this study, we performed an untargeted metabolomics analysis of imiquimod (IMQ)-induced psoriasis-like mice and healthy controls, and found that levels of a total of 4,188 metabolites differed in IMQ-induced psoriasis-like mice compared with those in control mice. Metabolomic data analysis using MetaboAnalyst showed that the metabolic pathways of primary metabolites, such as folate biosynthesis and galactose metabolism, were significantly altered in the skin of mice after treatment with IMQ. Furthermore, IMQ treatment also significantly altered metabolic pathways of secondary metabolites, including histidine metabolism, in mouse skin tissues. The metabolomic results were verified by transcriptomics analysis. RNA-seq results showed that histamine decarboxylase (HDC) mRNA levels were significantly upregulated after IMQ treatment. Targeted inhibition of histamine biosynthesis process using HDC-specific inhibitor, pinocembrin (PINO), significantly alleviated epidermal thickness, downregulated the expression of interleukin (IL)-17A and IL-23, and inhibited the infiltration of immune cells during IMQ-induced psoriasis-like skin inflammation. In conclusion, our study offers a validated and comprehensive understanding of metabolism during the development of psoriasis and demonstrated that PINO could protect against IMQ-induced psoriasis-like skin inflammation.

15.
Acad Radiol ; 2021 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-34452820

RESUMO

RATIONALE AND OBJECTIVES: The revised International Staging System (R-ISS) is the current risk stratifier for patients with newly diagnosed multiple myeloma (NDMM). We used histogram analysis based on apparent diffusion coefficient (ADC) maps of bone marrow to predict high-risk NDMM patients staged as R-ISS stage III. MATERIAL AND METHODS: Sixty-one NDMM patients were recruited prospectively and underwent whole-body diffusion-weighted MRI. Mean ADC and four ADC-based histogram parameters of representative background bone marrow were quantified with TexRAD software, including ADC entropy, ADC standard deviation (SD), ADC skewness and ADC kurtosis. Diagnostic performance to discriminate R-ISS III from I/II disease was evaluated by receiver-operating characteristics curve (ROC). Univariate and multivariate analysis using stepwise logistic regression model was performed to identify predictors for R-ISS III. RESULTS: ADC entropy of background marrow showed the highest areas under the ROC (0.784, sensitivity = 93.3%, specificity = 63.0%) for the detection of R-ISS stage III disease. Multivariate analysis showed that increased ADC entropy (>3.612) of background marrow can independently predict R-ISS stage III disease in the overall patients (Model 1 corrected for diffuse infiltration [DI] pattern: odds ratio [OR], 10.647; p = 0.008; Model 2 corrected for mean ADC: OR, 10.485; p = 0.010) and in the subgroup with DI pattern (OR, 7.043; p = 0.037). CONCLUSION: ADC entropy of background marrow may serve as a sensitive imaging biomarker facilitating the detection of high-risk NDMM patients staged as R-ISS stage III. Increased ADC entropy of background marrow can independently predict R-ISS stage III in the overall patients and in the subgroup with DI pattern.

16.
Ecotoxicol Environ Saf ; 223: 112597, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34365213

RESUMO

Quercetin is reported to be beneficial to or pose hazards to the health of animals, the inconsistence remains to be recognized and debated. This work was conducted to understand the neuroprotective or neurotoxic properties of quercetin, and investigate the different action mechanisms between low- and high-level quercetin. Therefore, we evaluated brain oxidative stress and monoamine neurotransmitters in adult zebrafish (Danio rerio) after exposure to 1 and 1000 µg/L quercetin. In addition, the brain transcriptional profiles were analyzed to identify genes and pathways that were differentially regulated in the brains. The results of oxidative stress and neurotransmitters suggest that low-level quercetin might be beneficial to nervous system, while high-level quercetin might exert detrimental effects. Furthermore, transcriptional profiles also suggested different toxic mechanisms occurred between low- and high-level quercetin. At 1 µg/L quercetin, enrichment analysis of differently expressed genes (DEGs) revealed that the fanconi anemia pathway might be an important mechanism in neuroprotective effects. At 1000 µg/L quercetin, the up-regulated DEGs were enriched in many Gene Ontology (GO) terms related to neuronal synapses, indicating potential neuroprotective effects; however, enrichment of up-regulated DEGs in GO terms of response to stimulus and the MAPK signaling pathway was also found, which indicated increases of stress. Notably, at 1000 µg/L quercetin, the down-regulated DEGs were enriched in several GO terms related to the proteostasis and the proteasome pathway, indicating impairment of proteasome functions which was involved in neurodegenerative diseases. Moreover, several hub genes involved in the pathology of neurodegenerative diseases were identified by Protein-protein interaction analysis at 1000 µg/L quercetin. Thus, high-level quercetin might pose potential risk inducing neurodegenerative diseases, which should receive more attention in the future. Additionally, our findings may provide awareness to society and researchers about toxicity possibilities of phytochemicals on wildlife and human.


Assuntos
Fármacos Neuroprotetores , Peixe-Zebra , Animais , Encéfalo , Perfilação da Expressão Gênica , Humanos , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo , Quercetina/farmacologia , Peixe-Zebra/genética
17.
IEEE Trans Biomed Eng ; PP2021 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-34357861

RESUMO

Using deep neural networks (DNNs) to explore spatial patterns and temporal dynamics of human brain activities has been an important yet challenging problem because the artificial neural networks are hard to be designed manually. There have been several promising deep learning methods, e.g., deep belief network (DBN), convolutional neural network (CNN), and deep sparse recurrent auto-encoder (DSRAE), that can decompose neuroscientific and meaningful spatiotemporal patterns from 4D functional Magnetic Resonance Imaging (fMRI) data. However, those previous studies still depend on hand-crafted neural network architectures and hyperparameters, which are not optimal in various senses. In this paper, we employ the evolutionary algorithms (EA) to optimize the deep neural architecture of DSRAE by minimizing the expected loss of initialized models, named eNAS-DSRAE (evolutionary Neural Architecture Search on Deep Sparse Recurrent Auto-Encoder). Also, validation experiments are designed and performed on the publicly available human connectome project (HCP) 900 datasets, and the results achieved by the optimized eNAS-DSRAE suggested that our framework can successfully identify the spatiotemporal features and perform better than the hand-crafted neural network models. To our best knowledge, the proposed eNAS-DSRAE is not only among the earliest NAS models that can extract connectome-scale meaningful spatiotemporal brain networks from 4D fMRI data, but also is an effective framework to optimize the RNN-based models.

18.
Endocr Connect ; 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-34355700

RESUMO

Polycystic ovary syndrome (PCOS) is associated with an increased risk of cardiovascular disease in women. Hyperhomocysteinemia (H-Hcy) is closely related to arterial stiffness (AS) in patients with cardiovascular disease. This study aimed to investigate the relationship between serum homocysteine (Hcy) level and brachial-ankle pulse wave velocity (baPWV) in Chinese women with PCOS. A total of 124 PCOS women were enrolled and divided into two groups according to their baPWV values: normal, baPWV <1400 cm/s; and high AS, baPWV ≥1400 cm/s. Univariate analysis was performed to investigate the relative factors for baPWV, and multiple regression analysis was used to evaluate the association of Hcy with baPWV. The group with high AS(n=35) had higher Hcy levels than the other group (n=89; P<0.05). Moreover, univariate analysis revealed that serum Hcy was positively correlated with baPWV (r = 0.133, P<0.01). In multiple regression analysis, the age-adjusted serum Hcy level was positively correlated with baPWV (ß = 0.201, P<0.01). It remained positively associated with baPWV (ß = 0.145, P<0.01) after further adjustments for age, body mass index, PCOS duration, systolic blood pressure and homeostasis model assessment-insulin resistance as well as several other factors correlated with baPWV. Our results demonstrated that H-Hcy was significantly and independently related to elevated baPWV, suggesting that Hcy might play a role in the pathologic process of AS in women with PCOS. Further researches with more subjects are needed to explore whether Hcy would be a promising biomarker for stratification management of PCOS women.

19.
Bioorg Chem ; 115: 105197, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34426159

RESUMO

Chinese herbal medicines (CHM) are frequently used to treat different types of inflammatory diseases and 15-Lipoxygenase (15-LOX) is a critical target enzyme for treating various inflammatory diseases. In this study, natural 15-LOX inhibitors were identified in CHM using an approach of virtual screening combined with the biological assays. First, an in-house Chinese medicine database containing 360 compounds was screened using a virtual screening approach based on pharmacophore and molecular docking to uncover several novel potential 15-LOX inhibitors. Secondly, the inhibitory effect of virtual screening hits against the 15-LOX enzyme was validated in an in vitro enzyme inhibition assay. Then, a tumor necrosis factor-α (TNF-α) release assay was carried out to explore the anti-inflammatory response of the active compounds. Furthermore, molecular dynamics (MD) simulation and binding free energy calculation were applied to analyze the process of inhibitors binding and also compared the mode of binding of the inhibitors by using the Molecular Mechanics-Generalized Born Surface Area (MM/GBSA) method. Finally, licochalcone B and eriodictyol were confirmed as inhibitors of the 15-LOX enzyme with IC50 values of 9.67 and 18.99 µM, respectively. In vitro cell-based assay showed that licochalcone B and eriodictyol inhibited the release of TNF-α factor in RAW264.7 cells stimulated by lipopolysaccharides (LPS) in a dose-dependent manner. Molecular dynamics and binding free energy analysis showed that the two 15-LOX-ligand systems immediately attained equilibrium with almost 1 Å fluctuation, the calculated binding free energies were found around -18.89 and -12.96 kcal/mol for licochalcone B and eriodictyol, respectively. Thr412, Arg415, Val420, Thr429, Ile602 and Trp606 were the main amino acid residues for the inhibition of 15-LOX enzyme activity. The current study confirms that licochalcone B and eriodictyol are 15-LOX inhibitors and can suppress the release of the TNF-α factor in RAW264.7 cells stimulated by LPS, thus providing a basis for the follow-up research and development for 15-LOX inhibitors.

20.
Food Chem Toxicol ; 155: 112388, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34242719

RESUMO

Aluminum (Al), as a common environmental pollutant, causes osteoblast (OB) dysfunction and then leads to Al-related bone diseases (ARBD). One of the mechanisms of ARBD is oxidative stress, which leads to an increase in the production of reactive oxygen species (ROS). ROS can induce mitochondrial damage, thereby inducing mitophagy and apoptosis. But whether mitophagy and apoptosis mediated by ROS, and the role of ROS in AlCl3-induced MC3T3-E1 cell dysfunction is still unclear. In this study, MC3T3-E1 cells used 0 mM Al (control group), 2 mM Al (Al group), 5 mM N-acetyl cysteine (NAC) (NAC group), 2 mM Al and 5 mM NAC (Al + NAC group) for 24 h. We found AlCl3-induced MC3T3-E1 cell dysfunction accompanied by oxidative stress, apoptosis, and mitophagy. While NAC, a ROS scavenger treatment, restored cell function and alleviated the mitophagy and apoptosis. These results suggested that mitophagy and apoptosis mediated by ROS participate in AlCl3-induced MC3T3-E1 cell dysfunction.

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