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1.
Artigo em Inglês | MEDLINE | ID: mdl-34648632

RESUMO

BACKGROUND: Integrase strand transfer inhibitor (InSTI)-based regimens have become the major first-line treatment for HIV-1-infected patients in Taiwan. Transmitted drug resistance (TDR) and several clinical characteristics are associated with time to virological failure or viral suppression; however, these have not been investigated in Taiwan. OBJECTIVES: To determine the impact of several factors on treatment outcomes in HIV-1-infected patients in Taiwan. METHODS: The cohort included 164 HIV-1 treatment-naive patients in Taiwan from 2018 to 2020. Blood specimens were collected to determine the genotypic drug resistance using the Stanford University HIV drug resistance database. Cox proportional hazards models were used to identify factors associated with time to virological failure or viral suppression. RESULTS: The prevalence of TDR in Taiwan was 27.4% and an increasing trend was seen from 2018 to 2020. TDR mutations related to NNRTIs were the most prevalent (21%) while TDR to InSTIs remained at a relatively low level (1.3%). A baseline HIV-1 viral load of ≥100 000 copies/mL was associated with a shorter time to virological failure [multivariate hazard ratio (mHR) 7.84; P = 0.018] and longer time to viral suppression (mHR 0.46; P < 0.001). Time to viral suppression was shorter in patients receiving InSTI-based regimens (mHR 2.18; P = 0.006). Different InSTI-based regimens as initial treatment did not affect the treatment outcomes. CONCLUSIONS: This study found an increasing trend of HIV-1 TDR prevalence from 2018 to 2020 in Taiwan. Baseline HIV-1 viral load and receiving InSTI-based regimens are important factors associated with time to virological failure or viral suppression.

2.
Zhongguo Zhong Yao Za Zhi ; 46(12): 3034-3042, 2021 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-34467693

RESUMO

To explore the mechanism of anti-inflammatory and analgesic effect of Zanthoxyli Pericarpium based on network pharmacology and inflammatory or pain mouse models. The effective components of Zanthoxyli Pericarpium were screened out by TCMSP database. And their potential corresponding targets were predicted by PharmMapper software. The possible targets relating to inflammation and pain were mainly collected through DrugBank, TTD and DisGeNET databases. The "active ingredient-gene-disease" network diagram was constructed by Cytoscape 3.7.0 software. The network pharmacology results showed 5 potential effective compounds, which were related to 29 targets; 132 targets relating to inflammation and pain were screened out in the DrugBank, TTD and DisGeNET databases. The network analysis results indicated that the phosphatidylinositol 3-kinase catalytic subunit gamma isoform(PIK3 CG) gene may be the key to the anti-inflammatory and analgesic effect of Zanthoxyli Pericarpium. The anti-inflammatory and analgesic effects of essential oil extract and dichloromethane extract of Zanthoxyli Pericarpium were explored through the mouse model of inflammation induced by xylene or carrageenan and the mouse model of pain induced by acetic acid or formalin. The experimental results showed that essential oil extract and dichloromethane extract of Zanthoxyli Pericarpium could reduce xylene-induced ear swelling and carrageenan-induced paw swelling and decrease the number of writhing responses in mice induced by acetic acid and the licking foot time of mice in phase Ⅱ induced by formalin. Western blot results showed that Zanthoxyli Pericarpium extract could inhibit the expressions of PIK3 CG, phosphonated nuclear factor kappaB(p-NF-κB) and phosphonated p38(p-p38 MAPK) protein. The present study showed the anti-inflammatory and analgesic effect of Zanthoxyli Pericarpium through multiple components and targets, so as to provide a pharmacodynamic basis for the study of Zanthoxyli Pericarpium and its mechanism.


Assuntos
Medicamentos de Ervas Chinesas , Óleos Voláteis , Analgésicos/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Edema/induzido quimicamente , Edema/tratamento farmacológico , Inflamação/tratamento farmacológico , Inflamação/genética , Camundongos , Extratos Vegetais
3.
Neurol Sci ; 2021 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-34455500

RESUMO

BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disease. Evidence has shown that lipocalin-2 (LCN2) is involved in the pathological process of PD. We aimed to explore whether serum levels of LCN2 could be a biomarker of PD. METHODS: We recruited consecutive PD patients and healthy controls (HC) in our hospital from June 2020 to July 2020. Serum LCN2 levels were detected using the LCN2 enzyme-linked immunosorbent assay (ELISA) kit. The motor section of the Unified Parkinson's Disease Rating Scale (UPDRS III) and the Hoehn and Yahr Staging Scale (H&Y) were assessed on admission to evaluate disease severity in patients with PD. Cognitive status was measured by the Montreal Cognitive Assessment (MoCA). RESULTS: We finally recruited 75 patients, including 40 PD patients and 35 HC. Serum LCN2 levels were not significantly increased in PD patients compared with HC (4.9 [- 0.7 to 18.6] vs 1.9 [- 1.5 to 16.9] ng/mL, P = 0.33). Besides, there was no significant difference in LCN2 levels between patients at early and advanced stage of PD (P = 0.75), as well as between cognitively impaired PD patients, PD patients with normal cognition, and HC (P = 0.30). Moreover, LCN2 had no correlation with disease duration (r = - 0.1, P = 0.37), UPDRS III score (r = 0.07, P = 0.65), and MoCA score (r = 0.221, P = 0.17). CONCLUSIONS: Overall, our study suggests that serum LCN2 levels may not be a biomarker for PD.

4.
Ecotoxicol Environ Saf ; 224: 112696, 2021 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-34455182

RESUMO

Benoxacor (BN) is a highly effective antidote of dichloroacetamide herbicides generally used to protect crops from herbicidal damage. As a commonly used agrochemical, this herbicide antidote is continuously discharged in watercourses thus causing toxicity to aquatic organisms, and ultimately leading to contamination of the food chain. To date, its potential toxicity to the cardiac development of aquatic organisms has not been evaluated. In the present study, we have selected the zebrafish as a model to study the impact of BN on embryonic developmental and cardiac toxicity. The zebrafish embryos were exposed in 0.5, 1.0 and 2.0 mg/L BN from 5.5 to 72 h post-fertilization (hpf). The results indicated that the exposure to BN led to increased mortality and diminished heart and hatching rates in the embryos. BN exposure also brought pericardial edema (PE) and linear stretching of heart. Besides, exposure to BN induced an excessive accumulation of reactive oxygen species (ROS) in the zebrafish embryos and abnormal activities of the antioxidant enzymes, including catalase (CAT) and malondialdehyde (MDA). Moreover, exposure to BN caused serious cardiac toxicity of the embryos, accompanied by abnormality of heart development- and apoptosis-related genes. Surprisingly, astaxanthin (ASTA), as a common antioxidant, was found to be able to partially rescue the cardiac toxicity caused by BN, which indicated that ROS are probably the major reason for the resulting cardiotoxicity in zebrafish embryos. Our results suggest the need for a comprehensive safety evaluation of the regular consumption of benoxacor, which provides scientific basis for the development of health standards and assessment of potential risk in aquatic organisms or even human.

5.
Artigo em Inglês | MEDLINE | ID: mdl-34417142

RESUMO

BACKGROUND: Tumor size is still considered a useful prognostic factor in currently available tumor-node-metastasis (TNM) classification staging systems for most solid tumors, but the significance of tumor size on the prognosis of ampullary carcinoma remains controversial. The aim of the current study was to propose a new T-stage classification system for ampullary carcinoma to address the impact of tumor size on the prognostic outcome. METHODS: Using the Surveillance, Epidemiology, and End Results (SEER) database, we identified 1080 patients with ampullary carcinoma who underwent radical surgical resection between 2004 and 2015. Based on the results obtained from analysis of various clinicopathologic factors, a new T-stage classification system was proposed. RESULTS: Among the 1080 patients, 618 were men and 462 were women, with a median tumor size of 2.3 (range 0.1-12) cm. Using the 7th edition of the American Joint Committee on Cancer (AJCC) staging manual, we noticed significant differences in overall survival (OS) between T2 vs. T3 tumors (P < 0.001) and T3 vs. T4 tumors (P = 0.002), but failed to observe significant differences between T1 vs. T2 tumors (P = 0.498) in our pair-wise comparison. Using the newly developed T-stage classification system, we were able to differentiate significant differences in OS between T1 vs. T2 tumors (P = 0.032), T2 vs. T3 tumors (P < 0.001) and T3 vs. T4 tumor (P = 0.003) in all pair-wise comparisons. The c-index of the new staging system was 0.653 (95% CI: 0.629-0.677), showing a better discriminatory power than the 0.636 of the 7th AJCC staging system (95% CI: 0.612-0.660). CONCLUSIONS: The new T-stage classification system described herein can better differentiate prognostic outcomes after radical resection in patients with ampullary carcinoma by incorporating tumor size and depth of tumor infiltration.

6.
Ecotoxicol Environ Saf ; 222: 112514, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34280841

RESUMO

Pendimethalin (PND) is one of the best sellers of selective herbicide in the world and has been frequently detected in the water. However, little is known about its effects on cardiac development. In this study, we used zebrafish to investigate the developmental and cardiac toxicity of PND. We exposed the zebrafish embryos with a serial of concentrations at 3, 4, and 5 mg/L at 5.5-72 h post-fertilization (hpf). We found that PND exposure can reduce the heart rate, survival rate, and body length of zebrafish embryos. Furthermore, we identified many malformations including pericardial and yolk sac edema, spinal deformity, and cardiac looping abnormality. In addition, PND increased the expression of reactive oxygen species and malondialdehyde and reduced the activity of superoxide dismutase (Antioxidant enzymes); We examined the expression of cardiac development-related genes and the apoptosis markers, and found changes of the following marker: vmhc, nppa, tbx5a, nkx2.5, gata4, tbx2b and FoxO1, bax, bcl-2, p53, casp-9, casp-3. Our data showed that activation of Wnt pathway can rescue the cardiac abnormalities caused by PND. Our results provided new evidence for the toxicity of PND and suggested that the PND residual should be treated as a hazard in the environment.


Assuntos
Embrião não Mamífero , Peixe-Zebra , Compostos de Anilina , Animais , Apoptose , Cardiotoxicidade/metabolismo , Embrião não Mamífero/metabolismo , Estresse Oxidativo , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
7.
Molecules ; 26(13)2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34279368

RESUMO

The purpose of this study was to identify new metal-based anticancer drugs; to this end, we synthesized two new copper(II) complexes, namely [Cu(ncba)4(phen)] (1) and [Cu(ncba)4(bpy)] (2), comprised 4-chloro-3-nitrobenzoic acid as the main ligand. The single-crystal XRD approach was employed to determine the copper(II) complex structures. Binding between these complexes and calf thymus DNA (CT-DNA) and human serum albumin (HSA) was explored by electronic absorption, fluorescence spectroscopy, and viscometry. Both complexes intercalatively bound CT-DNA and statically and spontaneously quenched DNA/HSA fluorescence. A CCK-8 assay revealed that complex 1 and complex 2 had substantial antiproliferative influences against human cancer cell lines. Moreover, complex 1 had greater antitumor efficacy than the positive control cisplatin. Flow cytometry assessment of the cell cycle demonstrated that these complexes arrested the HepG2 cell cycle and caused the accumulation of G0/G1-phase cells. The mechanism of cell death was elucidated by flow cytometry-based apoptosis assays. Western blotting revealed that both copper(II) complexes induced apoptosis by regulating the expression of the Bcl-2(Bcl-2, B cell lymphoma 2) protein family.


Assuntos
Antineoplásicos/síntese química , Clorobenzoatos/química , Complexos de Coordenação/síntese química , Cobre/química , Albumina Sérica Humana/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/farmacologia , DNA/química , Células Hep G2 , Humanos
8.
Chem Phys Lipids ; 239: 105112, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34216587

RESUMO

OBJECTIVE: We aimed to identify the detailed relationships between serum lipid levels and neuropsychiatric symptoms in patients with Parkinson's disease (PD). METHODS: Consecutive PD patients and healthy controls were recruited and demographic data were collected. The disease stages of PD patients were assessed using Hoehn-Yahr scale while neuropsychiatric symptoms were determined using Hamilton depression rating scale (HAMD), Hamilton anxiety rating scale (HAMA), and mini-mental state examination scale. Fast serum samples were obtained and the serum levels of lipids were identified. Linear regression analyses and correlation analyses were performed to explore the relationships between serum lipid levels and neuropsychiatric symptoms. RESULTS: The serum levels of triglyceride had significantly decreased while the levels of HDL-c and lipoprotein a had increased in PD patients. Linear regression analyses confirmed that the levels of triglyceride were mainly correlated with age and HAMA score, the levels of HDL-c were correlated with disease duration and gender, and the levels of lipoprotein a were correlated with HAMD score. Correlation analyses further confirmed that the levels of triglyceride were negatively correlated with HAMA score when the levels of lipoprotein a were negatively correlated with HAMD score. CONCLUSIONS: Lipid metabolism is significantly correlated with neuropsychiatric disorders in PD patients.

9.
Ecotoxicol Environ Saf ; 220: 112385, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34082241

RESUMO

Sulfometuron methyl (SM) is a widely used herbicide and thus leading to accumulation in the environment. The toxicity assessments of SM in model organisms are currently rare. In the present study, zebrafish were utilized for evaluating the detrimental effects of SM in aquatic vertebrates. Zebrafish embryos were exposed to 0, 10, 20, and 40 mg/L SM from 5.5 to 72 h post-fertilization (hpf), respectively. Consequently, SM exposure resulted in increasing the mortality rate and reducing hatching rate in larval zebrafish at 10, 20, and 40 mg/L SM-treated groups. The reduced numbers of immune cells (neutrophils and macrophages) were observed after SM exposure by a dose-dependent manner. The inflammatory responses (TLR4, MYD88, IL-1ß, IL-6, IL-8, IFN-γ, IL-10, and TGF-ß) were measured to estimate immune responses. Anti-inflammatory factors (IL-10 and TGF-ß) were down-regulated in all the treated groups and significantly altered at 40 mg/L exposure group. Additionally, behavioral tests suggested that SM treatment significantly increased the total distance, average speed, and maximum acceleration of larval zebrafish during light-dark transition and subsequently enzymology test displayed the same trend to locomotor behaviors. The content significantly increased in oxidative stress, as reflected in ROS level in all the treated groups. The numbers of cell apoptosis were significantly increased at 20, and 40 mg/L and the highest concentration group induced the substantial increment (P < 0.001) of apoptosis-related genes including p53, Bax/Bcl-2, caspase-9, and caspase-3. In summary, our results demonstrated that exposure to SM caused toxicity of development, immune system, locomotor behavior, oxidative stress, and cell apoptosis at the early developmental stages of zebrafish.


Assuntos
Embrião não Mamífero/efeitos dos fármacos , Herbicidas/toxicidade , Compostos de Sulfonilureia/toxicidade , Peixe-Zebra/crescimento & desenvolvimento , Animais , Apoptose/efeitos dos fármacos , Catalase/metabolismo , Citocinas/genética , Citocinas/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Larva/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio , Superóxido Dismutase/metabolismo , Poluentes Químicos da Água/toxicidade
10.
J Med Chem ; 64(13): 8992-9009, 2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34132534

RESUMO

Glycine-N-methyl transferase (GNMT) downregulation results in spontaneous hepatocellular carcinoma (HCC). Overexpression of GNMT inhibits the proliferation of liver cancer cell lines and prevents carcinogen-induced HCC, suggesting that GNMT induction is a potential approach for anti-HCC therapy. Herein, we used Huh7 GNMT promoter-driven screening to identify a GNMT inducer. Compound K78 was identified and validated for its induction of GNMT and inhibition of Huh7 cell growth. Subsequently, we employed structure-activity relationship analysis and found a potent GNMT inducer, K117. K117 inhibited Huh7 cell growth in vitro and xenograft in vivo. Oral administration of a dosage of K117 at 10 mpk (milligrams per kilogram) can inhibit Huh7 xenograft in a manner equivalent to the effect of sorafenib at a dosage of 25 mpk. A mechanistic study revealed that K117 is an MYC inhibitor. Ectopic expression of MYC using CMV promoter blocked K117-mediated MYC inhibition and GNMT induction. Overall, K117 is a potential lead compound for HCC- and MYC-dependent cancers.


Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Glicina N-Metiltransferase/genética , Ensaios de Triagem em Larga Escala , Neoplasias Hepáticas/tratamento farmacológico , Proteínas Proto-Oncogênicas c-myc/antagonistas & inibidores , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Feminino , Glicina N-Metiltransferase/metabolismo , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Neoplasias Hepáticas Experimentais/metabolismo , Neoplasias Hepáticas Experimentais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Regiões Promotoras Genéticas/efeitos dos fármacos , Regiões Promotoras Genéticas/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas
11.
Environ Pollut ; 285: 117323, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34091267

RESUMO

Evaluation of the toxicity of pesticide residues on non-target organisms in the ecosystem is an important part of pesticide environmental risk assessment. Flupyradifurone is a new type of butenolide insecticide produced by Bayer, who claims it to be "low toxic" to non-target organisms in the environment. However, there is little evidence in the literature to show how flupyradifurone affects aquatic organism development. In the current study, zebrafish embryos were treated with 0.1, 0.15, and 0.2 mg/mL of flupyradifurone within 6.0-72 h past fertilization (hpf). We found that the half-lethal concentration (LC50) of flupyradifurone for zebrafish embryos at 96 hpf was 0.21 mg/mL. Flupyradifurone decreases the heart rate, survival rate, and body length of zebrafish embryos. The flupyradifurone treatment also led to the failure of heart looping, and pericardial edema. Moreover, flupyradifurone increased the level of reactive oxygen species (ROS) and decreased the enzymatic catalysis of catalase (CAT) and superoxide dismutase (SOD). Alterations were induced in the transcription of apoptosis-related genes (bcl-2, bax, bax/bcl-2, p53 and caspase-9) and the heart development-related genes (gata4, myh6, nkx2.5, nppa, tbx2b, tbx5 and vmhc). In the current study, new evidences have been provided regarding the toxic effects of flupyradifurone and the risk of its residues in agricultural products and the environment.


Assuntos
Embrião não Mamífero , Peixe-Zebra , 4-Butirolactona/análogos & derivados , Animais , Apoptose , Ecossistema , Embrião não Mamífero/metabolismo , Desenvolvimento Embrionário , Estresse Oxidativo , Piridinas
12.
Ann Surg Oncol ; 28(8): 4668-4674, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33393026

RESUMO

BACKGROUND: The optimal surgical modality for duodenal gastrointestinal stromal tumor (GIST) remains undefined. The purpose of this study was to evaluate long-term survival outcomes of patients who underwent radical resection (RR) or limited resection (LR) of duodenal GIST. METHODS: A total of 325 patients identified from the Surveillance, Epidemiology and End Results (SEER) database who underwent surgery for duodenal GIST between 1986 and 2016 were classified into a LR group and a RR group based on the type of surgery received. Propensity score matching (PSM) was performed to minimize the selection bias in comparisons. Disease-specific survival (DSS) and overall survival (OS) were observed, and factors affecting the survival outcome were analyzed. RESULTS: In the entire cohort, 105 patients (32.3%) underwent RR and 220 (67.7%) received LR. Both the 5-year OS and DSS in RR group were significantly better than those in LR group (71.0% vs. 54.1%, P = 0.014; 66.6% vs. 49.1%, P = 0.025). PSM resulted in 95 pairs of patients, with long-term outcomes being comparable between the two groups. After adjusting covariates in the propensity matched cohort, the type of surgery still showed no significant impact on OS (hazard ratio [HR] 1.160; 95% confidence interval [CI] 0.662-2.033) and DSS (HR 1.208; 95% CI 0.686-2.128). CONCLUSIONS: Surgical modalities do not seem to have a significant impact on long-term survival outcomes of patients with duodenal GIST and should mainly depend on the tumor size and location.


Assuntos
Tumores do Estroma Gastrointestinal , Estudos de Coortes , Duodeno , Tumores do Estroma Gastrointestinal/cirurgia , Humanos , Pontuação de Propensão , Modelos de Riscos Proporcionais , Estudos Retrospectivos
14.
Neurosci Lett ; 745: 135626, 2021 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-33440238

RESUMO

OBJECTIVES: Anxiety disorder is a common non-motor symptom in patient with Parkinson's disease (PD). We aimed to explore its pathogenesis and identify plasma biomarkers using untargeted metabolomics analysis. METHODS: Consecutive PD patients and healthy controls were recruited. Clinical data were assessed and patients with Parkinson's disease related anxiety disorder (PDA) were recognized. Fast plasma samples were obtained and untargeted liquid chromatography-mass spectrometry-based metabolomics analysis was performed. Based on the differentially expressed metabolites from the above metabolomics analysis, correlation analyses and receiver operating characteristic curves (ROC) were further employed. RESULTS: According to the clinical data, PDA patients had lower plasma levels of total cholesterol, triglyceride, low-density lipoprotein cholesterol, and apolipoprotein B. There were thirty-nine differentially expressed metabolites in PDA patients when compared with the other two groups from the metabolomics analysis, respectively. Fourteen lipid metabolites were simultaneously altered between these two groups, and all of them were significantly decreased. They can be further subcategorized into fatty acyls, glycerolipids, sterol lipids, sphingolipids, and prenol lipids. The plasma levels of thirteen metabolites were negatively correlated with HAMA scores except 10-oxo-nonadecanoic acid. Based on the ROC curves, the fourteen lipid metabolites can be diagnostic biomarkers for PDA patients separately and the areas under the curve of the fourteen lipid metabolites ranged from 0.681 to 0.798. CONCLUSIONS: Significantly lower plasma lipoproteins can be found in PDA patients. A panel of fourteen lipid metabolites were also significantly decreased and can be clinical biomarkers for the diagnosis of PDA patients.


Assuntos
Transtornos de Ansiedade/sangue , Metabolismo dos Lipídeos/fisiologia , Lipídeos/sangue , Lipoproteínas/sangue , Metabolômica/métodos , Doença de Parkinson/sangue , Idoso , Transtornos de Ansiedade/diagnóstico , Transtornos de Ansiedade/epidemiologia , Biomarcadores/sangue , Bases de Dados Factuais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/diagnóstico , Doença de Parkinson/epidemiologia
15.
Metab Brain Dis ; 36(3): 463-470, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33433787

RESUMO

Dementia is very common in the late stage of patient with Parkinson's disease (PD). We aim to explore its underlying pathogenesis and identify candidate biomarkers using untargeted metabolomics analysis. Consecutive PD patients and healthy controls were recruited. Clinical data were assessed and patients were categorized into Parkinson's disease without dementia (PDND) and Parkinson's disease dementia (PDD). Fast plasma samples were obtained and untargeted liquid chromatography-mass spectrometry-based metabolomics analysis was performed. Based on the identified differentially-expressed metabolites from the metabolomics analysis, multivariate linear regression analyses and receiver operating characteristic (ROC) curves were further employed. According to the clinical data, the mean ages of PDND and PDD patients were significantly higher than those of healthy controls. The incidence of hypercholesterolemia was decreased in PDD patients. PDD patients also had lower levels of triglyceride, low-density lipoprotein cholesterol, and apolipoprotein B. There were 24 and 57 differentially expressed metabolites in PDD patients when compared with the healthy controls and PDND patients from the metabolomics analysis. Eleven lipid metabolites were simultaneously decreased between these two groups, and can be further subcategorized into fatty acyls, glycerolipids, glycerophospholipids, sphingolipids, and prenol lipids. The plasma levels of the eleven metabolites were positively correlated with MMSE score and can be candidate biomarkers for PDD patients with areas under the curve ranging from 0.724 to 0.806 based on the ROC curves. Plasma lipoproteins are significantly lower in PDD patients. A panel of eleven lipid metabolites were also decreased and can be candidate biomarkers for the diagnosis of PDD patients. Lipid metabolic dysregulation is involved in the pathogenesis of Parkinson's disease dementia.

16.
Chemosphere ; 263: 127860, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32829219

RESUMO

Iprodione is a highly effective broad-spectrum fungicide commonly used for early disease control in fruit trees and vegetables. Pesticides often flow into watercourses due to rainfall, causing toxicity in non-target organisms, eventually entering the food chain. However, little information is available in the current literature about the toxicity of iprodione to cardiac development. The present study aimed to investigate the effect of iprodione on early embryonic development and its cardiotoxicity in aquatic animals, using zebrafish as a model. At 6-72 h post-fertilization (hpf), zebrafish were exposed to concentrations of 15 mg/L, 20 mg/L, and 25 mg/L (72 h-LC50 = 21.15 mg/L). We found that exposure to iprodione resulted in yolk edema, increased mortality, and shortened body length in zebrafish embryos. In addition, iprodione was also found to induce edema in the pericardium of zebrafish, decrease heart rate, and cause the failure of cardiac cyclization. Exposure to iprodione significantly increased the accumulation of ROS and altered the activity of antioxidant enzymes (MDA, CAT) in zebrafish embryos. Moreover, iprodione induced changes in the transcription levels of heart developmental-related genes and apoptosis-related genes. In addition, Astaxanthin (antioxidant) can partially rescue the toxic phenotype caused by iprodione. Apoptosis-related genes and heart developmental-related genes were rescued after astaxanazin treatment. The results suggest that iprodione induces developmental and cardiac toxicity in zebrafish embryos, which provides new evidence of the toxicity of iprodione to organisms in aquatic ecosystems and assessing human health risks.


Assuntos
Cardiotoxicidade , Peixe-Zebra , Aminoimidazol Carboxamida/análogos & derivados , Animais , Ecossistema , Embrião não Mamífero/metabolismo , Desenvolvimento Embrionário , Hidantoínas , Estresse Oxidativo
17.
Nat Prod Res ; : 1-6, 2020 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-33289429

RESUMO

Zanthoxylum armatum, its peels possessed better special flavour, as well as various bioactivities, such as anti-inflammatory, anti-microbial and anti-tumour. In our chemical investigation on the peels of Z. armatum, two new lignans (1 and 2) and three known lignans (3-5) were isolated by silica gel column chromatography, ODS column and preparative HPLC and their structures were established as zanthlignans A and B (1-2), (-)-asarinin (3), phylligenin (4) and planispine A (5) through various spectroscopic techniques including UV, IR, HR-ESI-MS, NMR and CD methods.

18.
Ecotoxicol Environ Saf ; 205: 111339, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32961491

RESUMO

Famoxadone-cymoxanil is a new protective and therapeutic fungicide, but little research has been done on it or its toxicity in aquatic organisms. In this study, we used zebrafish to investigate the cardiotoxicity of famoxadone-cymoxanil and the potential mechanisms involved. Zebrafish embryos were exposed to different concentrations of famoxadone-cymoxanil until 72 h post-fertilization (hpf), then changes of heart morphology in zebrafish embryos were observed. We also detected the levels of oxidative stress, myocardial-cell proliferation and apoptosis, ATPase activity, and the expression of genes related to the cardiac development and calcium-signaling pathway. After famoxadone-cymoxanil exposure, pericardial edema, cardiac linearization, and reductions in the heart rate and cardiac output positively correlated with concentration. Although myocardial-cell apoptosis was not detected, proliferation of the cells was severely reduced and ATPase activity significantly decreased, resulting in a severe deficiency in heart function. In addition, indicators of oxidative stress changed significantly after exposure of the embryos to the fungicide. To better understand the possible molecular mechanisms of cardiovascular toxicity in zebrafish, we studied the transcriptional levels of cardiac development, calcium-signaling pathways, and genes associated with myocardial contractility. The mRNA expression levels of key genes in heart development were significantly down-regulated, while the expression of genes related to the calcium-signaling pathway (ATPase [atp2a1], cardiac troponin C [tnnc1a], and calcium channel [cacna1a]) was significantly inhibited. Expression of klf2a, a major endocardial flow-responsive gene, was also significantly inhibited. Mechanistically, famoxadone-cymoxanil toxicity might be due to the downregulation of genes associated with the calcium-signaling pathway and cardiac muscle contraction. Our results found that famoxadone-cymoxanil exposure causes cardiac developmental toxicity and severe energy deficiency in zebrafish.


Assuntos
Acetamidas/toxicidade , Embrião não Mamífero/efeitos dos fármacos , Fungicidas Industriais/toxicidade , Coração/efeitos dos fármacos , Estrobilurinas/toxicidade , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/metabolismo , Animais , Apoptose/efeitos dos fármacos , Sinalização do Cálcio/efeitos dos fármacos , Sinalização do Cálcio/genética , Cardiotoxicidade , Regulação para Baixo , Embrião não Mamífero/metabolismo , Embrião não Mamífero/patologia , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Coração/embriologia , Frequência Cardíaca/efeitos dos fármacos , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Peixe-Zebra/crescimento & desenvolvimento , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
19.
Front Mol Neurosci ; 13: 80, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32714143

RESUMO

Parkinson's disease (PD) is a common neurodegenerative disease in the elderly with a pathogenesis that remains unclear. We aimed to explore its pathogenesis through plasma integrated metabolomics and proteomics analysis. The clinical data of consecutively recruited PD patients and healthy controls were assessed. Fasting plasma samples were obtained and analyzed using metabolomics and proteomics methods. After that, differentially expressed metabolites and proteins were identified for further bioinformatics analysis. No significant difference was found in the clinical data between these two groups. Eighty-three metabolites were differentially expressed in PD patients identified by metabolomics analysis. These metabolites were predominately lipid and lipid-like molecules (63%), among which 25% were sphingolipids. The sphingolipid metabolism pathway was enriched and tended to be activated in the following KEGG pathway analysis. According to the proteomics analysis, forty proteins were identified to be differentially expressed, seven of which were apolipoproteins. Furthermore, five of the six top ranking Gene Ontology terms from cellular components and eleven of the other fourteen Gene Ontology terms from biological processes were directly associated with lipid metabolism. In KEGG pathway analysis, the five enriched pathways were also significantly related with lipid metabolism (p < 0.05). Overall, Parkinson's disease is associated with plasma lipid metabolic disturbance, including an activated sphingolipid metabolism and decreased apolipoproteins.

20.
Opt Lett ; 45(11): 3151-3154, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32479482

RESUMO

Topologically protected plasmonic modes located inside topological bandgaps are attracting increasing attention, chiefly due to their robustness against disorder-induced backscattering. Here, we introduce a bilayer graphene metasurface that possesses plasmonic topological valley interface modes when the mirror symmetry of the metasurface is broken by horizontally shifting the lattice of holes of the top layer of the two freestanding graphene layers in opposite directions. In this configuration, light propagation along the domain-wall interface of the bilayer graphene metasurface shows unidirectional features. Moreover, we have designed a molecular sensor based on the topological properties of this metasurface using the fact that the Fermi energy of graphene varies upon chemical doping. This effect induces strong variation of the transmission of the topological guided modes, which can be employed as the underlying working principle of gas sensing devices. Our work opens up new ways of developing robust integrated plasmonic devices for molecular sensing.

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