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1.
Biochem Pharmacol ; : 114745, 2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34454930

RESUMO

The repair of vascular endothelial cell dysfunction is an encouraging approach for the treatment of vascular complications associated with diabetes. It has been demonstrated that members of C1q/tumor necrosis factor-related protein (CTRP) family may improve endothelial function. Nevertheless, the protective properties of CTRPs in diabetic microvascular complications continue to be mostly unknown. Here, we demonstrate that the C1q-like globular domain of CTRP3, CTRP5, and CTRP9 (gCTRP3, 5, 9) exerted a vasorelaxant effect on the microvasculature, of which gCTRP3 was the most powerful one. In a murine model of type 2 diabetes mellitus, serum gCTRP3 level and endothelial function decreased markedly compared with controls. Two weeks of gCTRP3 treatment (0.5 µg/g/d) enhanced endothelium-dependent relaxation in microvessels, increased nitric oxide (NO·) production, and reduced retinal vascular leakage. In addition, Western blotting in human retinal microvascular endothelial cells indicated that gCTRP3 triggered AMP-activated protein kinase-α (AMPKα), hence increasing the endothelial NO synthase (eNOS) level and NO· production. In addition, incubation with gCTRP3 in vitro ameliorated the endothelial dysfunction induced by high glucose in the branch of the mesenteric artery. Blockade of either eNOS or AMPKα completely abolished the effects of gCTRP3 described above. Taken together, we demonstrate for the first time that gCTRP3 improves impaired vasodilatation of microvasculature in diabetes by ameliorating endothelial cell function through the AMPK/eNOS/NO· signaling pathway. This finding may suggest an effective intervention against diabetes-associated microvascular complications.

2.
Environ Res ; 202: 111775, 2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34333008

RESUMO

Per- and polyfluoroalkyl substances (PFASs) are anthropogenic compounds that are widely accumulated in human tissues, and the liver is considered a primary target organ for PFASs exposure. The occurrence and distribution of 21 PFASs in liver tissues with tumors (n = 55) and without tumors (n = 55) are investigated in this study. Eleven perfluorinated carboxylic acids (PFCAs) and five perfluorinated sulfonic acids (PFSAs) were detected at high frequencies (45.5%-100 %), while the detection frequencies of five perfluoroalkyl phosphate (PFPAs) were relatively lower (≤29.1 %). PFSAs and PFCAs accounted for up to 82.5%-92.7 % of the total PFASs. Although it was not found to be statistically significant, the concentrations of the total PFASs were slightly higher in the tumor liver samples (mean 64.3, range 5.70-303 ng/g) than those in the non-tumor liver samples (mean 62.7, range 4.08-240 ng/g).The perfluorooctanoic acid (PFOA), perfluorotridecanoic acid (PFTrDA), and perfluorobutanesulphonate (PFBS) showed significant differences (p < 0.05) between the tumor and non-tumor liver samples, and the different distribution levels of these three PFASs may have been a consequence of oxidative stress. The total concentrations of PFASs in the three age groups were in the decreasing order of middle-aged people (45-60) > old people (>60) > young people (<45). The PFASs in females were generally lower than in males, which may have been related to women's special excretion methods (such as childbirth and breastfeeding). The results should be valuable for further mechanistic studies regarding the toxic effects of PFASs in human livers.

3.
Clin Transl Med ; 11(8): e503, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34459131

RESUMO

Intrinsic resistance to CDK4/6 inhibitors hinders their clinical utility in cancer treatment. Furthermore, the predictive markers of CDK4/6 inhibitors in gastric cancer (GC) remain incompletely described. Here, we found that PAX6 expression was negatively correlated with the response to palbociclib in vitro and in vivo in GC. We observed that the PAX6 expression level was negatively correlated with the overall survival of GC patients and further showed that PAX6 can promote GC cell proliferation and the cell cycle. The cell cycle is regulated by the interaction of cyclins with their partner serine/threonine cyclin-dependent kinases (CDKs), and the G1/S-phase transition is the main target of CDK4/6 inhibitors. Therefore, we tested whether PAX6 expression was correlated with the GC response to palbociclib. We found that PAX6 hypermethylates the promoter of LATS2 and inactivates the Hippo pathway, which upregulates cyclin D1 (CCND1) expression. This results in a suppressed response to palbociclib in GC. Furthermore, we found that the induction of the Hippo signaling pathway or treatment with a DNA methylation inhibitor could overcome PAX6-induced palbociclib resistance in GC. These findings uncover a tumor promoter function of PAX6 in GC and establish overexpressed PAX6 as a mechanism of resistance to palbociclib.

4.
Artigo em Inglês | MEDLINE | ID: mdl-34410548

RESUMO

PURPOSE: Macrophage apoptosis coupled with a defective phagocytic clearance of the apoptotic cells promotes plaque necrosis in advanced atherosclerosis, which causes acute atherothrombotic vascular disease. Nonsteroidal anti-inflammatory drug sulindac derivative K-80003 treatment was previously reported to dramatically attenuate atherosclerotic plaque progression and destabilization. However, the underlying mechanisms are not fully understood. This study aimed to determine the role of K-80003 on macrophage apoptosis and elucidate the underlying mechanism. METHODS: The mouse model of vulnerable carotid plaque in ApoE-/- mice was developed in vivo. Consequently, mice were randomly grouped into two study groups: the control group and the K-80003 group (30 mg/kg/day). Samples of carotid arteries were collected to determine atherosclerotic necrotic core area, cellular apoptosis, and oxidative stress. The effects of K-80003 on RAW264.7 macrophage apoptosis, oxidative stress, and autophagic flux were also examined in vitro. RESULTS: K-80003 significantly suppressed necrotic core formation and inhibited cellular apoptosis of vulnerable plaques. K-80003 can also inhibit 7-ketocholesterol-induced macrophage apoptosis in vitro. Furthermore, K-80003 inhibited intraplaque cellular apoptosis mainly through the suppression of oxidative stress, which is a key cause of advanced lesional macrophage apoptosis. Mechanistically, K-80003 prevented 7-ketocholesterol-induced impairment of autophagic flux in macrophages, evidenced by the decreased LC3II and SQSTM1/p62 expression, GFP-RFP-LC3 cancellation upon K-80003 treatment. CONCLUSION: Inhibition of macrophage apoptosis and necrotic core formation by autophagy-mediated reduction of oxidative stress is one mechanism of the suppression of plaque progression and destabilization by K-80003.

6.
Artigo em Inglês | MEDLINE | ID: mdl-34329444

RESUMO

BACKGROUND: Little is known about the effects of lifestyle modification on biological aging in population-based studies of middle-aged and older adults. METHODS: We examined the individual and joint associations of multiple lifestyle factors with accelerated biological aging measured by change in frailty index (FI) over 8 years in a prospective study of Chinese adults. Data were obtained on 24,813 participants in the China Kadoorie Biobank (CKB) on lifestyle factors and frailty status at baseline and at 8 years after baseline. Adherence to healthy lifestyle factors included non-smoking or quitting smoking for reasons other than illness, avoidance of heavy alcohol consumption, daily intake of fruit and vegetables, being physically active, body mass index (BMI) of 18.5-23.9 kg/m 2, and waist-to-hip ratio (WHR) <0.90 (men)/0.85 (women). FI was constructed separately at baseline and resurvey using 25 age- and health-related items. RESULTS: Overall, 8,760 (35.3%) individuals had a worsening frailty status. In multivariable-adjusted logistic regression analyses, adherence to healthy lifestyle was associated with a lower risk of worsening frailty status. Compared with robust participants maintaining 0-1 healthy lifestyle factors, the corresponding OR (95% CI) was 0.93 (0.83-1.03), 0.75 (0.67-0.84), 0.68 (0.60-0.77), and 0.55 (0.46-0.65) for robust participants with 2, 3, 4, and 5-6 healthy lifestyle factors. The decreased risk of frailty status worsening by adherence to healthy lifestyle factors was similar in both middle-aged and older adults, and in both robust and prefrail participants at baseline. CONCLUSIONS: Adherence to a healthy lifestyle may attenuate the rate of change in biological aging in middle-aged and older Chinese adults.

7.
Respir Res ; 22(1): 203, 2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34243776

RESUMO

BACKGROUND: Thousands of Coronavirus Disease 2019 (COVID-19) patients have been discharged from hospitals Persistent follow-up studies are required to evaluate the prevalence of post-COVID-19 fibrosis. METHODS: This study involves 462 laboratory-confirmed patients with COVID-19 who were admitted to Shenzhen Third People's Hospital from January 11, 2020 to April 26, 2020. A total of 457 patients underwent thin-section chest CT scans during the hospitalization or after discharge to identify the pulmonary lesion. A total of 287 patients were followed up from 90 to 150 days after the onset of the disease, and lung function tests were conducted about three months after the onset. The risk factors affecting the persistence of pulmonary fibrosis were identified through regression analysis and the prediction model of the persistence of pulmonary fibrosis was established. RESULTS: Parenchymal bands, irregular interfaces, reticulation and traction bronchiectasis were the most common CT features in all COVID-19 patients. During the 0-30, 31-60, 61-90, 91-120 and > 120 days after onset, 86.87%, 74.40%, 79.56%, 68.12% and 62.03% patients developed with pulmonary fibrosis and 4.53%, 19.61%, 18.02%, 38.30% and 48.98% patients reversed pulmonary fibrosis, respectively. It was observed that Age, BMI, Fever, and Highest PCT were predictive factors for sustaining fibrosis even after 90 days from onset. A predictive model of the persistence with pulmonary fibrosis was developed based-on the Logistic Regression method with an accuracy, PPV, NPV, Sensitivity and Specificity of the model of 76%, 71%, 79%, 67%, and 82%, respectively. More than half of the COVID-19 patients revealed abnormal conditions in lung function after 90 days from onset, and the ratio of abnormal lung function did not differ on a statistically significant level between the fibrotic and non-fibrotic groups. CONCLUSIONS: Persistent pulmonary fibrosis was more likely to develop in patients with older age, higher BMI, severe/critical condition, fever, a longer viral clearance time, pre-existing disease and delayed hospitalization. Fibrosis developed in COVID-19 patients could be reversed in about a third of the patients after 120 days from onset. The pulmonary function of less than half of COVID-19 patients could turn to normal condition after three months from onset. An effective prediction model with an average area under the curve (AUC) of 0.84 was established to predict the persistence of pulmonary fibrosis in COVID-19 patients for early diagnosis.


Assuntos
COVID-19/virologia , Pulmão/virologia , Alta do Paciente , Fibrose Pulmonar/virologia , SARS-CoV-2/patogenicidade , Adolescente , Adulto , COVID-19/complicações , COVID-19/diagnóstico , China , Feminino , Interações Hospedeiro-Patógeno , Humanos , Pulmão/diagnóstico por imagem , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Fibrose Pulmonar/diagnóstico por imagem , Fibrose Pulmonar/fisiopatologia , Testes de Função Respiratória , Fatores de Tempo , Tomografia Computadorizada por Raios X , Adulto Jovem
8.
Biomed Res Int ; 2021: 7020637, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34195281

RESUMO

Hepatocellular carcinoma (HCC) is one of the most common and aggressive tumors in the world while the accuracy of the present tests for detecting HCC is poor. A novel diagnostic and prognostic biomarker for HCC is urgently needed. Overwhelming evidence has demonstrated the regulatory roles of small nucleolar RNA (snoRNA) in carcinogenesis. This study is aimed at analyzing the expression of a snoRNA, SNORA52, in HCC and exploring the correlation between its expression and various clinical characteristics of HCC patients. By using quantitative real-time PCR, we found that SNORA52 was downregulated in HCC cell lines (P < 0.05) and HCC tissues (P < 0.001). Correlation analysis showed that the expression of SNORA52 was obviously associated with tumor size (P = 0.011), lesion number (P = 0.007), capsular invasion (P = 0.011), tumor differentiation degree (P = 0.046), and TNM stage (P = 0.004). The disease-free survival (DFS) and overall survival (OS) analysis showed that patients with lower SNORA52 expression had a worse prognosis (P < 0.001). Univariate and multivariate Cox regression analysis showed that SNORA52 expression was a completely independent prognostic factor to predict DFS (P = 0.009) and OS (P = 0.012) of HCC patients. Overall, our findings showed SNORA52 expression levels were downregulated in HCC tissues and correlated with multiple clinical variables, and SNORA52 was an independent prognostic factor for HCC patients, which suggested that SNORA52 could function as a potential diagnostic and prognostic biomarker for HCC patients.

9.
Front Immunol ; 12: 691879, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34163488

RESUMO

Increasing human Adenovirus (HAdV) infections complicated with acute respiratory distress syndrome (ARDS) even fatal outcome were reported in immunocompetent adolescent and adult patients. Here, we characterized the cytokine/chemokine expression profiles of immunocompetent patients complicated with ARDS during HAdV infection and identified biomarkers for disease severity/progression. Forty-eight cytokines/chemokines in the plasma samples from 19 HAdV-infected immunocompetent adolescent and adult patients (ten complicated with ARDS) were measured and analyzed in combination with clinical indices. Immunocompetent patients with ARDS caused by severe acute respiratory disease coronavirus (SARS-CoV)-2, 2009 pandemic H1N1 (panH1N1) or bacteria were included for comparative analyses. Similar indices of disease course/progression were found in immunocompetent patients with ARDS caused by HAdV, SARS-CoV-2 or panH1N infections, whereas the HAdV-infected group showed a higher prevalence of viremia, as well as increased levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and creatine kinase (CK). Expression levels of 33 cytokines/chemokines were increased significantly in HAdV-infected patients with ARDS compared with that in healthy controls, and many of them were also significantly higher than those in SARS-CoV-2-infected and panH1N1-infected patients. Expression of interferon (IFN)-γ, interleukin (IL)-1ß, hepatocyte growth factor (HGF), monokine induced by IFN-γ (MIG), IL-6, macrophage-colony stimulating factor (M-CSF), IL-10, IL-1α and IL-2Ra was significantly higher in HAdV-infected patients with ARDS than that in those without ARDS, and negatively associated with the ratio of the partial pressure of oxygen in arterial blood/fraction of inspired oxygen (PaO2/FiO2). Analyses of the receiver operating characteristic curve (ROC) showed that expression of IL-10, M-CSF, MIG, HGF, IL-1ß, IFN-γ and IL-2Ra could predict the progression of HAdV infection, with the highest area under the curve (AUC) of 0.944 obtained for IL-10. Of note, the AUC value for the combination of IL-10, IFN-γ, and M-CSF reached 1. In conclusion, the "cytokine storm" occurred during HAdV infection in immunocompetent patients, and expression of IL-10, M-CSF, MIG, HGF, IL-1ß, IFN-γ and IL-2Ra was closely associated with disease severity and could predict disease progression.


Assuntos
Infecções por Adenovirus Humanos/sangue , Citocinas/sangue , Síndrome do Desconforto Respiratório/sangue , Infecções por Adenovirus Humanos/complicações , Infecções por Adenovirus Humanos/patologia , Adenovírus Humanos , Adolescente , Adulto , Bactérias , Infecções Bacterianas/sangue , Infecções Bacterianas/complicações , Infecções Bacterianas/patologia , Biomarcadores/sangue , COVID-19/sangue , COVID-19/complicações , COVID-19/patologia , Progressão da Doença , Feminino , Humanos , Vírus da Influenza A Subtipo H1N1 , Influenza Humana/sangue , Influenza Humana/complicações , Influenza Humana/patologia , Masculino , Síndrome do Desconforto Respiratório/complicações , Síndrome do Desconforto Respiratório/patologia , SARS-CoV-2 , Índice de Gravidade de Doença , Viremia/sangue , Viremia/complicações , Viremia/patologia , Adulto Jovem
10.
J Mol Cell Cardiol ; 159: 91-104, 2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34147480

RESUMO

AIMS: Pathological cardiac hypertrophy induced by activation of the renin-angiotensin-aldosterone system (RAAS) is one of the leading causes of heart failure. However, in current clinical practice, the strategy for targeting the RAAS is not sufficient to reverse hypertrophy. Here, we investigated the effect of prostaglandin E1 (PGE1) on angiotensin II (AngII)-induced cardiac hypertrophy and potential molecular mechanisms underlying the effect. METHODS AND RESULTS: Adult male C57 mice were continuously infused with AngII or saline and treated daily with PGE1 or vehicle for two weeks. Neonatal rat cardiomyocytes were cultured to detect AngII-induced hypertrophic responses. We found that PGE1 ameliorated AngII-induced cardiac hypertrophy both in vivo and in vitro. The RNA sequencing (RNA-seq) and expression pattern analysis results suggest that Netrin-1 (Ntn1) is the specific target gene of PGE1. The protective effect of PGE1 was eliminated after knockdown of Ntn1. Moreover, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that the PGE1-mediated signaling pathway changes are associated with the mitogen-activated protein kinase (MAPK) pathway. PGE1 suppressed AngII-induced activation of the MAPK signaling pathway, and such an effect was attenuated by Ntn1 knockdown. Blockade of MAPK signaling rescued the phenotype of cardiomyocytes caused by Ntn1 knockdown, indicating that MAPK signaling may act as the downstream effector of Ntn1. Furthermore, inhibition of the E-prostanoid (EP) 3 receptor, as opposed to the EP1, EP2, or EP4 receptor, in cardiomyocytes reversed the effect of PGE1, and activation of EP3 by sulprostone, a specific agonist, mimicked the effect of PGE1. CONCLUSION: In conclusion, PGE1 ameliorates AngII-induced cardiac hypertrophy through activation of the EP3 receptor and upregulation of Ntn1, which inhibits the downstream MAPK signaling pathway. Thus, targeting EP3, as well as the Ntn1-MAPK axis, may represent a novel approach for treating pathological cardiac hypertrophy.

11.
Environ Pollut ; 287: 117581, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34166999

RESUMO

While bioremediation using soil microorganisms is considered an energy-efficient and eco-friendly approach to treat polycyclic aromatic hydrocarbon (PAH)-contaminated soils, a variety of polar PAH metabolites, particularly oxygenated ones, could increase the toxicity of the soil after biodegradation. In this study, a typical bio-oxidative transformation of PAH into quinones was investigated in soil amended with laccase using three PAHs with different structures (anthracene, benzo[a]anthracene, and benzo[a]pyrene) to assess the toxicity after oxidative bioremediation. The results show that during a 2-month incubation period the oxidation process promoted the formation of non-extractable residues (NERs) of PAHs, and different effects on mineralization were observed among the three PAHs. Oxidation enhanced the mineralization of the high-molecular-weight (HMW) PAHs (benzo[a]anthracene and benzo[a]pyrene) but inhibited the mineralization of the low-molecular-weight (LMW) PAH (anthracene). The inhibition of anthracene suggests increased toxicity after oxidative bioremediation, which coincided with a decrease in soil nitrification activity, bacterial diversity and PAH-ring hydroxylating dioxygenase gene copies. The analysis of PAH metabolites in soil extract indicated that oxidation by laccase was competitive with the natural transformation processes of PAHs and revealed that intermediates other than quinone metabolites increased the toxicity of soil during subsequent degradation. The different metabolic profiles of the three PAHs indicated that the toxicity of soil after PAH oxidation by laccase was strongly affected by the PAH structure. Despite the potential increase in toxicity, the results suggest that oxidative bioremediation is still an eco-friendly method for the treatment of HMW PAHs since the intermediates from HMW PAHs are more easily detoxified via NER formation than LMW PAHs.


Assuntos
Hidrocarbonetos Policíclicos Aromáticos , Poluentes do Solo , Biodegradação Ambiental , Lacase/metabolismo , Estresse Oxidativo , Hidrocarbonetos Policíclicos Aromáticos/toxicidade , Solo , Microbiologia do Solo , Poluentes do Solo/toxicidade
12.
J Nat Med ; 75(4): 854-870, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34043154

RESUMO

Astragalus polysaccharide (APS) has been frequently used as an adjuvant agent responsible for its immunoregulatory activity to enhance efficacy and reduce toxicity of chemotherapy used in the management of breast cancer. However, the other synergism mechanism of APS remains unclear. This study was performed to evaluate the potential targets and possible mechanism behind APS in vivo direct anti-tumor activity on breast cancer. Multiple biological detections were conducted to investigate the protein and mRNA expression levels of key targets. In total, 116 down-regulated and 73 up-regulated differential expressed genes (DEGs) were examined from 7 gene expression datasets. Top ten hub genes were obtained in four typical protein-protein interaction (PPI) network of DEGs involved in each specific biological process (BP, cell cycle, cell proliferation, cell apoptosis and death) that was related to inhibitory activity of APS in vitro against breast cancer cell lines. Four common DEGs (EGFR, ANXA1, KIF14 and IGF1) were further identified in the above four BP-PPI networks, among which EGFR and ANXA1 were the hub genes that were potentially linked to the progression of breast cancer. The results of biological detections indicated that the expression of EGFR in breast cancer cells was down-regulated, while the expression of ANXA1 was markedly increased in response to APS. In conclusion, the present study may provide potential molecular therapeutic targets and a new insight into the mechanism of APS against breast cancer.

13.
PLoS One ; 16(5): e0250649, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33945569

RESUMO

Treatment for the lethal primary adult brain tumor glioblastoma (GBM) includes the chemotherapy temozolomide (TMZ), but TMZ resistance is common and correlates with promoter methylation of the DNA repair enzyme O-6-methylguanine-DNA methyltransferase (MGMT). To improve treatment of GBMs, including those resistant to TMZ, we explored the potential of targeting dopamine receptor signaling. We found that dopamine receptor 3 (DRD3) is expressed in GBM and is also a previously unexplored target for therapy. We identified novel antagonists of DRD3 that decreased the growth of GBM xenograft-derived neurosphere cultures with minimal toxicity against human astrocytes and/or induced pluripotent stem cell-derived neurons. Among a set of DRD3 antagonists, we identified two compounds, SRI-21979 and SRI-30052, that were brain penetrant and displayed a favorable therapeutic window analysis of The Cancer Genome Atlas data demonstrated that higher levels of DRD3 (but not DRD2 or DRD4) were associated with worse prognosis in primary, MGMT unmethylated tumors. These data suggested that DRD3 antagonists may remain efficacious in TMZ-resistant GBMs. Indeed, SRI-21979, but not haloperidol, significantly reduced the growth of TMZ-resistant GBM cells. Together our data suggest that DRD3 antagonist-based therapies may provide a novel therapeutic option for the treatment of GBM.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Glioblastoma/patologia , Receptores de Dopamina D3/antagonistas & inibidores , Temozolomida/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos
14.
Food Chem ; 359: 129925, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-33964657

RESUMO

A modified QuEChERS method for determining cyenopyrafen in strawberries, mandarins and their processed products was established with a good linearity (R2 > 0.9981), accuracy (recoveries of 83% to 111%) and precision (relative standard deviations of 0.9% to 14%). The limit of quantification (LOQ) was 0.01 mg/kg. Field results showed that the half-lives of cyenopyrafen were 6.8 and 11.8 d in strawberry and mandarin respectively, and that the final residues were within established maximum residue limits (MRLs). The household processing factors (PFs) for cyenopyrafen residues in strawberry and mandarin fruits were also studied: residues increased in strawberry jam (PF 1.51) and mandarin juice (1.31) but decreased in strawberries (0.58) and mandarin pulp (<0.17) after washing and peeling, respectively. A risk assessment showed that the risk from long-term dietary exposures to cyenopyrafen was 73.73%, indicating that consuming these products was unlikely to present a public health concern.


Assuntos
Acrilonitrila/análogos & derivados , Citrus sinensis/química , Fragaria/química , Frutas/química , Resíduos de Praguicidas/química , Pirazóis/química , Acrilonitrila/análise , Acrilonitrila/química , Exposição Dietética , Resíduos de Praguicidas/análise , Pirazóis/análise , Medição de Risco
15.
J Fluoresc ; 31(4): 1133-1141, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33974180

RESUMO

A new spiropyran-based fluorescent probe was developed for dual detection of Fe2+ ion and pH. Addition of Fe2+ and Ag+ to the probe solution enhanced the fluorescence intensity by 6 and 5 fold, respectively. Addition of Fe3+, Hg2+ and Ni2+ caused slight increase in the fluorescence intensity of the probe. While addition of other common metal ions did not bring about substantial change of the fluorescence. Thus the probe can be used for fluorescence turn-on detection of Fe2+ ion in ethanol/water (9:1) medium. The detection limit of the probe for Fe2+ is 0.77 µM. The suitable pH range for the probe to detect Fe2+ was pH 3 - 9. Other metal ions including Li+, Na+, K+, Ag+, Cu2+, Zn2+, Co2+, Ni2+, Mn2+, Sr2+, Hg2+, Ca2+, Mg2+, Al3+, Cr3+, and Fe3+ did not cause marked interference with Fe2+ recognition. The color of the probe solution was yellow at pH 1 - 2 and colorless at other pH values. The fluorescence intensity of the probe was low at pH 1 - 12 and increased significantly when the pH was 13 and 14, indicating that the probe can be used as a colorimetric and fluorescent probe for sensing extremely acidic or extremely alkaline conditions through different channels.

16.
J Biol Chem ; 296: 100660, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33862083

RESUMO

The proteasome is a large protease complex that degrades many different cellular proteins. In eukaryotes, the 26S proteasome contains six different subunits of the ATPases associated with diverse cellular activities family, Rpt1-Rpt6, which form a hexameric ring as part of the base subcomplex that drives unfolding and translocation of substrates into the proteasome core. Archaeal proteasomes contain only a single Rpt-like ATPases associated with diverse cellular activities ATPase, the proteasome-activating nucleotidase, which forms a trimer of dimers. A key proteasome-activating nucleotidase proline residue (P91) forms cis- and trans-peptide bonds in successive subunits around the ring, allowing efficient dimerization through upstream coiled coils. However, the importance of the equivalent Rpt prolines for eukaryotic proteasome assembly was unknown. Here we showed that the equivalent proline is highly conserved in Rpt2, Rpt3, and Rpt5, and loosely conserved in Rpt1, in deeply divergent eukaryotes. Although in no case was a single Pro-to-Ala substitution in budding yeast strongly deleterious to growth, the rpt5-P76A mutation decreased levels of the protein and induced a mild proteasome assembly defect. Moreover, the rpt2-P103A, rpt3-P93A, and rpt5-P76A mutations all caused synthetic defects when combined with deletions of specific proteasome base assembly chaperones. The rpt2-P103A rpt5-P76A double mutant had uniquely strong growth defects attributable to defects in proteasome base formation. Several Rpt subunits in this mutant formed aggregates that were cleared, at least in part, by Hsp42 chaperone-mediated protein quality control. We propose that the conserved Rpt linker prolines promote efficient 26S proteasome base assembly by facilitating specific ATPase heterodimerization.


Assuntos
Proteínas de Choque Térmico/metabolismo , Prolina/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas Repressoras/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Sequência de Aminoácidos , Proteínas de Choque Térmico/genética , Mutação , Prolina/genética , Complexo de Endopeptidases do Proteassoma/genética , Ligação Proteica , Domínios Proteicos , Proteínas Repressoras/genética , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética , Homologia de Sequência , Ubiquitina-Proteína Ligases/genética
17.
Clin Hemorheol Microcirc ; 78(4): 339-353, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33843667

RESUMO

BACKGROUND: Described to be antithrombotic and antihypertensive, nattokinase is consumed for putative cardiovascular benefit. However, no large-scale, long-term cardiovascular study has been conducted with nattokinase supplementation. OBJECTIVE: To determine the effect of nattokinase on subclinical atherosclerosis progression and atherothrombotic biomarkers. METHODS: In this double-blinded trial, 265 individuals of median age 65.3 years, without clinical evidence of cardiovascular disease (CVD) were randomized to oral nattokinase 2,000 fibrinolytic units or matching placebo. Primary outcome was rate of change in subclinical atherosclerosis measured by serial carotid ultrasound every 6 months as carotid artery intima-media thickness (CIMT) and carotid arterial stiffness (CAS). Additional outcomes determined at least every 6 months were clinical parameters including blood pressure and laboratory measures including metabolic factors, blood rheology parameters, blood coagulation and fibrinolysis factors, inflammatory markers and monocyte/macrophage cellular activation markers. RESULTS: After median 3 years of randomized treatment, annualized rate of change in CIMT and CAS did not significantly differ between nattokinase supplementation and placebo. Additionally, there was no significant effect of nattokinase supplementation on blood pressure or any laboratory determination. CONCLUSIONS: Results of this trial show that nattokinase supplementation has a null effect on subclinical atherosclerosis progression in healthy individuals at low risk for CVD.

18.
Plant J ; 107(1): 149-165, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33866633

RESUMO

Recent studies have shown that global metabolic reprogramming is a common event in plant innate immunity; however, the relevant molecular mechanisms remain largely unknown. Here, we identified a pathogen-induced glycosyltransferase, UGT73C7, that plays a critical role in Arabidopsis disease resistance through mediating redirection of the phenylpropanoid pathway. Loss of UGT73C7 function resulted in significantly decreased resistance to Pseudomonas syringae pv. tomato DC3000, whereas constitutive overexpression of UGT73C7 led to an enhanced defense response. UGT73C7-activated immunity was demonstrated to be dependent on the upregulated expression of SNC1, a Toll/interleukin 1 receptor-type NLR gene. Furthermore, in vitro and in vivo assays indicated that UGT73C7 could glycosylate p-coumaric acid and ferulic acid, the upstream metabolites in the phenylpropanoid pathway. Mutations that lead to the loss of UGT73C7 enzyme activities resulted in the failure to induce SNC1 expression. Moreover, glycosylation activity of UGT73C7 resulted in the redirection of phenylpropanoid metabolic flux to biosynthesis of hydroxycinnamic acids and coumarins. The disruption of the phenylpropanoid pathway suppressed UGT73C7-promoted SNC1 expression and the immune response. This study not only identified UGT73C7 as an important regulator that adjusts phenylpropanoid metabolism upon pathogen challenge, but also provided a link between phenylpropanoid metabolism and an NLR gene.


Assuntos
Proteínas de Arabidopsis/imunologia , Arabidopsis/fisiologia , Glicosiltransferases/metabolismo , Imunidade Vegetal/fisiologia , Arabidopsis/efeitos dos fármacos , Proteínas de Arabidopsis/genética , Ácidos Cumáricos/metabolismo , Resistência à Doença/imunologia , Regulação da Expressão Gênica de Plantas , Glicosilação , Glicosiltransferases/genética , Glicosiltransferases/imunologia , Interações Hospedeiro-Patógeno/fisiologia , Ácidos Isonicotínicos/farmacologia , Doenças das Plantas/imunologia , Plantas Geneticamente Modificadas , Pseudomonas syringae/patogenicidade
19.
J Exp Bot ; 2021 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-33693583

RESUMO

Hypoxia induced by flooding or submergence is a serious abiotic stress affecting crop productivity worldwide. During evolution, plants have developed different metabolism mechanisms to cope with the energy crisis caused by hypoxia stress. Among those, the metabolism of γ-aminobutyric acid (GABA), a non-protein amino acid, is recognized as a crucial component for low-oxygen stress responses because of its link both in carbon and nitrogen metabolism. However, it is largely unknown how to control GABA homeostasis. In this study, we identified a novel glycosyltransferase encoding gene, UGT79B7, which was significantly downregulated by low-oxygen treatment in Arabidopsis. ugt79b7 knockout mutants showed increased resistance to hypoxia, while the overexpression lines showed increased sensitivity. We demonstrated that glycosyltransferase UGT79B7 could catalyze GABA to form GABA glucose conjugate (GABA-Glc) in vitro. The in vivo biochemical function of UGT79B7 in controlling GABA glycosylation was also verified. Moreover, we also demonstrated that UGT79B7 could negatively modulate the accumulation of GABA under hypoxia stress. Our data suggest that the glycosylation of GABA plays an important role in GABA homeostasis and reveal a new way for the regulation of plant hypoxia response through a dynamic balance of GABA and its glycosylation products, GABA-Glc.

20.
J Am Chem Soc ; 2021 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-33535753

RESUMO

The inorganic lead-free Cs2AgBiBr6 double perovskite structure is the promising development direction in perovskite solar cells (PSCs) to solve the problem of the instability of the APbX3 structure and lead toxicity. However, the low short-circuit current and power conversion efficiency (PCE) caused by the low crystallization of Cs2AgBiBr6 greatly limit the optoelectronic application. Herein, we adopt a simple strategy to dope single-layered MXene nanosheets into titania (Ti3C2Tx@TiO2) as a multifunctional electron transport layer for stable and efficient Cs2AgBiBr6 double PSCs. The single-layered MXene nanosheets significantly improve the electrical conductivity and electron extraction rate of TiO2; meanwhile, the single-layered MXene nanosheets change the surface wettability of the electron transport layer and promote the crystallization of the Cs2AgBiBr6 double perovskite in solar cell devices. Therefore, the PCE went up by more than 40% to 2.81% compared to that of a TiO2 based device, and the hysteresis was greatly suppressed. Furthermore, the device based on Ti3C2Tx@TiO2 showed the long-term operating stability. After storing the device for 15 days under ambient air conditions, the PCE still remained a retention rate of 93% of the initial one. Our finding demonstrates the potential of Ti3C2Tx@TiO2 in electron transfer material of high-performance double PSCs.

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