RESUMO
BACKGROUND: Existing evidence on the associations of urinary element profiles with related food intake and cardiometabolic diseases has been limited in China. OBJECTIVES: To examine the associations of urinary toxic metals and other elements with food intakes and with the prevalence of cardiometabolic diseases. METHODS: Inductively coupled plasma mass spectrometry was used to measure the concentrations of cadmium (Cd), arsenic (As), nickel (Ni), aluminum (Al), copper (Cu), and 16 other elements in spot urine samples collected from 19,380 adults in 10 geographically diverse areas of China during 2013-2014. The levels of creatinine-corrected elements were used to analyze their correlations with self-reported dietary intake and associations with prevalent diabetes (n = 1862), stroke (n = 1322) and ischemic heart disease (IHD) (n = 1690). RESULTS: Overall, the mean (SD) age was 59.2 (10.1) years with a mean BMI of 24.2 (3.5) kg/m2. Of the 21 elements, the median (IQR) concentrations varied from 0.49 (0.31-0.82) µg/g creatinine for vanadium (V) to 1666 (1189-2321) mg/g creatinine for potassium (K). Nine urinary elements [Cd, As, Ni, lead (Pb), boron (B), magnesium (Mg), rubidium (Rb), strontium (Sr), and cesium (Cs); all rs > 0.20, p < 0.001] were positively correlated with staple food intake, five [Cd, As, selenium (Se), Rb, and Cs; all rs > 0.20, p < 0.001] with animal-sourced food group, and one (Cd; r = 0.21, p < 0.05) with pickled vegetable intake. For diabetes, adjusted prevalence ratios (PRs) per SD of specific element levels were 1.10 [95% confidence interval (CI): 1.03-1.18] for Cd, 1.24 (1.18-1.31) for As, 1.33 (1.27-1.39) for Ni, 1.14 (1.09-1.20) for Al, and 1.24 (1.18-1.30) for Cu. Cd was positively associated with stroke (PR per SD = 1.13, 1.04-1.23), while none of the elements were significantly associated with IHD. CONCLUSION: In China, the urinary levels of several toxic metals were significantly associated with the consumption of specific food groups and the risk of cardiometabolic diseases including diabetes and stroke.
Assuntos
Arsênio , Doenças Cardiovasculares , Oligoelementos , Animais , Arsênio/análise , Cádmio/urina , Doenças Cardiovasculares/epidemiologia , China/epidemiologia , Estudos Transversais , Humanos , Oligoelementos/análiseRESUMO
Protein quality control is crucial for maintaining cellular homeostasis and its dysfunction is closely linked to human diseases. The post-translational protein quality control machinery mainly composed of BCL-2-associated athanogene 6 (BAG6) is responsible for triage of mislocalized membrane proteins (MLPs). However, it is unknown how the BAG6-mediated degradation of MLPs is regulated. We report here that PAQR9, a member of the Progesterone and AdipoQ receptor (PAQR) family, is able to modulate BAG6-mediated triage of MLPs. Analysis with mass spectrometry identified that BAG6 is one of the major proteins interacting with PAQR9 and such interaction is confirmed by co-immunoprecipitation and co-localization assays. The protein degradation rate of representative MLPs is accelerated by PAQR9 knockdown. Consistently, the polyubiquitination of MLPs is enhanced by PAQR9 knockdown. PAQR9 binds to the DUF3538 domain within the proline-rich stretch of BAG6. PAQR9 reduces the binding of MLPs to BAG6 in a DUF3538 domain-dependent manner. Taken together, our results indicate that PAQR9 plays a role in the regulation of protein quality control of MLPs via affecting the interaction of BAG6 with membrane proteins.
Assuntos
Homeostase/genética , Proteínas de Membrana/genética , Chaperonas Moleculares/genética , Receptores de Progesterona/genética , Humanos , Proteínas de Membrana/química , Chaperonas Moleculares/química , Ligação Proteica/genética , Domínios Proteicos/genética , Transporte Proteico/genética , Proteínas Proto-Oncogênicas c-bcl-2/química , Proteínas Proto-Oncogênicas c-bcl-2/genética , Receptores de Progesterona/química , Ubiquitinação/genética , Ubiquitinas/química , Ubiquitinas/genéticaRESUMO
Adenosylmethionine decarboxylase 1 (AMD1) is a key enzyme involved in biosynthesis of polyamines including spermidine and spermine. The potential function of AMD1 in human gastric cancers is unknown. We analyzed AMD1 expression level in 319 human gastric cancer samples together with the adjacent normal tissues. The protein expression level of AMD1 was significantly increased in human gastric cancer samples compared with their corresponding para-cancerous histological normal tissues (P < 0.0001). The expression level of AMD1 was positively associated with Helicobactor pylori 16sRNA (P < 0.0001), tumor size (P < 0.0001), tumor differentiation (P < 0.05), tumor venous invasion (P < 0.0001), tumor lymphatic invasion (P < 0.0001), blood vessel invasion (P < 0.0001), and tumor lymph node metastasis (TNM) stage (P < 0.0001). Patients with high expression of AMD1 had a much shorter overall survival than those with normal/low expression of AMD1. Knockdown of AMD1 in human gastric cancer cells suppressed cell proliferation, colony formation and cell migration. In a tumor xenograft model, knockdown of AMD1 suppressed the tumor growth in vivo. Inhibition of AMD1 by an inhibitor SAM486A in human gastric cancer cells arrested cell cycle progression during G1-to-S transition. Collectively, our studies at the cellular, animal and human levels indicate that AMD1 has a tumorigenic effect on human gastric cancers and affect the prognosis of the patients.
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Adenocarcinoma/patologia , Adenosilmetionina Descarboxilase/metabolismo , Carcinogênese/patologia , Infecções por Helicobacter/patologia , Neoplasias Gástricas/patologia , Adenocarcinoma/microbiologia , Adenocarcinoma/mortalidade , Adenosilmetionina Descarboxilase/antagonistas & inibidores , Adenosilmetionina Descarboxilase/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Amidinas/farmacologia , Animais , Diferenciação Celular , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Infecções por Helicobacter/microbiologia , Helicobacter pylori/genética , Helicobacter pylori/isolamento & purificação , Humanos , Indanos/farmacologia , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Poliaminas/metabolismo , Prognóstico , Estômago/patologia , Neoplasias Gástricas/microbiologia , Neoplasias Gástricas/mortalidade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Liquorice (Glycyrrhiza uralensis) is an important medicinal plant for which there is a huge market demand. It has been reported that arbuscular mycorrhizal (AM) symbiosis and drought stress can stimulate the accumulation of the active ingredients, glycyrrhizin and liquiritin, in liquorice plants, but the potential interactions of AM symbiosis and drought stress remain largely unknown. In the present work, we investigated mycorrhizal effects on plant growth and accumulation of glycyrrhizin and liquiritin in liquorice plants under different water regimes. The results indicated that AM plants generally exhibited better growth and physiological status including stomatal conductance, photosynthesis rate, and water use efficiency compared with non-AM plants. AM inoculation up-regulated the expression of an aquaporin gene PIP and decreased root abscisic acid (ABA) concentrations under drought stress. In general, AM plants displayed lower root carbon (C) and nitrogen (N) concentrations, higher phosphorus (P) concentrations, and therefore, lower C:P and N:P ratios but higher C:N ratio than non-AM plants. On the other hand, AM inoculation increased root glycyrrhizin and liquiritin concentrations, and the mycorrhizal effects were more pronounced under moderate drought stress than under well-watered condition or severe drought stress for glycyrrhizin accumulation. The accumulation of glycyrrhizin and liquiritin in AM plants was consistent with the C:N ratio changes in support of the carbon-nutrient balance hypothesis. Moreover, the glycyrrhizin accumulation was positively correlated with the expression of glycyrrhizin biosynthesis genes SQS1, ß-AS, CYP88D6, and CYP72A154. By contrast, no significant interaction of AM inoculation with water treatment was observed for liquiritin accumulation, while we similarly observed a positive correlation between liquiritin accumulation and the expression of a liquiritin biosynthesis gene CHS. These results suggested that AM inoculation in combination with proper water management potentially could improve glycyrrhizin and liquiritin accumulation in liquorice roots and may be practiced to promote liquorice cultivation.
Assuntos
Regulação da Expressão Gênica de Plantas , Glomeromycota/fisiologia , Glycyrrhiza uralensis/microbiologia , Glycyrrhiza uralensis/fisiologia , Micorrizas/fisiologia , Secas , Flavanonas/metabolismo , Glucosídeos/metabolismo , Glycyrrhiza uralensis/genética , Glycyrrhiza uralensis/crescimento & desenvolvimento , Ácido Glicirrízico/metabolismo , Minerais/metabolismo , Fotossíntese , Estresse Fisiológico/fisiologiaRESUMO
Objective: This study was designed to investigate the protective effects of didymin (Did) on doxorubicin (DOX)-induced cardiotoxicity. Methods: After pretreatment with Did (2, 4, 8 mg/kg intraperitoneal i.p.) for 7 d, the male C57 mice were injected with single dose of DOX (20 mg/kg i.p.). The cardioprotective effect of Did was observed on the 7th day after DOX treatment. Results: DOX delayed body growth and caused cardiac tissue injury, oxidative stress, and mitochondrial dysfunction. Similar experiments in H9C2 cardiomyocytes showed that DOX reduced cell viability, increased generation of reactive oxygen species (ROS) and fragmentation of DNA, decreased mitochondrial membrane potential, and induced cardiomyocyte apoptosis. However, all of these adverse effects were suppressed by Did pretreatment. Did increased protein expression of glutamate-L-cysteine ligase catalytic subunit (GCL), heme oxygenase 1 (HO-1), and nuclear factor erythroid 2-related factor 2 (Nrf2). Besides, Did also induced activation of PI3K/AKT. Conclusion: These findings indicated Did prevented DOX-induced cardiac injury and apoptosis via activating PI3K/AKT/Nrf2 signaling pathway.
RESUMO
PURPOSE: To investigate the protective effects of Shenkang injection (SKI) on adenine-induced chronic renal failure (CRF) in rat. METHODS: Sprague Dawley rats were randomly divided into five groups: control, model, and SKI groups (5, 10, 20 mL/kg). Rats in model and SKI groups were treated with adenine i.g. at a dose of 150 mg/kg every day for 12 weeks to induce CRF. Twelve weeks later, SKI was administered to the rat i.p. for four weeks. The effects of SKI on kidney injury and fibrosis were detected. RESULTS: SKI inhibited the elevation of the urine level of N-acetyl-b-D-glucosaminidase, kidney injury molecule-1, beta-2-microglobulin, urea protein in CRF rats. The serum levels of uric acid and serum creatinine increased and albumin decreased in the model group, which was prevented by SKI. SKI inhibited the release of inflammatory cytokines and increasing the activities of antioxidant enzymes in serum. SKI inhibited the expression of transforming growth factor-ß1, vascular cell adhesion molecule 1, intercellular adhesion molecule 1, collagen I, collagen III, endothelin-1, laminin in kidney of CRF rats. CONCLUSIONS: SKI protected against adenine-induced kidney injury and fibrosis and exerted anti-inflammatory, and antioxidant effects in CRF rats.
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Falência Renal Crônica , Insuficiência Renal Crônica , Adenina/metabolismo , Adenina/farmacologia , Adenina/uso terapêutico , Animais , Medicamentos de Ervas Chinesas , Fibrose , Rim , Falência Renal Crônica/induzido quimicamente , Falência Renal Crônica/tratamento farmacológico , Falência Renal Crônica/prevenção & controle , Ratos , Ratos Sprague-Dawley , Insuficiência Renal Crônica/tratamento farmacológicoRESUMO
Realtime xCELLigence analysis (RTCA) is a new cell detection technology to continuously monitor, record and analyze a variety of information generated by cell activity. In drug research, it plays an important role in assessing myocardial toxicity and cell biological activity. Here, we first introduce the underlying mechanisms and characteristics of RTCA. Then we review the applications of RTCA in the research of myocardial toxicity and cell biological activity, to provides the fundamental baseline for understanding and exploiting RTCA. With the real-time, unlabeled, non-invasive, high throughput, and high accuracy features, RTCA not only promotes drug research and development, but also has a broad and good application prospect in other fields.
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Preparações FarmacêuticasRESUMO
BACKGROUND: Scutellarin (Scu) shows both anti-inflammatory and antioxidant activities. The study investigates cardioprotective effects of Scu in mice with type 1 diabetes and the underlying molecular mechanism. METHODS: Streptozotocin (STZ) was used to induce diabetic cardiomyopathy (DCM) in C57BL/6 mice by intraperitoneal injection (i.p.). Normal and diabetic mice were divided into 6 groups: control, diabetic model group (DM), DM + Scu (5 mg/kg), DM + Scu (10 mg/kg), DM + Scu (20 mg/kg), DM + pioglitazone (Pio) (10 mg/kg). Scu was administered to the mice intraperitoneally and Pio was administrated by oral. Mice in control and DM groups were simply treated normal saline. Four weeks later, myocardial function, myocardial fibrosis, the levels inflammatory factors and oxidative stress were detected. RESULTS: Scu improved cardiac function and reduced heart injury in diabetic mice, which was indicated by increasing Left ventricular (LV) end-diastolic volume (LVVd), fractional shortening (FS), and ejection fraction (EF) levels and decreased pathological changes of heart. Scu inhibited the level of myocardial fibrosis by reducing the release of inflammatory cytokines and increasing activities of antioxidant enzymes. Further study showed that Scu inhibited the activation of nucleotide-binding oligomerization domain-like receptor with a pyrin domain 3 (NLRP3) and nuclear factor-kappa B (NF-κB) and activated phospho-protein kinase B (p-AKT), nuclear factor E2-related factor 2 (Nrf2), and heme oxygenase (HO-1). CONCLUSIONS: Scu protects against DCM in STZ-induced diabetic mice by inhibiting oxidative stress and inflammatory responses and might be a potential therapeutic agent to treat DCM.
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Diabetes Mellitus Experimental , Cardiomiopatias Diabéticas , Animais , Apigenina , Diabetes Mellitus Experimental/tratamento farmacológico , Cardiomiopatias Diabéticas/tratamento farmacológico , Cardiomiopatias Diabéticas/prevenção & controle , Glucuronatos , Camundongos , Camundongos Endogâmicos C57BL , Estresse OxidativoRESUMO
Dietary interventions such as fasting have been proved to be effective in the prevention of metabolic and autoimmune diseases as well as aging-related conditions. The complicated interaction between nutrition and immunity has drawn wide attention in recent years. In this study, we investigated the therapeutic effect of intermittent caloric restriction on autoimmune encephalomyelitis (EAE), a model of multiple sclerosis, in mice. EAE was induced by immunization of C57BL/6 mice with myelin oligodendrocyte glycoprotein 35-55 peptide. After the EAE symptoms became obvious at the 4th week post-immunization, the mice were administered with a modified fasting-mimicking diet (FMD) at 1/3 cal of control for 3 days, followed by ad libitum with normal chow for 4 days. A total of two cycles of FMD was applied. Compared with the mice without receiving caloric restriction, the mice using FMD had significant decreases in EAE severity, immune cell infiltration in spinal cord and CNS demyelination. FMD administration also reversed EAE-mediated CNS accumulation of total CD4+ T cells and in particular, IFN-γ-producing CD4+ T cells. Moreover, FMD application elevated the cell proliferation rate in CNS and enhanced expression of brain-derived neurotrophic factor (BDNF) and remyelination markers. In conclusion, our results indicate that intermittent caloric restriction using the modified FMD was effective in the treatment of EAE through ameliorating inflammatory response and promoting recovery of the damaged tissue.
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Restrição Calórica , Jejum , Esclerose Múltipla/dietoterapia , Animais , Autoimunidade , Restrição Calórica/métodos , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologiaRESUMO
Macroautophagy/autophagy is an evolutionarily conserved intracellular process that recycles and degrades intracellular components to sustain homeostasis in response to deficiency of nutrients or growth factors. PAQR3 is a newly discovered tumor suppressor that also regulates autophagy induced by nutrient starvation via AMPK and MTORC1 signaling pathways. In this study, we investigated whether PAQR3 modulates EGFR-mediated autophagy and whether such regulation is associated with the tumor suppressive activity of PAQR3. PAQR3 is able to inhibit the in vitro and in vivo growth of non-small cell lung cancer (NSCLC) cells. PAQR3 potentiates autophagy induced by EGFR inhibitor erlotinib. Knockdown of PAQR3 abrogates erlotinib-mediated reduction of BECN1 interaction with autophagy inhibitory proteins RUBCN/Rubicon and BCL2. PAQR3 blocks the interaction of BECN1 with the activated form of EGFR and inhibits tyrosine phosphorylation of BECN1. Furthermore, inhibition of autophagy by knocking down ATG7 abrogates the tumor suppressive activity of PAQR3 in NSCLC cells. Collectively, these data indicate that PAQR3 suppresses tumor progression of NSCLC cells through modulating EGFR-regulated autophagy. ABBREVIATIONS: AKT: thymoma viral proto-oncogene; ATG5: autophagy related 5; ATG7: autophagy related 7; ATG14: autophagy related 14; BCL2: B cell leukemia/lymphoma 2; BECN1: beclin 1; CCK-8: cell counting kit-8; CQ: chloroquine diphosphate; DMEM: Dulbecco's modified Eagle's medium; EdU: 5-ethynyl-2'-deoxyuridine; EGFR: epidermal growth factor receptor; FBS: fetal bovine serum; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; IgG: Immunoglobulin G; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MTOR: mechanistic target of rapamycin kinase; MTORC1: mechanistic target of rapamycin kinase complex 1; MTT: thiazolyl blue tetrazolium bromide; NSCLC: Non-small cell lung cancer; MAP2K/MEK: mitogen-activated protein kinase kinase; MAPK/ERK: mitogen-activated protein kinase; PAQR3: progestin and adipoQ receptor family member 3; PI3K: phosphatidylinositol-4,5-bisphosphate 3-kinase; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PIK3R4/VPS15: phosphoinositide-3-kinase regulatory subunit 4; PRKAA/AMPK: protein kinase, AMP-activated alpha catalytic; RUBCN: rubicon autophagy regulator; RPS6: ribosomal protein S6; RAS: Ras proto-oncogene; RAF: Raf proto-oncogene; TKI: tyrosine kinase inhibitor; TUBA4A: tubulin alpha 4a; UVRAG: UV radiation resistance associated.
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Autofagia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Receptores ErbB/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Proteínas de Membrana/metabolismo , Animais , Autofagia/efeitos dos fármacos , Proteína Beclina-1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cloridrato de Erlotinib/farmacologia , Cloridrato de Erlotinib/uso terapêutico , Células HEK293 , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Camundongos Nus , Fosforilação/efeitos dos fármacos , Proto-Oncogene MasRESUMO
BACKGROUND: Activation of NLRP3 inflammasome plays a key role in cardiac dysfunction for acute myocardial ischemia-reperfusion injury. Scutellarin (Scu) is a flavonoid purified from Erigeron breviscapus. Whether Scu has any influence on the activation of NLRP3 inflammasome in cardiomyocytes remains unknown. PURPOSE: We aimed to examine the therapeutic effect of Scu on cardiomyocyte ischemia-reperfusion (I/R) injury and its effect on NLRP3 inflammasome in rats with acute myocardial I/R injury and anoxia/reoxygenation (A/R)-induced H9c2 injuries. METHODS: Heart injuries were induced through 30 min of ischemia followed by 24 h of reperfusion. Scu was intraperitoneally administered 15 min before vascular ligation. Effects of Scu on cardiac injury were detected by echocardiograms, TTC staining, and histological and immunohistochemical analyses. The effects of Scu on biochemical parameters were analyzed. H9c2 cells were pretreated with different concentrations of Scu for 6 h before A/R exposure. Afterward, cell viability, LDH release, and Hoechst 33342 and peromide iodine double staining were determined. Western blot analyses of proteins, including those involved in autophagy, NLRP3, mTOR complex 1 (mTORC1), and Akt signaling, were conducted. RESULTS: In vivo study revealed that Scu improved diastolic dysfunction, ameliorated myocardium structure abnormality, inhibited myocyte apoptosis and inflammatory response, and promoted autophagy. Scu reduced NLRP3 inflammasome activation, inhibited mTORC1 activity, and increased Akt phosphorylation. In vitro investigation showed the same results. The Scu-mediated NLRP3 inflammasome and mTORC1 inhibition and cardioprotection were abolished through the genetic silencing of Akt by siRNA. CONCLUSIONS: The cardioprotective effect of Scu was achieved through its anti-inflammatory effect. It suppressed the activation of NLRP3 inflammasome. In addition, inflammasome restriction by Scu was dependent on Akt activation and mTORC1 inhibition.
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Apigenina/farmacologia , Cardiotônicos/farmacologia , Glucuronatos/farmacologia , Inflamassomos/efeitos dos fármacos , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Linhagem Celular , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Sprague-DawleyRESUMO
Endoplasmic reticulum (ER)-to-Golgi anterograde transport is driven by COPII vesicles mainly composed of a Sec23/Sec24 inner shell and a Sec13/Sec31 outer cage. How COPII vesicles are tethered to the Golgi is not completely understood. We demonstrated here that PAQR3 can facilitate tethering of COPII vesicles to the Golgi. Proximity labeling using PAQR3 fused with APEX2 identified that many proteins involved in intracellular transport are in close proximity to PAQR3. ER-to-Golgi trafficking of N-acetylgalactosaminyltransferase-2 on removal of brefeldin A is delayed by PAQR3 deletion. RUSH assay also revealed that ER-to-Golgi trafficking is affected by PAQR3. The N-terminal end of PAQR3 can interact with the WD domains of Sec13 and Sec31A. PAQR3 enhances Golgi localization of Sec13 and Sec31A. Furthermore, PAQR3 is localized in the ERGIC and cis-Golgi structures, the acceptor sites for COPII vesicles. Taken together, our study uncovers a role for PAQR3 as a player in regulating ER-to-Golgi transport of COPII vesicles.