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1.
Sci Adv ; 7(1)2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33523844

RESUMO

Light-inducible gene switches represent a key strategy for the precise manipulation of cellular events in fundamental and applied research. However, the performance of widely used gene switches is limited due to low tissue penetrance and possible phototoxicity of the light stimulus. To overcome these limitations, we engineer optogenetic synthetic transcription factors to undergo liquid-liquid phase separation in close spatial proximity to promoters. Phase separation of constitutive and optogenetic synthetic transcription factors was achieved by incorporation of intrinsically disordered regions. Supported by a quantitative mathematical model, we demonstrate that engineered transcription factor droplets form at target promoters and increase gene expression up to fivefold. This increase in performance was observed in multiple mammalian cells lines as well as in mice following in situ transfection. The results of this work suggest that the introduction of intrinsically disordered domains is a simple yet effective means to boost synthetic transcription factor activity.

2.
Toxins (Basel) ; 12(12)2020 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-33260619

RESUMO

The epidermal growth factor receptor (EGFR) was found to be a valuable target on prostate cancer (PCa) cells. However, EGFR inhibitors mostly failed in clinical studies with patients suffering from PCa. We therefore tested the targeted toxins EGF-PE40 and EGF-PE24mut consisting of the natural ligand EGF as binding domain and PE40, the natural toxin domain of Pseudomonas Exotoxin A, or PE24mut, the de-immunized variant thereof, as toxin domains. Both targeted toxins were expressed in the periplasm of E.coli and evoked an inhibition of protein biosynthesis in EGFR-expressing PCa cells. Concentration- and time-dependent killing of PCa cells was found with IC50 values after 48 and 72 h in the low nanomolar or picomolar range based on the induction of apoptosis. EGF-PE24mut was found to be about 11- to 120-fold less toxic than EGF-PE40. Both targeted toxins were more than 600 to 140,000-fold more cytotoxic than the EGFR inhibitor erlotinib. Due to their high and specific cytotoxicity, the EGF-based targeted toxins EGF-PE40 and EGF-PE24mut represent promising candidates for the future treatment of PCa.

3.
J Behav Med ; 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-33083923

RESUMO

Using a social-ecological framework, we identify social determinants that interact to influence sleep health, identify gaps in the literature, and make recommendations for targeting sleep health in rural mothers. Rural mothers experience unique challenges and protective factors in maintaining adequate sleep health during the postpartum and early maternal years. Geographic isolation, barriers to comprehensive behavioral medicine services, and intra-rural ethno-racial disparities are discussed at the societal (e.g., public policy), social (e.g., community) and individual levels (e.g., stress) of the social-ecological model. Research on sleep health would benefit from attention to methodological considerations of factors affecting rural mothers such as including parity in population-level analyses or applying community-based participatory research principles. Future sleep health programs would benefit from using existing social support networks to disseminate sleep health information, integrating behavioral health services into clinical care frameworks, and tailoring culturally-appropriate Telehealth/mHealth programs to enhance the sleep health of rural mothers.

4.
Pain ; 161(11): 2511-2519, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32569094

RESUMO

Posttraumatic stress disorder (PTSD) symptoms and other negative psychosocial factors have been implicated in the transition from acute to persistent pain. Women (N = 375) who presented to an inner-city emergency department (ED) with complaints of acute pain were followed up for 3 months. They completed a comprehensive battery of questionnaires at an initial visit and provided ratings of pain intensity at the site of pain presented in the ED during 3 monthly phone calls. Latent class growth analyses were used to detect possible trajectories of change in pain intensity from the initial visit to 3 months later. A 3-trajectory solution was found, which identified 3 groups of participants. One group (early recovery; n = 93) had recovered to virtually no pain by the initial visit, whereas a second group (delayed recovery; n = 120) recovered to no pain only after 1 month. A third group (no recovery; n = 162) still reported elevated pain at 3 months after the ED visit. The no recovery group reported significantly greater PTSD symptoms, anger, sleep disturbance, and lower social support at the initial visit than both the early recovery and delayed recovery groups. Results suggest that women with high levels of PTSD symptoms, anger, sleep disturbance, and low social support who experience an acute pain episode serious enough to prompt an ED visit may maintain elevated pain at this pain site for at least 3 months. Such an array of factors may place women at an increased risk of developing persistent pain following acute pain.

5.
Blood Adv ; 4(8): 1760-1769, 2020 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-32343795

RESUMO

Diamond-Blackfan anemia (DBA) is a congenital pure red cell aplasia associated with congenital abnormalities and cancer predisposition. Allogeneic hematopoietic stem cell transplantation (HSCT) can correct the hematological phenotype and is indicated in transfusion-dependent patients. In 70 children reported to the German DBA and French HSCT registries, HSCT was performed from 1985 to 2017. Median age at HSCT was 5.5 years (range, 0.9-17.3 years). Two-thirds of patients (64%) were transplanted from a matched sibling donor (MSD), and most procedures were performed after the year 1999 (73%). Primary engraftment was achieved in all patients. One patient developed secondary graft failure. Cumulative incidence of acute graft-versus-host disease (GVHD) was 24% for °II-IV (95% confidence interval [CI], 16% to 37%) and 7% for °III-IV (95% CI, 3% to 17%); cumulative incidence of chronic GVHD was 11% (95% CI, 5% to 22%). The probability of chronic GVHD-free survival (cGFS) was 87% (95% CI, 79% to 95%) and significantly improved over time (<2000: 68% [95% CI, 47% to 89%] vs ≥2000: 94% [95% CI, 87% to 100%], P < .01). cGFS was comparable following HSCT from a MSD and an unrelated donor (UD). Of note, no severe chronic GVHD or deaths were reported following MSD-HSCT after 1999. The difference of cGFS in children transplanted <10 years of age compared with older patients did not reach statistical significance (<10 years: 90% [95% CI, 81% to 99%] vs 10-18 years 78% [95% CI, 58% to 98%]). In summary, these data indicate that HSCT is efficient and safe in young DBA patients and should be considered if a MSD or matched UD is available. HSCT for transfusion dependency only must be critically discussed in older patients.

6.
J Clin Biochem Nutr ; 66(1): 24-35, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32001953

RESUMO

To gain a better understanding of how nitrate may affect carbohydrate and lipid metabolism, female wild-type mice were fed a high-fat, high-fructose diet supplemented with either 0, 400, or 800 mg nitrate/kg diet for 28 days. Additionally, obese female db/db mice were fed a 5% fat diet supplemented with the same levels and source of nitrate. Nitrate decreased the sodium-dependent uptake of glucose by ileal mucosa in wild-type mice. Moreover, nitrate significantly decreased triglyceride content and mRNA expression levels of Pparγ in liver and Glut4 in skeletal muscle. Oral glucose tolerance as well as plasma cholesterol, triglyceride, insulin, leptin, glucose and the activity of ALT did not significantly differ between experimental groups but was higher in db/db mice than in wild-type mice. Nitrate changed liver fatty acid composition and mRNA levels of Fads only slightly. Further hepatic genes encoding proteins involved in lipid and carbohydrate metabolism were not significantly different between the three groups. Biomarkers of inflammation and autophagy in the liver were not affected by the different dietary treatments. Overall, the present data suggest that short-term dietary supplementation with inorganic nitrate has only modest effects on carbohydrate and lipid metabolism in genetic and dietary-induced mouse models of obesity.

7.
Nutrients ; 12(1)2019 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-31877869

RESUMO

Kuding tea (KT) is a traditional Chinese beverage rich in plant bioactives that may exhibit various health benefits. However, little is known about the safety of KT extract (KTE) when consumed long term at high doses as a dietary supplement. Therefore, in this study, we investigated aspects of the safety of KTE. Male C57BL/6 mice were fed a high-fat, high-fructose, Western-type diet (control) supplemented with either 12.88% γ-cyclodextrin (γCD), 7.12% KTE (comprising 0.15% ursolic acid, UA) encapsulated in 12.88% γCD (KTE-γCD), or 0.15% UA over a 6-week experimental period. The dietary treatments did not affect food intake, body weight or body composition. However, treatment with KTE-γCD, but not γCD and UA, increased liver weight and hepatic fat accumulation, which was accompanied by increased hepatic PPARγ and CD36 mRNA levels. KTE-γCD treatment elevated plasma cholesterol and CYP7A1 mRNA and protein levels compared to those in control mice. KTE-γCD substantially increased the mRNA and protein levels of hepatic CYP3A and GSTA1, which are central to the detoxification of drugs and xenobiotics. Furthermore, we observed a moderate elevation in hepatic CYP3A (5-fold change) and GSTA1 (1.7-fold change) mRNA levels in UA-fed mice. In vitro data collected in HepG2 cells indicated a dose-dependent increase in hepatic cytotoxicity in response to KTE treatment, which may have been partly mediated by UA. Overall, the present data may contribute to the safety assessment of KTE and suggest that KTE encapsulated in γCD affects liver fat storage and the hepatic phase I and phase II responses in mice.


Assuntos
Hidrocarboneto de Aril Hidroxilases/metabolismo , Indução Enzimática/efeitos dos fármacos , Fígado/enzimologia , Extratos Vegetais/farmacologia , Chá/química , Tecido Adiposo , Animais , Hidrocarboneto de Aril Hidroxilases/genética , Composição Corporal/efeitos dos fármacos , Camellia sinensis/química , Suplementos Nutricionais , Células Hep G2 , Humanos , Fígado/anatomia & histologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Tamanho do Órgão , Extratos Vegetais/química
8.
COPD ; 16(3-4): 272-277, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31405301

RESUMO

A diet rich in nutrients has been suggested to have protective effects against the development of chronic obstructive pulmonary disease (COPD). Since the traditional Mediterranean diet is high in nutrients, including antioxidants, vitamins, and minerals, it is of interest to study as a protective factor against COPD. Our aim was therefore to study its associations with development of COPD using population-based prospective data from the Västerbotten Intervention Programme (VIP) cohort. Data on diet from 370 individuals, who later visited the Department of Medicine at the University Hospital, Umeå, Sweden, with a diagnosis of COPD, were compared to 1432 controls. Adherence to a Mediterranean diet was assessed by a modified version of the Mediterranean diet score (MDS). Cases were diagnosed with COPD 11.1 years (mean) (standard deviation [SD] 4.5 years) after first stating their dietary habits in the VIP at a mean age of 55.5 years (SD 6.6 years). Higher MDS was associated with a higher level of education and not living alone. After adjustment for co-habiting and education level, individuals with an intermediate MDS and those with the highest MDS had a lower odds of developing COPD (odds ratio [OR] 0.73, 95% confidence interval [CI] 0.56-0.95; OR 0.56, 95% CI 0.37-0.86, respectively). These results remained also after adjustment for smoking intensity, i.e., numbers of cigarettes smoked per day (OR 0.73, 95% CI 0.53-0.99; OR 0.59, 95% CI 0.35-0.97), respectively). To conclude, adherence to a Mediterranean-like diet seems to be inversely associated with the development of COPD.


Assuntos
Dieta Mediterrânea , Cooperação do Paciente , Doença Pulmonar Obstrutiva Crônica/prevenção & controle , Doença Pulmonar Obstrutiva Crônica/psicologia , Adulto , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Comportamentos Relacionados com a Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Suécia
9.
Photosynth Res ; 141(3): 367-376, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31020482

RESUMO

Although the importance of nonphotochemical quenching (NPQ) on photosynthetic biomass production and crop yields is well established, the in vivo operation of the individual mechanisms contributing to overall NPQ is still a matter of controversy. In order to investigate the timescale and activation dynamics of specific quenching mechanisms, we have developed a technique called snapshot transient absorption (TA) spectroscopy, which can monitor molecular species involved in the quenching response with a time resolution of 30 s. Using intact thylakoid membrane samples, we show how conventional TA kinetic and spectral analyses enable the determination of the appropriate wavelength and time delay for snapshot TA experiments. As an example, we show how the chlorophyll-carotenoid charge transfer and excitation energy transfer mechanisms can be monitored based on signals corresponding to the carotenoid (Car) radical cation and Car S1 excited state absorption, respectively. The use of snapshot TA spectroscopy together with the previously reported fluorescence lifetime snapshot technique (Sylak-Glassman et al. in Photosynth Res 127:69-76, 2016) provides valuable information such as the concurrent appearance of specific quenching species and overall quenching of excited Chl. Furthermore, we show that the snapshot TA technique can be successfully applied to completely intact photosynthetic organisms such as live cells of Nannochloropsis. This demonstrates that the snapshot TA technique is a valuable method for tracking the dynamics of intact samples that evolve over time, such as the photosynthetic system in response to high-light exposure.


Assuntos
Processos Fotoquímicos , Análise Espectral , Difusão , Cinética , Spinacia oleracea/metabolismo , Termodinâmica , Tilacoides/metabolismo
10.
Proc Natl Acad Sci U S A ; 116(9): 3385-3390, 2019 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-30808735

RESUMO

Nonphotochemical quenching (NPQ) is a proxy for photoprotective thermal dissipation processes that regulate photosynthetic light harvesting. The identification of NPQ mechanisms and their molecular or physiological triggering factors under in vivo conditions is a matter of controversy. Here, to investigate chlorophyll (Chl)-zeaxanthin (Zea) excitation energy transfer (EET) and charge transfer (CT) as possible NPQ mechanisms, we performed transient absorption (TA) spectroscopy on live cells of the microalga Nannochloropsis oceanica We obtained evidence for the operation of both EET and CT quenching by observing spectral features associated with the Zea S1 and Zea●+ excited-state absorption (ESA) signals, respectively, after Chl excitation. Knockout mutants for genes encoding either violaxanthin de-epoxidase or LHCX1 proteins exhibited strongly inhibited NPQ capabilities and lacked detectable Zea S1 and Zea●+ ESA signals in vivo, which strongly suggests that the accumulation of Zea and active LHCX1 is essential for both EET and CT quenching in N. oceanica.


Assuntos
Transferência de Energia/genética , Microalgas/metabolismo , Fotossíntese/genética , Zeaxantinas/química , Carotenoides/genética , Carotenoides/metabolismo , Clorofila/química , Clorofila/genética , Clorofila/metabolismo , Luz , Complexos de Proteínas Captadores de Luz/química , Complexos de Proteínas Captadores de Luz/metabolismo , Microalgas/química , Microalgas/genética , Complexo de Proteína do Fotossistema II/química , Complexo de Proteína do Fotossistema II/genética , Complexo de Proteína do Fotossistema II/metabolismo , Xantofilas/química , Xantofilas/genética , Xantofilas/metabolismo , Zeaxantinas/genética , Zeaxantinas/metabolismo
11.
J Am Chem Soc ; 140(38): 11965-11973, 2018 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-30183270

RESUMO

Nonphotochemical quenching (NPQ) provides an essential photoprotection in plants, assuring safe dissipation of excess energy as heat under high light. Although excitation energy transfer (EET) between chlorophyll (Chl) and carotenoid (Car) molecules plays an important role in NPQ, detailed information on the EET quenching mechanism under in vivo conditions, including the triggering mechanism and activation dynamics, is very limited. Here, we observed EET between the Chl Q y state and the Car S1 state in high-light-exposed spinach thylakoid membranes. The kinetic and spectral analyses using transient absorption (TA) spectroscopy revealed that the Car S1 excited state absorption (ESA) signal after Chl excitation has a maximum absorption peak around 540 nm and a lifetime of ∼8 ps. Snapshot TA spectroscopy at multiple time delays allowed us to track the Car S1 ESA signal as the thylakoid membranes were exposed to various light conditions. The obtained snapshots indicate that maximum Car S1 ESA signal quickly rose and slightly dropped during the initial high-light exposure (<3 min) and then gradually increased with a time constant of ∼5 min after prolonged light exposure. This suggests the involvement of both rapidly activated and slowly activated mechanisms for EET quenching. 1,4-Dithiothreitol (DTT) and 3,3'-dithiobis(sulfosuccinimidyl propionate) (DTSSP) chemical treatments further support that the Car S1 ESA signal (or the EET quenching mechanism) is primarily dependent on the accumulation of zeaxanthin and partially dependent on the reorganization of membrane proteins, perhaps due to the pH-sensing protein photosystem II subunit S.

12.
Nat Commun ; 8(1): 2126, 2017 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-29259247

RESUMO

Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative disorder of early childhood characterized by mutations activating RAS signaling. Established clinical and genetic markers fail to fully recapitulate the clinical and biological heterogeneity of this disease. Here we report DNA methylome analysis and mutation profiling of 167 JMML samples. We identify three JMML subgroups with unique molecular and clinical characteristics. The high methylation group (HM) is characterized by somatic PTPN11 mutations and poor clinical outcome. The low methylation group is enriched for somatic NRAS and CBL mutations, as well as for Noonan patients, and has a good prognosis. The intermediate methylation group (IM) shows enrichment for monosomy 7 and somatic KRAS mutations. Hypermethylation is associated with repressed chromatin, genes regulated by RAS signaling, frequent co-occurrence of RAS pathway mutations and upregulation of DNMT1 and DNMT3B, suggesting a link between activation of the DNA methylation machinery and mutational patterns in JMML.


Assuntos
Metilação de DNA , Leucemia Mielomonocítica Juvenil/genética , Síndrome de Noonan/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Transdução de Sinais/genética , Antineoplásicos/uso terapêutico , Biópsia , Criança , Pré-Escolar , Cromatina/genética , Cromatina/metabolismo , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , DNA (Citosina-5-)-Metiltransferases/metabolismo , Análise Mutacional de DNA , Epigenômica , Feminino , Regulação Leucêmica da Expressão Gênica , Transplante de Células-Tronco Hematopoéticas , Humanos , Lactente , Leucemia Mielomonocítica Juvenil/mortalidade , Leucemia Mielomonocítica Juvenil/patologia , Leucemia Mielomonocítica Juvenil/terapia , Masculino , Mutação , Síndrome de Noonan/patologia , Prognóstico , Estudos Prospectivos , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Proteínas Proto-Oncogênicas c-cbl , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Regulação para Cima
13.
J Phys Chem Lett ; 8(22): 5548-5554, 2017 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-29083901

RESUMO

Nonphotochemical quenching mechanisms regulate light harvesting in oxygenic photosynthesis. Measurement techniques for nonphotochemical quenching have typically focused on downstream effects of quenching, such as measuring reduced chlorophyll fluorescence. Here, to directly measure a species involved in quenching, we report snapshot transient absorption (TA) spectroscopy, which rapidly tracks carotenoid radical cation signals as samples acclimate to excess light. The formation of zeaxanthin radical cations, which is possible evidence of zeaxanthin-chlorophyll charge-transfer (CT) quenching, was investigated in spinach thylakoids. Together with fluorescence lifetime snapshot data and time-resolved high-performance liquid chromatography (HPLC) measurements, snapshot TA reveals that Zea•+ formation is closely related to energy-dependent quenching (qE) in nonphotochemical quenching. Quantitative and dynamic information on CT quenching discussed in this work give insight into the design principles of photoprotection in natural photosynthesis.


Assuntos
Complexos de Proteínas Captadores de Luz/química , Fotossíntese , Tilacoides/química , Zeaxantinas/química , Carotenoides , Cátions , Clorofila/química , Fluorescência , Luz , Análise Espectral , Spinacia oleracea , Xantofilas
14.
J Med Food ; 20(9): 846-854, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28622482

RESUMO

Type 2 diabetes mellitus (T2DM) is a common and increasingly prevalent metabolic disorder, and effective preventive strategies against this disease are needed. The aim of the present study was to evaluate the potential antidiabetic properties of a dietary apple/kale extract (AKE), which was rich in phlorizin and flavonoids, in laboratory mice. Mice were fed a control diet, a Western-type high-sugar, high-fat diet (WTD), or a WTD plus AKE for 10 weeks. Body weight, food and energy intake, body composition, and blood glucose level were recorded in addition to the postprandial rise in blood glucose concentration after a single administration of glucose (oral glucose tolerance test, OGTT). Furthermore, changes in glucose-induced short-circuit current (ISC) in response to AKE and phlorizin administration were evaluated in situ in intestinal tissues with Ussing chambers. In addition, the in vitro inhibition of α-glucosidase by AKE was determined. The present data suggest that supplementation of an AKE to a WTD significantly improved both blood glucose levels and OGTT in mice. Furthermore, in situ uptake of glucose was significantly inhibited by AKE. Finally, we showed that AKE significantly inhibits α-glucosidase activity in vitro. We conclude that AKE exhibits antidiabetic properties by a dual mechanism, including the inhibition of α-glucosidase and sodium-dependent glucose transporter 1 (SGLT1). Thus, AKE has the potential to serve as a natural plant bioactive compound for dietary prevention strategies against T2DM.


Assuntos
Brassica/química , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Malus/química , Extratos Vegetais/administração & dosagem , Animais , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Dieta Hiperlipídica/efeitos adversos , Feminino , Flavonoides/administração & dosagem , Teste de Tolerância a Glucose , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Florizina/administração & dosagem , Transportador 1 de Glucose-Sódio/genética , Transportador 1 de Glucose-Sódio/metabolismo , alfa-Glucosidases/genética , alfa-Glucosidases/metabolismo
15.
Int J Mol Sci ; 18(6)2017 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-28587122

RESUMO

Ageing is often accompanied by chronic inflammation. A fat- and sugar-rich Western-type diet (WTD) may accelerate the ageing phenotype. Cell culture studies have indicated that artepillin C-containing Brazilian green propolis exhibits anti-inflammatory properties. However, little is known regarding its anti-inflammatory potential in mouse liver in vivo. In this study, female C57BL/6NRj wild-type mice were fed a WTD, a WTD supplemented with Brazilian green propolis supercritical extract (GPSE) encapsulated in γ-cyclodextrin (γCD) or a WTD plus γCD for 10 weeks. GPSE-γCD did not affect the food intake, body weight or body composition of the mice. However, mRNA levels of the tumour necrosis factor α were significantly downregulated (p < 0.05) in these mice compared to those in the WTD-fed controls. Furthermore, the gene expression levels of other pro-inflammatory markers, including serum amyloid P, were significantly (p < 0.001) decreased following GPSE-γCD treatment. GPSE-γCD significantly induced hepatic ferritin gene expression (p < 0.01), which may contribute to its anti-inflammatory properties. Conversely, GPSE-γCD did not affect the biomarkers of endogenous antioxidant defence, including catalase, glutathione peroxidase-4, paraoxonase-1, glutamate cysteine ligase and nuclear factor erythroid 2-related factor-2 (Nrf2). Overall, the present data suggest that dietary GPSE-γCD exhibits anti-inflammatory, but not antioxidant activity in mouse liver in vivo. Thus, GPSE-γCD has the potential to serve as a natural hepatoprotective bioactive compound for dietary-mediated strategies against chronic inflammation.


Assuntos
Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Dieta Ocidental , Suplementos Nutricionais , Própole/química , Própole/farmacologia , gama-Ciclodextrinas/química , Ração Animal , Animais , Biomarcadores , Glicemia/efeitos dos fármacos , Composição Corporal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Cromatografia Líquida , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/tratamento farmacológico , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Espectrometria de Massas , Camundongos , Transcriptoma
16.
PLoS One ; 11(12): e0167124, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27907044

RESUMO

Aging is associated with sarcopenia, which is a loss of skeletal muscle mass and function. Coenzyme Q10 (CoQ10) is involved in several important functions that are related to bioenergetics and protection against oxidative damage; however, the role of CoQ10 as a determinant of muscular strength is not well documented. The aim of the present study was to evaluate the determinants of muscular strength by examining hand grip force in relation to CoQ10 status, gender, age and body mass index (BMI) in two independent cohorts (n = 334, n = 967). Furthermore, peak flow as a function of respiratory muscle force was assessed. Spearman's correlation revealed a significant positive association between CoQ10/cholesterol level and hand grip in the basic study population (p<0.01) as well as in the validation population (p<0.001). In the latter, we also found a negative correlation with the CoQ10 redox state (p<0.01), which represents a lower percentage of the reduced form of CoQ10 (ubiquinol) in subjects who exhibit a lower muscular strength. Furthermore, the age of the subjects showed a negative correlation with hand grip (p<0.001), whereas BMI was positively correlated with hand grip (p<0.01), although only in the normal weight subgroup (BMI <25 kg/m2). Analysis of the covariance (ANCOVA) with hand grip as the dependent variable revealed CoQ10/cholesterol as a determinant of muscular strength and gender as the strongest effector of hand grip. In conclusion, our data suggest that both a low CoQ10/cholesterol level and a low percentage of the reduced form of CoQ10 could be an indicator of an increased risk of sarcopenia in humans due to their negative associations to upper body muscle strength, peak flow and muscle mass.


Assuntos
Envelhecimento/metabolismo , Colesterol/sangue , Metabolismo Energético/fisiologia , Força da Mão/fisiologia , Músculo Esquelético/metabolismo , Ubiquinona/análogos & derivados , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Estudos de Coortes , Creatina Quinase/sangue , Creatinina/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oxirredução , Fatores Sexuais , Ubiquinona/sangue
17.
Arch Med Sci ; 12(4): 715-20, 2016 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-27478450

RESUMO

INTRODUCTION: Coenzyme Q10 (CoQ10) is a lipophilic endogenously synthesised antioxidant that is present in nearly all human tissues and plays an important role in mitochondrial energy production. It has been postulated that smoking has a consumptive effect on CoQ10. MATERIAL AND METHODS: To further define the relation between smoking and the serum CoQ10 status, 276 healthy volunteers aged 19 to 62 years were grouped into non-smokers (n = 113; 77 male, 36 female) and smokers (n = 163; 102 male, 61 female). Serum lipid profile was analysed by standard clinical chemistry. Coenzyme Q10 concentration and redox status were analysed by high-pressure liquid chromatography with electrochemical detection. RESULTS: Male smokers showed higher serum CoQ10 levels than female smokers. This sex-related difference was accounted for when CoQ10 was related to low-density lipoprotein (LDL) cholesterol as the main carrier of CoQ10 in the circulation. Neither LDL-adjusted CoQ10 concentration nor redox status significantly differed when smokers and non-smokers were compared. Regarding the smoking history, the number of cigarettes consumed per day did not significantly affect the CoQ10 status. Interestingly, with increasing time of smoking habit we observed increasing levels of LDL-adjusted serum CoQ10 concentration (Spearman's p < 0.002) and of the reduced form of CoQ10 (Spearman's p < 0.0001). CONCLUSIONS: As an adaptive response to oxidative stress in long-term smokers an increased demand for antioxidant capacity may be covered by increasing levels of LDL-adjusted CoQ10 serum concentrations and by a concomitantly increased availability of the reduced, active form of CoQ10, possibly by induction of enzymes that are involved in converting CoQ10ox to CoQ10red.

18.
J Clin Biochem Nutr ; 58(3): 240-5, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27257350

RESUMO

Coenzyme Q10 (CoQ10) is synthesized in almost all human tissues and presumably involved in age-related alterations and diseases. Here, we examined the impact of aging and sex on the serum CoQ10 status in 860 European adults ranging in age from 18 to 82 years. We identified an inverse U-shaped relationship between CoQ10 concentration and age. Women showed lower cholesterol-adjusted CoQ10 levels than men, irrespective of age. As observed in both sexes, the decrease in CoQ10 concentration in older subjects was accompanied by a shift in the redox status in favour of the oxidized form. A strong positive correlation was found for total CoQ10 and cholesterol concentrations (Spearman's, p≤1E-74). We found strong negative correlations between total (Spearman's, p≤1E-07) and between cholesterol-adjusted CoQ10 concentration (Spearman's, p≤1E-14) and the proportion of the oxidized form of CoQ10. These correlations were not dependent on age and sex and were attenuated by supplementation with 150 mg/day reduced CoQ10 for 14 days. Overall, our results are useful to define risk groups with critical CoQ10 status in humans. In particular, older subjects were characterized by impaired CoQ10 status due to their lowered serum CoQ10 concentration and concomitant decrease of CoQ10 redox capacity.

19.
Biofactors ; 42(3): 268-76, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26910885

RESUMO

In the present study the relationship between the CoQ10 redox state (% oxidized form of CoQ10 ) and the serum level of c-reactive protein (CRP) was investigated in a large Caucasian study population (n = 1319). In order to evaluate independently the influence of the variables that predict the outcome of CRP, an analysis of covariance (ANCOVA) was performed with CRP as the dependent variable. Gender was taken as an independent factor and CoQ10 redox and BMI as independent covariates. Results were substantiated with findings from a human intervention study (n = 53), receiving 150 mg/day ubiquinol for 14 days. Spearman's correlation revealed a significant (P < 0.001) association between the CoQ10 redox state and CRP concentrations in the whole study population. Thus, higher CRP concentrations were found in subjects having more oxidized CoQ10 . Similar results were evident for further inflammatory markers (interleukin-6, number of leucocytes). The ANCOVA revealed a significant (P < 0.001) prediction of CRP concentrations by CoQ10 redox state, after controlling for the effect of BMI and separately for gender. In the intervention study it was further found that the oral intake of ubiquinol increased its proportion significantly (P < 0.001), with the highest increase in those persons having a low basal serum ubiquinol content (<92.3%). Here it was discovered that the ubiquinol status significantly correlated to the concentration of the inflammation marker monocyte chemotactic protein 1. It is concluded that CoQ10 redox state predicts the concentration of CRP. Persons at risk with lower ubiquinol status, higher BMI, and low grade inflammation may benefit from ubiquinol supplementation. © 2016 BioFactors, 42(3):268-276, 2016.


Assuntos
Proteína C-Reativa/metabolismo , Inflamação/dietoterapia , Ubiquinona/análogos & derivados , Adolescente , Adulto , Índice de Massa Corporal , Quimiocina CCL2/sangue , Suplementos Nutricionais , Humanos , Inflamação/sangue , Interleucina-6/biossíntese , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Oxirredução , Estatísticas não Paramétricas , Ubiquinona/administração & dosagem , Ubiquinona/sangue
20.
J Clin Biochem Nutr ; 57(3): 171-7, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26566301

RESUMO

Coenzyme Q (CoQ) is necessary for mitochondrial energy production and modulates the expression of genes that are important for inflammatory processes, growth and detoxification reactions. A cellular surveillance-activated detoxification and defenses (cSADDs) pathway has been recently identified in C. elegans. The down-regulation of the components of the cSADDs pathway initiates an aversion behavior of the nematode. Here we hypothesized that CoQ regulates genes of the cSADDs pathway. To verify this we generated CoQ-deficient worms ("CoQ-free") and performed whole-genome expression profiling. We found about 30% (120 genes) of the cSADDs pathway genes were differentially regulated under CoQ-deficient condition. Remarkably, 83% of these genes were down-regulated. The majority of the CoQ-sensitive cSADDs pathway genes encode for proteins involved in larval development (enrichment score (ES) = 38.0, p = 5.0E(-37)), aminoacyl-tRNA biosynthesis, proteasome function (ES 8.2, p = 5.9E(-31)) and mitochondria function (ES 3.4, p = 1.7E(-5)). 67% (80 genes) of these genes are categorized as lethal. Thus it is shown for the first time that CoQ regulates a substantial number of essential genes that function in the evolutionary conserved cellular surveillance-activated detoxification and defenses pathway in C. elegans.

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