RESUMEN
Autophagy plays a vital role in cell homeostasis by eliminating nonfunctional components and promoting cell survival. Here, we examined the levels of autophagy signaling proteins after 7 days of overload hypertrophy in the extensor digitorum longus (EDL) and soleus muscles of control and diabetic rats. We compared control and 3-day streptozotocin-induced diabetic rats, an experimental model for type 1 diabetes mellitus (T1DM). EDL muscles showed increased levels of basal autophagy signaling proteins. The diabetic state did not affect the extent of overload-induced hypertrophy or the levels of autophagy signaling proteins (p-ULK1, Beclin-1, Atg5, Atg12-5, Atg7, Atg3, LC3-I and II, and p62) in either muscle. The p-ULK-1, Beclin-1, and p62 protein expression levels were higher in the EDL muscle than in the soleus before the hypertrophic stimulus. On the contrary, the soleus muscle exhibited increased autophagic signaling after overload-induced hypertrophy, with increases in Beclin-1, Atg5, Atg12-5, Atg7, Atg3, and LC3-I expression in the control and diabetic groups, in addition to p-ULK-1 in the control groups. After hypertrophy, Beclin-1 and Atg5 levels increased in the EDL muscle of both groups, while p-ULK1 and LC3-I increased in the control group. In conclusion, the baseline EDL muscle exhibited higher autophagy than the soleus muscle. Although TDM1 promotes skeletal muscle mass loss and strength reduction, it did not significantly alter the extent of overload-induced hypertrophy and autophagy signaling proteins in EDL and soleus muscles, with the two groups exhibiting different patterns of autophagy activation.
Asunto(s)
Diabetes Mellitus Experimental , Ratas , Animales , Beclina-1/metabolismo , Diabetes Mellitus Experimental/metabolismo , Músculo Esquelético/metabolismo , Hipertrofia/metabolismo , AutofagiaRESUMEN
Nonalcoholic fatty liver disease (NAFLD), often associated with obesity, is becoming one of the most common liver diseases worldwide. It is estimated to affect one billion individuals and may be present in approximately 25% of the population globally. NAFLD is viewed as a hepatic manifestation of metabolic syndrome, with humans and animal models presenting dyslipidemia, hypertension, and diabetes. The gut-liver axis has been considered the main pathogenesis branch for NAFLD development. Considering that foods or beverages could modulate the gastrointestinal tract, immune system, energy homeostasis regulation, and even the gut-liver axis, we conducted an exploratory study to analyze the effects of kombucha probiotic on hepatic steatosis, glucose tolerance, and hepatic enzymes involved in carbohydrate and fat metabolism using a pre-clinical model. The diet-induced obese mice presented glucose intolerance, hyperinsulinemia, hepatic steatosis, increased collagen fiber deposition in liver vascular spaces, and upregulated TNF-alpha and SREBP-1 gene expression. Mice receiving the kombucha supplement displayed improved glucose tolerance, reduced hyperinsulinemia, decreased citrate synthase and phosphofructokinase-1 enzyme activities, downregulated G-protein-coupled bile acid receptor, also known as TGR5, and farnesol X receptor gene expression, and attenuated steatosis and hepatic collagen fiber deposition. The improvement in glucose tolerance was accompanied by the recovery of acute insulin-induced liver AKT serine phosphorylation. Thus, it is possible to conclude that this probiotic drink has a beneficial effect in reducing the metabolic alterations associated with diet-induced obesity. This probiotic beverage deserves an extension of studies to confirm or refute its potentially beneficial effects.
Asunto(s)
Resistencia a la Insulina , Té de Kombucha , Enfermedad del Hígado Graso no Alcohólico , Humanos , Ratones , Animales , Ratones Obesos , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Citrato (si)-Sintasa/metabolismo , Farnesol/metabolismo , Farnesol/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Hígado , Obesidad/complicaciones , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Insulina/metabolismo , Glucosa/metabolismo , Ácidos y Sales Biliares/metabolismo , Carbohidratos/farmacología , Serina/metabolismo , Serina/farmacología , Fosfofructoquinasa-1/metabolismo , Proteínas de Unión al GTP/metabolismo , Colágeno/metabolismo , Ratones Endogámicos C57BL , Dieta Alta en GrasaRESUMEN
Smoking has been associated with renal disease progression in ADPKD but the underlying deleterious mechanisms and whether it specifically worsens the cardiac phenotype remain unknown. To investigate these matters, Pkd1-deficient cystic mice and noncystic littermates were exposed to smoking from conception to 18 weeks of age and, along with nonexposed controls, were analyzed at 13-18 weeks. Renal cystic index and cyst-lining cell proliferation were higher in cystic mice exposed to smoking than nonexposed cystic animals. Smoking increased serum urea nitrogen in cystic and noncystic mice and independently enhanced tubular cell proliferation and apoptosis. Smoking also increased renal fibrosis, however this effect was much higher in cystic than in noncystic animals. Pkd1 deficiency and smoking showed independent and additive effects on reducing renal levels of glutathione. Systolic function and several cardiac structural parameters were also negatively affected by smoking and the Pkd1-deficient status, following independent and additive patterns. Smoking did not increase, however, cardiac apoptosis or fibrosis in cystic and noncystic mice. Notably, smoking promoted a much higher reduction in body weight in Pkd1-deficient than in noncystic animals. Our findings show that smoking aggravated the renal and cardiac phenotypes of Pkd1-deficient cystic mice, suggesting that similar effects may occur in human ADPKD.
Asunto(s)
Enfermedades Renales Poliquísticas , Fumar , Animales , Progresión de la Enfermedad , Ratones , FenotipoRESUMEN
The phenotypes of allergic airway diseases are influenced by the interplay between host genetics and the gut microbiota, which may be modulated by probiotics. We investigated the probiotic effects on allergic inflammation in A/J and C57BL/6 mice. C57BL/6 mice had increased gut microbiota diversity compared to A/J mice at baseline. Acetate producer probiotics differentially modulated and altered the genus abundance of specific bacteria, such as Akkermansia and Allistipes, in mouse strains. We induced airway inflammation followed by probiotic treatment and found that only A/J mice exhibited decreased inflammation, and the beneficial effects of probiotics in A/J mice were partially due to acetate production. To understand the relevance of microbial composition colonization in the development of allergic diseases, we implanted female C57BL/6 mice with A/J embryos to naturally modulate the microbial composition of A/J mice, which increased gut microbiota diversity and reduced eosinophilic inflammation in A/J. These data demonstrate the central importance of microbiota to allergic phenotype severity. Video Abstract.
Asunto(s)
Microbioma Gastrointestinal , Probióticos , Animales , Femenino , Inflamación , Ratones , Ratones Endogámicos C57BL , Sistema RespiratorioRESUMEN
We investigate the binding of native ß-cyclodextrin (ß-CD) and eight novel ß-CD derivatives with two different guest compounds, using isothermal calorimetry and 2D NOESY NMR. In all cases, the stoichiometry is 1:1 and binding is exothermic. Overall, modifications at the 3' position of ß-CD, which is at the secondary face, weaken binding by several kJ/mol relative to native ß-CD, while modifications at the 6' position (primary face) maintain or somewhat reduce the binding affinity. The variations in binding enthalpy are larger than the variations in binding free energy, so entropy-enthalpy compensation is observed. Characterization of the bound conformations with NOESY NMR shows that the polar groups of the guests may be situated at either face, depending on the host molecule, and, in some cases, both orientations are populated. The present results were used in the SAMPL7 blinded prediction challenge whose results are detailed in the same special issue of JCAMD.
Asunto(s)
Ciclodextrinas/metabolismo , Ciclohexanoles/metabolismo , Rimantadina/metabolismo , Termodinámica , beta-Ciclodextrinas/metabolismo , Ciclodextrinas/química , Ciclohexanoles/química , Entropía , Estructura Molecular , Rimantadina/química , beta-Ciclodextrinas/químicaRESUMEN
BACKGROUND/AIMS: Obesity is a risk factor associated with cardiometabolic complications. Recently, we reported that miRNA-22 deletion attenuated high-fat diet-induced adiposity and prevented dyslipidemia without affecting cardiac hypertrophy in male mice. In this study, we examined the impact of miRNA-22 in obesogenic diet-induced cardiovascular and metabolic disorders in females. METHODS: Wild type (WT) and miRNA-22 knockout (miRNA-22 KO) females were fed a control or an obesogenic diet. Body weight gain, adiposity, glucose tolerance, insulin tolerance, and plasma levels of total cholesterol and triglycerides were measured. Cardiac and white adipose tissue remodeling was assessed by histological analyses. Echocardiography was used to evaluate cardiac function and morphology. RNA-sequencing analysis was employed to characterize mRNA expression profiles in female hearts. RESULTS: Loss of miRNA-22 attenuated body weight gain, adiposity, and prevented obesogenic diet-induced insulin resistance and dyslipidemia in females. WT obese females developed cardiac hypertrophy. Interestingly, miRNA-22 KO females displayed cardiac hypertrophy without left ventricular dysfunction and myocardial fibrosis. Both miRNA-22 deletion and obesogenic diet changed mRNA expression profiles in female hearts. Enrichment analysis revealed that genes associated with regulation of the force of heart contraction, protein folding and fatty acid oxidation were enriched in hearts of WT obese females. In addition, genes related to thyroid hormone responses, heart growth and PI3K signaling were enriched in hearts of miRNA-22 KO females. Interestingly, miRNA-22 KO obese females exhibited reduced mRNA levels of Yap1, Egfr and Tgfbr1 compared to their respective controls. CONCLUSION: This study reveals that miRNA-22 deletion induces cardiac hypertrophy in females without affecting myocardial function. In addition, our findings suggest miRNA-22 as a potential therapeutic target to treat obesity-related metabolic disorders in females.
Asunto(s)
Cardiomegalia , Dieta Alta en Grasa/efectos adversos , Eliminación de Gen , Enfermedades Metabólicas , MicroARNs/genética , Miocardio , Obesidad , Animales , Cardiomegalia/inducido químicamente , Cardiomegalia/genética , Cardiomegalia/metabolismo , Cardiomegalia/patología , Femenino , Enfermedades Metabólicas/inducido químicamente , Enfermedades Metabólicas/genética , Enfermedades Metabólicas/metabolismo , Enfermedades Metabólicas/patología , Ratones , Ratones Noqueados , MicroARNs/metabolismo , Miocardio/metabolismo , Miocardio/patología , Obesidad/inducido químicamente , Obesidad/genética , Obesidad/metabolismo , Obesidad/patologíaRESUMEN
Fructose consumption by rodents modulates both hepatic and intestinal lipid metabolism and gluconeogenesis. We have previously demonstrated that in utero exposure to dexamethasone (DEX) interacts with fructose consumption during adult life to exacerbate hepatic steatosis in rats. The aim of this study was to clarify if adult rats born to DEX-treated mothers would display differences in intestinal gluconeogenesis after excessive fructose intake. To address this issue, female Wistar rats were treated with DEX during pregnancy and control (CTL) mothers were kept untreated. Adult offspring born to CTL and DEX-treated mothers were assigned to receive either tap water (Control-Standard Chow (CTL-SC) and Dexamethasone-Standard Chow (DEX-SC)) or 10% fructose in the drinking water (CTL-fructose and DEX-fructose). Fructose consumption lasted for 80 days. All rats were subjected to a 40 h fasting before sample collection. We found that DEX-fructose rats have increased glucose and reduced lactate in the portal blood. Jejunum samples of DEX-fructose rats have enhanced phosphoenolpyruvate carboxykinase (PEPCK) expression and activity, higher facilitated glucose transporter member 2 (GLUT2) and facilitated glucose transporter member 5 (GLUT5) content, and increased villous height, crypt depth, and proliferating cell nuclear antigen (PCNA) staining. The current data reveal that rats born to DEX-treated mothers that consume fructose during adult life have increased intestinal gluconeogenesis while recapitulating metabolic and morphological features of the neonatal jejunum phenotype.
Asunto(s)
Dexametasona/efectos adversos , Carbohidratos de la Dieta/efectos adversos , Células Epiteliales/patología , Fructosa/efectos adversos , Gluconeogénesis , Mucosa Intestinal/citología , Mucosa Intestinal/metabolismo , Yeyuno/metabolismo , Exposición Materna/efectos adversos , Intercambio Materno-Fetal/fisiología , Efectos Tardíos de la Exposición Prenatal , Fenómenos Fisiológicos Nutricionales de los Animales/fisiología , Animales , Femenino , Transportador de Glucosa de Tipo 2/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Metabolismo de los Lípidos , Fenómenos Fisiologicos Nutricionales Maternos/fisiología , Fosfoenolpiruvato Carboxiquinasa (GTP)/metabolismo , Embarazo , Ratas WistarRESUMEN
Pioglitazone belongs to the class of drugs thiazolidinediones (TZDs) and is an oral hypoglycemic drug, used in the treatment of type 2 diabetes, which improves insulin sensitivity in target tissues. Adipose tissue is the main target of pioglitazone, a PPARg and PPARa agonist; however, studies also point to skeletal muscle as a target. Non-PPAR targets of TZDs have been described, thus we aimed to study the direct effects of pioglitazone on skeletal muscle and the possible role of microRNAs as targets of this drug. Pioglitazone treatment of obese mice increased insulin-mediated glucose transport as a result of increased fatty acid oxidation and mitochondrial activity. PPARg blockage by treatment with GW9662 nullified pioglitazone's effect on systemic and muscle insulin sensitivity and citrate synthase activity of obese mice. After eight weeks of high-fat diet, miR-221-3p expression in soleus muscle was similar among the groups and miR-23b-3p and miR-222-3p were up-regulated in obese mice compared to the control group, and treatment with pioglitazone was able to reverse this condition. In vitro studies in C2C12 cells suggest that inhibition of miR-222-3p protects C2C12 cells from insulin resistance and increased non-mitochondrial respiration induced by palmitate. Together, these data demonstrate a role of pioglitazone in the downregulation of microRNAs that is not dependent on PPARg. Moreover, miR-222 may be a novel PPARg-independent mechanism through which pioglitazone improves insulin sensitivity in skeletal muscle.
Asunto(s)
Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , MicroARNs/metabolismo , Músculo Esquelético/efectos de los fármacos , Pioglitazona/farmacología , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Animales , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Regulación hacia Abajo/efectos de los fármacos , Glucosa/metabolismo , Prueba de Tolerancia a la Glucosa , Hipoglucemiantes , Insulina/metabolismo , Resistencia a la Insulina/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Músculo Esquelético/metabolismo , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , PPAR alfa/metabolismo , PPAR gamma/metabolismo , Palmitatos/farmacología , Tiazolidinedionas/farmacología , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Distinct environmental insults might interact with fructose consumption and contribute to the development of metabolic disorders. To address whether in utero glucocorticoid exposure and fructose intake modulate metabolic responses, adult female Wistar rats were exposed to dexamethasone (DEX) during pregnancy, and the offspring were administered fructose at a later time. Briefly, dams received DEX during the third period of pregnancy, while control dams remained untreated. Offspring born to control and DEX-treated mothers were defined as CTL-off and DEX-off, respectively, while untreated animals were designated CTL-off-CTL and DEX-off-CTL. CLT-off and DEX-off treated with 10% fructose in the drinking water for 8 weeks are referred to as CTL-off-FRU and DEX-off-FRU. We found that fructose promoted glucose intolerance and whole-body gluconeogenesis in both CTL-off-FRU and DEX-off-FRU animals. On the other hand, hepatic lipid accumulation was significantly stimulated in DEX-off-FRU rats when compared to the CTL-off-FRU group. The DEX-off-FRU group also displayed impaired very-low-density lipoprotein (VLDL) production and reduced hepatic expression of apoB, mttp, and sec22b. DEX-off-FRU has lower hepatic levels of autophagy markers. Taken together, our results support the unprecedented notion that in utero glucocorticoid exposure exacerbates hepatic steatosis caused by fructose consumption later in life.
Asunto(s)
Dexametasona/toxicidad , Azúcares de la Dieta/toxicidad , Hígado Graso/inducido químicamente , Fructosa/toxicidad , Metabolismo de los Lípidos/efectos de los fármacos , Hígado/efectos de los fármacos , Efectos Tardíos de la Exposición Prenatal , Animales , Apolipoproteínas B/genética , Apolipoproteínas B/metabolismo , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Hígado Graso/genética , Hígado Graso/metabolismo , Hígado Graso/patología , Femenino , Edad Gestacional , Gluconeogénesis/efectos de los fármacos , Metabolismo de los Lípidos/genética , Lipoproteínas VLDL/metabolismo , Hígado/metabolismo , Hígado/patología , Masculino , Embarazo , Proteínas R-SNARE/genética , Proteínas R-SNARE/metabolismo , Ratas WistarRESUMEN
Directed connectivity inference has become a cornerstone in neuroscience to analyze multivariate data from neuroimaging and electrophysiological techniques. Here we propose a nonparametric significance method to test the nonzero values of multivariate autoregressive model to infer interactions in recurrent networks. We use random permutations or circular shifts of the original time series to generate the null-hypothesis distributions. The underlying network model is the same as used in multivariate Granger causality, but our test relies on the autoregressive coefficients instead of error residuals. By means of numerical simulation over multiple network configurations, we show that this method achieves a good control of false positives (type 1 error) and detects existing pairwise connections more accurately than using the standard parametric test for the ratio of error residuals. In practice, our method aims to detect temporal interactions in real neuronal networks with nodes possibly exhibiting redundant activity. As a proof of concept, we apply our method to multiunit activity (MUA) recorded from Utah electrode arrays in a monkey and examine detected interactions between 25 channels. We show that during stimulus presentation our method detects a large number of interactions that cannot be solely explained by the increase in the MUA level.
RESUMEN
We investigated the effect of the crude herbal extract from Uncaria tomentosa (UT) on non-alcoholic fatty liver disease (NAFLD) in two models of obesity: high fat diet (HFD) and genetically obese (ob/ob) mice. Both obese mouse models were insulin resistant and exhibited an abundance of lipid droplets in the hepatocytes and inflammatory cell infiltration in the liver, while only the HFD group had collagen deposition in the perivascular space of the liver. UT treatment significantly reduced liver steatosis and inflammation in both obese mouse models. Furthermore, serine phosphorylation of IRS-1 was reduced by 25% in the HFD mice treated with UT. Overall, UT treated animals exhibited higher insulin sensitivity as compared to vehicle administration. In conclusion, Uncaria tomentosa extract improved glucose homeostasis and reverted NAFLD to a benign hepatic steatosis condition and these effects were associated with the attenuation of liver inflammation in obese mice.
Asunto(s)
Uña de Gato/metabolismo , Resistencia a la Insulina/fisiología , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Animales , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Inflamación/tratamiento farmacológico , Insulina/farmacología , Hígado/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/fisiopatología , Obesidad/fisiopatología , Extractos Vegetales/farmacologíaRESUMEN
Graph theory constitutes a widely used and established field providing powerful tools for the characterization of complex networks. The intricate topology of networks can also be investigated by means of the collective dynamics observed in the interactions of self-sustained oscillations (synchronization patterns) or propagationlike processes such as random walks. However, networks are often inferred from real-data-forming dynamic systems, which are different from those employed to reveal their topological characteristics. This stresses the necessity for a theoretical framework dedicated to the mutual relationship between the structure and dynamics in complex networks, as the two sides of the same coin. Here we propose a rigorous framework based on the network response over time (i.e., Green function) to study interactions between nodes across time. For this purpose we define the flow that describes the interplay between the network connectivity and external inputs. This multivariate measure relates to the concepts of graph communicability and the map equation. We illustrate our theory using the multivariate Ornstein-Uhlenbeck process, which describes stable and non-conservative dynamics, but the formalism can be adapted to other local dynamics for which the Green function is known. We provide applications to classical network examples, such as small-world ring and hierarchical networks. Our theory defines a comprehensive framework that is canonically related to directed and weighted networks, thus paving a way to revise the standards for network analysis, from the pairwise interactions between nodes to the global properties of networks including community detection.
RESUMEN
In this study, the lymphocyte activation status (surface expression of CD95, CD28, CD25, and CTLA-4), lymphocyte number, lymphocyte subpopulations, lymphocyte necrosis and/or apoptosis, and lymphocyte release of reactive oxygen species (ROS) were investigated in blood samples from 16 futsal athletes before and immediately following a competitive match. Lymphocytes were isolated from the blood samples, and the cellular parameters were assessed by flow cytometry. The futsal match induced lymphocytosis and lymphocyte apoptosis, as indicated by phosphatidylserine externalization, CD95 expression, and DNA fragmentation. Additionally, the competitive match induced the necrotic death of lymphocytes. No differences in the percentage of CD4+ and CD8+ T cells or in the T-helper/suppressor profile between before and immediately after the match were observed. Additionally, after the futsal match, the CD95 and CD28 expression levels were decreased, and the lymphocytes spontaneously released higher levels of ROS. Regardless of the origin, the situation-specific knowledge of lymphocyte behavior obtained herein may facilitate the design of strategies to control the processes that result in infection and tissue injury and that subsequently decrease athletic performance.
RESUMEN
The effect of fenofibrate on the metabolism of skeletal muscle and visceral white adipose tissue of diet-induced obese (DIO) mice was investigated. C57BL/6J male mice were fed either a control or high-fat diet for 8 weeks. Fenofibrate (50 mg/Kg BW, daily) was administered by oral gavage during the last two weeks of the experimental period. Insulin-stimulated glucose metabolism in soleus muscles, glucose tolerance test, insulin tolerance test, indirect calorimetry, lipolysis of visceral white adipose tissue, expression of miR-103-3p in adipose tissue, and miR-1a, miR-133a/b, miR-206, let7b-5p, miR-23b-3p, miR-29-3p, miR-143-3p in soleus muscle, genes related to glucose and fatty acid metabolism in adipose tissue and soleus muscle, and proteins (phospho-AMPKα2, Pgc1α, Cpt1b), intramuscular lipid staining, and activities of fatty acid oxidation enzymes in skeletal muscle were investigated. In DIO mice, fenofibrate prevented weight gain induced by HFD feeding by increasing energy expenditure; improved whole body glucose homeostasis, and in skeletal muscle, increased insulin dependent glucose uptake, miR-1a levels, reduced intramuscular lipid accumulation, and phospho-AMPKα2 levels. In visceral adipose tissue of obese mice, fenofibrate decreased basal lipolysis rate and visceral adipocytes hypertrophy, and induced the expression of Glut-4, Irs1, and Cav-1 mRNA and miR-103-3p suggesting a higher insulin sensitivity of the adipocytes. The evidence is presented herein that beneficial effects of fenofibrate on body weight, glucose homeostasis, and muscle metabolism might be related to its action in adipose tissue. Moreover, fenofibrate regulates miR-1a-3p in soleus and miR-103-3p in adipose tissue, suggesting these microRNAs might contribute to fenofibrate beneficial effects on metabolism.
Asunto(s)
Adipocitos/efectos de los fármacos , Dieta Alta en Grasa , Fenofibrato/farmacología , Hipolipemiantes/farmacología , Músculo Esquelético/efectos de los fármacos , Tejido Adiposo Blanco/metabolismo , Animales , Dieta Alta en Grasa/efectos adversos , Metabolismo Energético/efectos de los fármacos , Glucosa/metabolismo , Resistencia a la Insulina/genética , Grasa Intraabdominal/efectos de los fármacos , Metabolismo de los Lípidos/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , Músculo Esquelético/metabolismo , Obesidad/tratamiento farmacológico , Obesidad/metabolismoRESUMEN
Herein, we report a new approach to bio-inspired catalyst design. The molecular catalyst employed in these studies is based on the robust and selective Re(bpy)(CO)3Cl-type (bpy = 2,2'-bipyridine) homogeneous catalysts, which have been extensively studied for their ability to reduce CO2 electrochemically or photochemically in the presence of a photosensitizer. These catalysts can be highly active photocatalysts in their own right. In this work, the bipyridine ligand was modified with amino acids and synthetic peptides. These results build on earlier findings wherein the bipyridine ligand was functionalized with amide groups to promote dimer formation and CO2 reduction by an alternate bimolecular mechanism at lower overpotential (ca. 250 mV) than the more commonly observed unimolecular process. The bio-inspired catalysts were designed to allow for the incorporation of proton relays to support reduction of CO2 to CO and H2O. The coupling of amino acids tyrosine and phenylalanine led to the formation of two structurally similar Re catalyst/peptide catalysts for comparison of proton transport during catalysis. This article reports the synthesis and characterization of novel catalyst/peptide hybrids by molecular dynamics (MD simulations of structural dynamics), NMR studies of solution phase structures, and electrochemical studies to measure the activities of new bio-inspired catalysts in the reduction of CO2.
Asunto(s)
Aminoácidos/síntesis química , Dióxido de Carbono/química , Compuestos Organometálicos/química , Péptidos/síntesis química , Protones , Aminoácidos/química , Dióxido de Carbono/metabolismo , Catálisis , Enlace de Hidrógeno , Estructura Molecular , Oxidación-Reducción , Péptidos/químicaRESUMEN
A number of genes that confer resistance to coffee leaf rust (SH 1-SH 9) have been identified within the genus Coffea, but despite many years of research on this pathosystem, the complementary avirulence genes of Hemileia vastatrix have not been reported. After identification of H. vastatrix effector candidate genes (HvECs) expressed at different stages of its lifecycle, we established an assay to characterize HvEC proteins by delivering them into coffee cells via the type-three secretion system (T3SS) of Pseudomonas syringae pv. garcae (Psgc). Employing a calmodulin-dependent adenylate cyclase assay, we demonstrate that Psgc recognizes a heterologous P. syringae T3SS secretion signal which enables us to translocate HvECs into the cytoplasm of coffee cells. Using this Psgc-adapted effector detector vector (EDV) system, we found that HvEC-016 suppresses the growth of Psgc on coffee genotypes with the SH 1 resistance gene. Suppression of bacterial blight symptoms in SH 1 plants was associated with reduced bacterial multiplication. By contrast, HvEC-016 enhanced bacterial multiplication in SH 1-lacking plants. Our findings suggest that HvEC-016 may be recognized by the plant immune system in a SH 1-dependent manner. Thus, our experimental approach is an effective tool for the characterization of effector/avirulence proteins of this important pathogen.
Asunto(s)
Basidiomycota/fisiología , Coffea/genética , Coffea/microbiología , Resistencia a la Enfermedad/genética , Proteínas Fúngicas/metabolismo , Genes de Plantas , Enfermedades de las Plantas/microbiología , Pseudomonas syringae/patogenicidad , Adenilil Ciclasas/metabolismo , Secuencia de Aminoácidos , Sistemas de Secreción Bacterianos , Basidiomycota/genética , Exones/genética , Proteínas Fúngicas/química , Regulación de la Expresión Génica de las Plantas , Genes Fúngicos , Genotipo , Intrones/genética , Pseudomonas syringae/crecimiento & desarrollo , Alineación de SecuenciaRESUMEN
The effects of either eicosapentaenoic (EPA)- or docosahexaenoic (DHA)-rich fish oils on hindlimb suspension (HS)-induced muscle disuse atrophy were compared. Daily oral supplementations (0.3 mL/100 g b.w.) with mineral oil (MO) or high EPA or high DHA fish oils were performed in adult rats. After 2 weeks, the animals were subjected to HS for further 2 weeks. The treatments were maintained alongside HS At the end of 4 weeks, we evaluated: body weight gain, muscle mass and fat depots, composition of fatty acids, cross-sectional areas (CSA) of the soleus muscle and soleus muscle fibers, activities of cathepsin L and 26S proteasome, and content of carbonylated proteins in the soleus muscle. Signaling pathway activities associated with protein synthesis (Akt, p70S6K, S6, 4EBP1, and GSK3-beta) and protein degradation (atrogin-1/MAFbx, and MuRF1) were evaluated. HS decreased muscle mass, CSA of soleus muscle and soleus muscle fibers, and altered signaling associated with protein synthesis (decreased) and protein degradation (increased). The treatment with either fish oil decreased the ratio of omega-6/omega-3 fatty acids and changed protein synthesis-associated signaling. EPA-rich fish oil attenuated the changes induced by HS on 26S proteasome activity, CSA of soleus muscle fibers, and levels of p-Akt, total p70S6K, p-p70S6K/total p70S6K, p-4EBP1, p-GSK3-beta, p-ERK2, and total ERK 1/2 proteins. DHA-rich fish oil attenuated the changes induced by HS on p-4EBP1 and total ERK1 levels. The effects of EPA-rich fish oil on protein synthesis signaling were more pronounced. Both EPA- and DHA-rich fish oils did not impact skeletal muscle mass loss induced by non-inflammatory HS.
Asunto(s)
Ácidos Docosahexaenoicos/administración & dosificación , Ácido Eicosapentaenoico/administración & dosificación , Aceites de Pescado/química , Redes Reguladoras de Genes , Suspensión Trasera/efectos adversos , Trastornos Musculares Atróficos/metabolismo , Animales , Ácidos Docosahexaenoicos/farmacología , Ácido Eicosapentaenoico/farmacología , Redes Reguladoras de Genes/efectos de los fármacos , Masculino , Músculo Esquelético/efectos de los fármacos , Trastornos Musculares Atróficos/etiología , Ratas , Transducción de Señal/efectos de los fármacosRESUMEN
While the plasticity of excitatory synaptic connections in the brain has been widely studied, the plasticity of inhibitory connections is much less understood. Here, we present recent experimental and theoretical findings concerning the rules of spike timing-dependent inhibitory plasticity and their putative network function. This is a summary of a workshop at the COSYNE conference 2012.
Asunto(s)
Potenciales de Acción/fisiología , Red Nerviosa/fisiología , Inhibición Neural/fisiología , Plasticidad Neuronal/fisiología , Sinapsis/fisiología , Animales , Humanos , Potenciales Postsinápticos Inhibidores/fisiología , Factores de TiempoRESUMEN
INTRODUCTION: Abnormalities of liver function tests have been occasionally described in large series of Lyme disease, but only one case of hepatitis directly related to infection have been described in literature. CASE REPORT: A 78-year-old-man, with a past medical history of polymyalgia rheumatica (PMR) who had discontinued corticosteroids two years before, presented a transient acute fever and liver cholestasis and cytolysis after an exposure to tick bites. A few days later, cervical pain occurred and corticosteroids were resumed as a PMR relapse was suspected. Hematogenous dissemination with acute meningoradiculitis and multiple erythema migrans led to conclude to a stage 2 Lyme disease. CONCLUSION: Although hepatitis complicating the course of Lyme disease has been described in literature, the marked inflammation in our patient led us to investigate the possibility of a co-infection. Also, we discuss the responsibility of corticosteroids in clinical worsening of Lyme disease if they are prescribed without concomitant antibiotics.