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BACKGROUND: Severe malaria can cause respiratory symptoms, which may lead to malaria-acute lung injury (MA-ALI) due to inflammation and damage to the blood-gas barrier. Patients with severe malaria also often present thrombocytopenia, and the use of acetylsalicylic acid (ASA), a commonly used non-steroidal anti-inflammatory drug with immunomodulatory and antiplatelet effects, may pose a risk in regions where malaria is endemic. Thus, this study aimed to investigate the systemic impact of ASA and dihydroartemisinin (DHA) on ALI induced in mice by Plasmodium berghei NK65 (PbNK65). METHODS: C57BL/6 mice were randomly divided into control (C) and PbNK65 infected groups and were inoculated with uninfected or 104 infected erythrocytes, respectively. Then, the animals were treated with DHA (3 mg/kg) or vehicle (DMSO) at the 8-day post-infection (dpi) for 7 days and with ASA (100 mg/kg, single dose), and analyses were performed at 9 or 15 dpi. Lung mechanics were performed, and lungs were collected for oedema evaluation and histological analyses. RESULTS: PbNK65 infection led to lung oedema, as well as increased lung static elastance (Est, L), resistive (ΔP1, L) and viscoelastic (ΔP2, L) pressures, percentage of mononuclear cells, inflammatory infiltrate, hemorrhage, alveolar oedema, and alveolar thickening septum at 9 dpi. Mice that received DHA or DHA + ASA had an increase in Est, L, and CD36 expression on inflammatory monocytes and higher protein content on bronchoalveolar fluid (BALF). However, only the DHA-treated group presented a percentage of inflammatory monocytes similar to the control group and a decrease in ΔP1, L and ΔP2, L compared to Pb + DMSO. Also, combined treatment with DHA + ASA led to an impairment in diffuse alveolar damage score and lung function at 9 dpi. CONCLUSIONS: Therapy with ASA maintained lung morpho-functional impairment triggered by PbNK65 infection, leading to a large influx of inflammatory monocytes to the lung tissue. Based on its deleterious effects in experimental MA-ALI, ASA administration or its treatment maintenance might be carefully reconsidered and further investigated in human malaria cases.
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Lesión Pulmonar Aguda , Antimaláricos , Artemisininas , Aspirina , Pulmón , Malaria , Ratones Endogámicos C57BL , Plasmodium berghei , Animales , Artemisininas/farmacología , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/parasitología , Aspirina/farmacología , Aspirina/administración & dosificación , Malaria/tratamiento farmacológico , Malaria/complicaciones , Ratones , Antimaláricos/farmacología , Plasmodium berghei/efectos de los fármacos , Pulmón/patología , Pulmón/efectos de los fármacos , Quimioterapia Combinada , Modelos Animales de Enfermedad , Masculino , Pruebas de Función RespiratoriaRESUMEN
Long-term ß-adrenoceptor (ß-AR) stimulation is a pathological mechanism associated with cardiovascular diseases resulting in endothelial and perivascular adipose tissue (PVAT) dysfunction. In this study, we aimed to identify whether ß-adrenergic signaling has a direct effect on PVAT. Thoracic aorta PVAT was obtained from male Wistar rats and cultured ex vivo with the ß-AR agonist isoproterenol (Iso; 1â µM) or vehicle for 24 hours. Conditioned culture medium (CCM) from Iso-treated PVAT induced a marked increase in aorta contractile response, induced oxidative stress, and reduced nitric oxide production in PVAT compared to vehicle. In addition, Iso-treated PVAT and PVAT-derived differentiated adipocytes exhibited higher corticosterone release and protein expression of 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1), an enzyme responsible for de novo synthesis of corticosterone. Macrophages exposed to Iso also exhibited increased corticosterone release in response to ß-AR stimulation. Incubation of Iso-treated PVAT and PVAT-derived differentiated adipocytes with ß3-AR antagonist restored aorta contractile function modulated by Iso-CCM and normalized 11ß-HSD1 protein expression. These results show that ß3-AR signaling leads to upregulation of 11ß-HSD1 in PVAT, thus increasing corticosterone release and contributing to impair the anticontractile function of this tissue.
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11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1 , Corticosterona , Isoproterenol , Animales , Masculino , Ratas , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/genética , Adipocitos/metabolismo , Adipocitos/efectos de los fármacos , Tejido Adiposo/metabolismo , Agonistas Adrenérgicos beta/farmacología , Aorta Torácica/efectos de los fármacos , Aorta Torácica/metabolismo , Corticosterona/metabolismo , Medios de Cultivo Condicionados/farmacología , Isoproterenol/farmacología , Óxido Nítrico/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratas Wistar , Receptores Adrenérgicos beta/metabolismoRESUMEN
OBJECTIVES: To evaluate the effect of mono and multi-wave light-curing units (LCUs) on the Knoop hardness of resin-based composites (RBC) that use different photoinitiators. METHODS: Central incisor-shaped specimens 12 mm long, 9 mm wide, and 1.5 mm thick were made from 2 RBCs that use different photoinitiators: Tetric N-Ceram (Ivoclar Vivadent) - and Vittra APS (FGM), both A2E shade. They were light-cured with 4 different LCUs: two claimed to be multi-wave - VALO Grand (Ultradent) and Emitter Now Duo (Schuster); and two were monowave - Radii Xpert (SDI) and Elipar DeepCure-L (3 M Oral Care) using 2 different light exposure protocols: one 40 s exposure centered over the specimen; and two 20 s light exposures that delivered light from two positions to better cover the entire tooth. 16 groups with 10 specimens in each group were made. The Knoop hardness (KH, kg/mm2) was measured at the top and bottom of the specimen in the center and at the cervical, incisal, mesial, and distal peripheral regions. The active tip diameters (mm) and spectral radiant powers (mW/nm) of the LCUs were measured with and without the interposition of the RBC, as well as the radiant exposure beam profiles (J/cm²) delivered to the top of the RBCs. The data was analyzed using Three-way ANOVA and Tukey's tests (α = 0.05). RESULTS: The VALO Grand (1029 mW) emitted twice the power of the Radii Xpert (500 mW). The KH values of VI and TN resin composite specimens were significantly affected by the LCU used (p < .001), the measurement location (p < .001), and the surface of the specimen (p < .001). LCUs with wider tip diameters produced greater Knoop hardness values at the peripheries of the 12 mm of long, 9 mm wide specimens. In general, the VALO Grand produced the highest KH values, followed by Elipar DeepCure-L, then by Radii Xpert. The Emitter Now Duo LCU produced the lowest values. Exposing the veneers from two locations reduced the differences between the LCUs and the effect of the measurement location. Only the VALO Grand could fully cover the composite veneer with light when the two locations were used. SIGNIFICANCE: The light tip must cover the entire restoration to photocure the RBC beneath the light tip.
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Luces de Curación Dental , Curación por Luz de Adhesivos Dentales , Dureza , Ensayo de Materiales , Resinas Compuestas , Materiales Dentales , PolimerizacionRESUMEN
OBJECTIVE: The use of a fiber glass post (FGP) type and choice of FGP diameter to restore endodontically treated incisors without ferrule is controversial. This study evaluated survival rate and failure mode of severely compromised central incisors without ferrule rehabilitated using resin-based composite (RBC) with or without FGP with different diameters. METHODOLOGY: A total of 60 decoronated bovine incisors without a ferrule were endodontically treated and prepared for 1.4, 1.6, and 1.8 mm diameter FGPs (Whitepost System DC 0.5, Fit 0.4, and DCE 0.5; FGM). Half of the teeth received FGPs cemented using dual-cure resin cement (Allcem Core; FGM), the other half were filled using only bulk-fill RBC (OPUS Bulk Fill; FGM). The crowns were directly restored with RBC. The roots were embedded in polystyrene resin and the periodontal ligament was simulated with polyether impression material. Fatigue testing was conducted under 5 Hz cyclic loading at 30 degrees to the incisal edge, beginning at 50 N (5,000 cycles) as a warmup. After, the load was increased 100 N every 15,000 cycles until fracture occurred. All specimens were subjected to transillumination, micro-CT analysis, and digital radiography before and after fatigue testing. Fracture mode was classified according to severity and repair potential. Data were analyzed with Kaplan-Meier survival test and post hoc log-rank test (α=0.05) for pairwise comparisons. RESULTS: Using FGP significantly increased the number of cycles to failure, irrespective of FGP diameters (p=0.001). The FGP diameters had no statistically significant effect on cycles to failure or failure mode. CONCLUSION: Using FGP without ferrule improved survival rate of structurally severely compromised central incisors compared with rehabilitation without FGP. The diameter of the FGPs had no effect on the survival rate and failure mode.
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Técnica de Perno Muñón , Fracturas de los Dientes , Diente no Vital , Animales , Bovinos , Resinas Compuestas , Coronas , Materiales Dentales , Vidrio , Análisis del Estrés Dental , Fracaso de la Restauración DentalRESUMEN
CETP activity reduces plasma HDL-cholesterol concentrations, a correlate of an increased risk of atherosclerotic events. However, our recent findings suggest that CETP expression in macrophages promotes an intracellular antioxidant state, reduces free cholesterol accumulation and phagocytosis, and attenuates pro-inflammatory gene expression. To determine whether CETP expression in macrophages affects atherosclerosis development, we transplanted bone marrow from transgenic mice expressing simian CETP or non-expressing littermates into hypercholesterolemic LDL-receptor-deficient mice. The CETP expression did not change the lipid-stained lesion areas but decreased the macrophage content (CD68), neutrophil accumulation (LY6G), and TNF-α aorta content of young male transplanted mice and decreased LY6G, TNF-α, iNOS, and nitrotyrosine (3-NT) in aged female transplanted mice. These findings suggest that CETP expression in bone-marrow-derived cells reduces the inflammatory features of atherosclerosis. These novel mechanistic observations may help to explain the failure of CETP inhibitors in reducing atherosclerotic events in humans.
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Aterosclerosis , Médula Ósea , Humanos , Ratones , Animales , Masculino , Femenino , Anciano , Médula Ósea/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Proteínas de Transferencia de Ésteres de Colesterol/genética , Proteínas de Transferencia de Ésteres de Colesterol/metabolismo , Aterosclerosis/metabolismo , Colesterol/metabolismo , Ratones Transgénicos , Ratones Endogámicos C57BLRESUMEN
BACKGROUND/AIMS: Recombinant adeno-associated viruses (rAAV) are an important tool for lung targeted gene therapy. Substitution of tyrosine with phenylalanine residues (Y-F) in the capsid have been shown to protect the AAV vector from ubiquitin/proteasome degradation, increasing transduction efficiency. We tested the mutant Y733F-AAV8 vector for mucus diffusion, as well as the safety and efficacy of pigment epithelium-derived factor (PEDF) gene transfer to the lung. METHODS: For this purpose, Y733F-AAV8-PEDF (1010 viral genome) was administered intratracheally to C57BL/6 mice. Lung mechanics, morphometry, and inflammation were evaluated 7, 14, 21, and 28 days after injection. RESULTS: The tyrosine-mutant AAV8 vector was efficient at penetrating mucus in ex vivo assays and at transferring the gene to lung cells after in vivo instillation. Increased levels of transgene mRNA were observed 28 days after vector administration. Overexpression of PEDF did not affect in vivo lung parameters. CONCLUSION: These findings provide a basis for further development of Y733F-AAV8-based gene therapies for safe and effective delivery of PEDF, which has anti-angiogenic, anti-inflammatory and anti-fibrotic activities and might be a promising therapy for lung inflammatory disorders.
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Proteínas del Ojo , Técnicas de Transferencia de Gen , Serpinas , Animales , Ratones , Proteínas del Ojo/genética , Ratones Endogámicos C57BL , Factores de Crecimiento Nervioso/genética , Serpinas/genéticaRESUMEN
Endothelial dysfunction is an early manifestation of atherosclerosis. The cholesteryl ester transfer protein (CETP) has been considered proatherogenic by reducing plasma HDL levels. However, CETP may exhibit cell- or tissue-specific effects. We have previously reported that male mice expressing the human CETP gene show impaired endothelium-mediated vascular relaxation associated with oxidative stress. Although sexual dimorphisms on the metabolic role of CETP have been proposed, possible sex differences in the vascular effects of CETP were not previously studied. Thus, here we investigated the endothelial function of female CETP transgenic mice as compared with nontransgenic controls (NTg). Aortas from CETP females presented preserved endothelium-dependent relaxation to acetylcholine and an endothelium-dependent reduction of phenylephrine-induced contraction. eNOS phosphorylation (Ser1177) and calcium-induced NO levels were enhanced, whereas reactive oxygen species (ROS) production and NOX2 and SOD2 expression were reduced in the CETP female aortas. Furthermore, CETP females exhibited increased aortic relaxation to 17ß-estradiol (E2) and upregulation of heat shock protein 90 (HSP90) and caveolin-1, proteins that stabilize estrogen receptor (ER) in the caveolae. Indeed, CETP females showed an increased E2-induced relaxation in a manner sensitive to estrogen receptor-α (ERα) and HSP90 inhibitors methylpiperidinopyrazole (MPP) and geldanamycin, respectively. MPP also impaired the relaxation response to acetylcholine in CETP but not in NTg females. Altogether, the study indicates that CETP expression ameliorates the anticontractile endothelial effect and relaxation to E2 in females. This was associated with less ROS production, and increased eNOS-NO and E2-ERα pathways. These results highlight the need for considering the sex-specific effects of CETP on cardiovascular risk.NEW & NOTEWORTHY Here we demonstrated that CETP expression has a sex-specific impact on the endothelium function. Contrary to what was described for males, CETP-expressing females present preserved endothelium-dependent relaxation to acetylcholine and improved relaxation response to 17ß-estradiol. This was associated with less ROS production, increased eNOS-derived NO, and increased expression of proteins that stabilize estrogen receptor-α (ERα), thus increasing E2-ERα signaling sensitivity. These results highlight the need for considering the sex-specific effects of CETP on cardiovascular risk.
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Proteínas de Transferencia de Ésteres de Colesterol , Receptor alfa de Estrógeno , Óxido Nítrico Sintasa de Tipo III , Animales , Femenino , Ratones , Acetilcolina/farmacología , Proteínas de Transferencia de Ésteres de Colesterol/genética , Endotelio/metabolismo , Endotelio Vascular/metabolismo , Estradiol/farmacología , Receptor alfa de Estrógeno/genética , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Especies Reactivas de Oxígeno/metabolismo , VasodilataciónRESUMEN
Lycopene is a carotenoid with potential use in the treatment of chronic illnesses. Here, different formulations of lycopene were studied: lycopene-rich extract from red guava (LEG), purified lycopene from red guava (LPG) and a self-emulsifying drug delivery system loaded with LPG (nanoLPG). The effects of administering orally various doses of LEG to hypercholesterolemic hamsters were evaluated regarding the liver function of the animals. The cytotoxicity of LPG in Vero cells was analyzed by a crystal violet assay and by fluorescence microscopy. In addition, nanoLPG was employed in stability tests. LPG and nanoLPG were tested for their cytotoxic effect on human keratinocytes and antioxidant capacity on cells in an endothelial dysfunction model in an isolated rat aorta. Finally, the effect of different nanoLPG concentrations on the expression of immune-related genes (IL-10, TNF-α, COX-2 and IFN-γ) from peripheral blood mononuclear cells (PBMC) using real-time PCR was also analyzed. Results suggest that LEG, despite not being able to improve blood markers indicative of liver function in hypercholesterolemic hamsters, reduced hepatic degenerative changes. Additionally, LPG did not show cytotoxicity in Vero cells. In relation to nanoLPG, the effects produced by heat stress evaluated by Dynamics Light Scattering (DLS) and visually were loss of color, texture change and phase separation after 15 days without interfering with the droplet size, so the formulation proved to be efficient in stabilizing the encapsulated lycopene. Although LPG and nanoLPG showed moderate toxicity to keratinocytes, which may be related to cell lineage characteristics, both revealed potent antioxidant activity. LPG and nanoLPG showed vasoprotective effects in aortic preparations. The gene expression assay indicates that, although no significant differences were observed in the expression of IL-10 and TNF-α, the PBMCs treated with nanoLPG showed a reduction in transcriptional levels of IFN-γ and an increased expression of COX-2. Thus, the work adds evidence to the safety of the use of lycopene by humans and shows that tested formulations, mainly nanoLPG due to its stability, stand out as promising and biosafe products for the treatment of diseases that have oxidative stress and inflammation in their etiopathology.
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Abstract Objective The use of a fiber glass post (FGP) type and choice of FGP diameter to restore endodontically treated incisors without ferrule is controversial. This study evaluated survival rate and failure mode of severely compromised central incisors without ferrule rehabilitated using resin-based composite (RBC) with or without FGP with different diameters. Methodology A total of 60 decoronated bovine incisors without a ferrule were endodontically treated and prepared for 1.4, 1.6, and 1.8 mm diameter FGPs (Whitepost System DC 0.5, Fit 0.4, and DCE 0.5; FGM). Half of the teeth received FGPs cemented using dual-cure resin cement (Allcem Core; FGM), the other half were filled using only bulk-fill RBC (OPUS Bulk Fill; FGM). The crowns were directly restored with RBC. The roots were embedded in polystyrene resin and the periodontal ligament was simulated with polyether impression material. Fatigue testing was conducted under 5 Hz cyclic loading at 30 degrees to the incisal edge, beginning at 50 N (5,000 cycles) as a warmup. After, the load was increased 100 N every 15,000 cycles until fracture occurred. All specimens were subjected to transillumination, micro-CT analysis, and digital radiography before and after fatigue testing. Fracture mode was classified according to severity and repair potential. Data were analyzed with Kaplan-Meier survival test and post hoc log-rank test (α=0.05) for pairwise comparisons. Results Using FGP significantly increased the number of cycles to failure, irrespective of FGP diameters (p=0.001). The FGP diameters had no statistically significant effect on cycles to failure or failure mode. Conclusion Using FGP without ferrule improved survival rate of structurally severely compromised central incisors compared with rehabilitation without FGP. The diameter of the FGPs had no effect on the survival rate and failure mode.
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Plasma cholesteryl ester transfer protein (CETP) activity diminishes HDL-cholesterol levels and thus may increase atherosclerosis risk. Experimental evidence suggests CETP may also exhibit anti-inflammatory properties, but local tissue-specific functions of CETP have not yet been clarified. Since oxidative stress and inflammation are major features of atherogenesis, we investigated whether CETP modulates macrophage oxidant production, inflammatory and metabolic profiles. Comparing macrophages from CETP-expressing transgenic mice and non-expressing littermates, we observed that CETP expression reduced mitochondrial superoxide anion production and H2O2 release, increased maximal mitochondrial respiration rates, and induced elongation of the mitochondrial network and expression of fusion-related genes (mitofusin-2 and OPA1). The expression of pro-inflammatory genes and phagocytic activity were diminished in CETP-expressing macrophages. In addition, CETP-expressing macrophages had less unesterified cholesterol under basal conditions and after exposure to oxidized LDL, as well as increased HDL-mediated cholesterol efflux. CETP knockdown in human THP1 cells increased unesterified cholesterol and abolished the effects on mitofusin-2 and TNFα. In summary, the expression of CETP in macrophages modulates mitochondrial structure and function to promote an intracellular antioxidant state and oxidative metabolism, attenuation of pro-inflammatory gene expression, reduced cholesterol accumulation, and phagocytosis. These localized functions of CETP may be relevant for the prevention of atherosclerosis and other inflammatory diseases.
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AIMS: Considering the inconsistencies in the literature on the atorvastatin effect on blood pressure (BP), we performed these meta-analyses. METHODS AND RESULTS: Through a search of the Excerpta Medica Database (EMBASE), PubMed, and Web of Science databases, 1412 articles were identified, from which 33 randomized clinical trials (RCT) and 44 pre-clinical were selected. Populations from RCT were stratified according to baseline BP and lipid levels. We performed meta-analyses of the effect of atorvastatin on systolic (SBP), diastolic and mean BP; heart rate (HR); HR variability, and baroreflex. Atorvastatin reduced SBP in the overall population (P = 0.05 vs. placebo; P = 0.03 vs. baseline), in normotensive and hyperlipidaemic (P = 0.04 vs. placebo; P = 0.0001 vs. baseline) and in hypertensive and hyperlipidaemic (P = 0.02 vs. placebo; P = 0.008 vs. baseline) individuals in parallel RCT, but it did not affect SBP in normotensive and normolipidaemic individuals (P = 0.51 vs. placebo; P = 0.4 vs. baseline). Although an effect of atorvastatin was detected in hyperlipidaemic individuals, the meta-regression coefficient for the association of low density lipoprotein (LDL)-cholesterol reduction with SBP reduction in the overall population demonstrated that SBP reduction is not dependent on the changes in LDL-cholesterol. A meta-analysis of preclinical reports demonstrated that SBP was reduced in atorvastatin-treated hypertensive and normolipidaemic rats (spontaneously hypertensive rats: P < 0.00001), but not in normotensive and normolipidaemic rats (control rats: P = 0.97). Atorvastatin also reduced the HR in spontaneously hypertensive rat. CONCLUSION: Atorvastatin lowers BP independent of LDL-cholesterol levels. Additional studies are needed to estimate the involvement of the autonomic nervous system in the BP-lowering effect of atorvastatin.
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Hipertensión , Humanos , Ratas , Animales , Atorvastatina/farmacología , Atorvastatina/uso terapéutico , Presión Sanguínea , Frecuencia Cardíaca , Hipertensión/tratamiento farmacológico , ColesterolRESUMEN
The main goal of the present survey was to elaborate, characterize and evaluate the efficiency of ferrite-based nanoparticles modified with cetyltrimethylammonium bromide (CTAB) as potential magnetic nanoadsorbents to remove Remazol Brilliant Blue R (RBBR) from water. It is proposed an innovative nanomaterial architecture based on highly magnetic and chemically stable core@shell nanoparticles covered by an adsorptive surface layer of CTAB (CoFe2O4@γ-Fe2O3@CTAB). Samples of two different mean sizes (7.5 and 14.6â nm) were synthesized using a hydrothermal coprecipitation followed by surface treatment and functionalization. Batch tests were performed to evaluate the influence of contact time, temperature, pH, shaking rate, presence of interferents and mean size on the performance of the proposed nanomaterials. The kinetics of the adsorption process followed the pseudo-second-order model with an equilibrium time of 20â min. The adsorption capacity was estimated by the Langmuir isotherm model and was found to be 56.3â mg/g (smaller size) and 45.6â mg/g (larger size) at pH = 3 and a shaking rate of 400â rpm. The process was spontaneous, exothermic, and showed increased randomness. Sulphate ions negatively impacted the removal of RBBR. The best performance of the nanoadsorbent based on smaller mean sizes can be correlated to its larger surface area. Regeneration and readsorption tests showed that the nanoadsorbents retain more than 80% of their original removal capacity, therefore they can be effectively recycled and reused.
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Statins are successful drugs used to treat hypercholesterolemia, a primary cause of atherosclerosis. In this work, we investigated how hypercholesterolemia and pravastatin treatment impact macrophage and mitochondria functions, the key cell involved in atherogenesis. By comparing bone marrow-derived macrophages (BMDM) of wild-type (WT) and LDL receptor knockout (LDLr-/-) mice, we observed hypercholesterolemia increased the number of contact sites at mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), enhanced mitochondrial hydrogen peroxide release, altered the gene expression of inflammatory markers, and increased oxidized LDL (ox-LDL) uptake and phagocytic activity. Three months of in vivo pravastatin treatment of LDLr-/- mice reversed the number of contact sites at the MAM, ox-LDL uptake, and phagocytosis in LDLr-/- BMDM. Additionally, pravastatin increased BMDM mitochondrial network branching. In peritoneal macrophages (PMs), hypercholesterolemia did not change MAM stability, but stimulated hydrogen peroxide production and modulated gene expression of pro- and anti-inflammatory markers. It also increased mitochondrial branching degree and had no effects on ox-LDL uptake and phagocytosis in PM. Pravastatin treatment increased superoxide anion production and changed inflammation-related gene expression in LDLr-/- PM. In addition, pravastatin increased markedly the expression of the mitochondrial dynamics-related genes Mfn2 and Fis1 in both macrophages. In summary, our results show that hypercholesterolemia and pravastatin treatment affect macrophage mitochondria network structure as well as their interaction with the endoplasmic reticulum (ER). These effects impact on macrophage conversion rates to foam cell and macrophage phagocytic capacity. These findings associate MAM stability changes with known mechanisms involved in atherosclerosis progression and resolution.
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OBJECTIVE: To verify corneal alterations in patients with keratoconus who wear scleral contact lenses (ScCLs), focusing on corneal endothelial assessment. METHODS: Scleral contact lenses were fitted in 22 patients with keratoconus. During a 90-day follow-up, patients were assessed in three visits: at baseline, after 30 days, and after 90 days. Patients underwent visual acuity measurement, slitlamp biomicroscopy of the anterior segment, specular microscopy of the corneal endothelium, corneal pachymetry, measurement of the clearance between the cornea and the lens, and follow-up of ectasia. RESULTS: Variables related to endothelial morphology and pachymetry values did not change significantly over time. Central clearance measurements decreased in the 90-day period. No progression of corneal ectasia was observed, neither were infectious or inflammatory processes in the same period. CONCLUSION: Daily wear of ScCLs in patients with keratoconus was not associated with adverse effects on the cornea or endothelium over a period of 90 days nor was there evidence of disease progression. Central clearance values diminished over that period, but the significance of this observation remains unclear.
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Lentes de Contacto , Queratocono , Lentes de Contacto/efectos adversos , Córnea , Topografía de la Córnea , Dilatación Patológica , Humanos , Queratocono/terapia , EscleróticaRESUMEN
Fridericia chica (Bonpl.) L.G. Lohmann (synonym Arrabidaea chica Verlot) is widely used in Brazilian folk medicine. Considering overcoming pitfalls of scaling up production of plant extracts, herein the effects of N2 atmosphere for extract spray-drying process is reported. Samples were monitored by in vitro antioxidant activity and microbiological evaluation. The drying atmosphere influenced 3-deoxyanthocyanines content when using air as atomizing gas, decreasing carajurin (37.5%) content with concomitant increase in luteolin yield (24.1%). Both drying processes preserved the pharmacological activity. In the cell migration test with HaCaT cells, the extract dried under air flow (5 µg/mL) promoted wound closure by 78% (12 hours) whereas the extract dried using N2 flow promoted 49% (12 hours), with 98% closure (12 hours) for the positive control. The antimicrobial evaluation for Staphylococcus aureus did not differ within drying atmospheres, with MIC (minimum inhibitory concentration) at 0.39 mg/mL. Therefore, the drying process reported herein did not interfere with the biological activity's outcome.
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Bignoniaceae , Antioxidantes/farmacología , Atmósfera , Extractos Vegetales/farmacología , Cicatrización de HeridasRESUMEN
Significance: Altered plasma triglyceride metabolism and changes in dietary fatty acid types and levels are major contributors to the development of metabolic and cardiovascular diseases such as fatty liver disease, obesity, diabetes, and atherosclerosis. Lipid accumulation in visceral adipose tissue and ectopically in other organs, as well as lipid-induced redox imbalance, is connected to mitochondrial dysfunction in a range of oxidative stress-associated metabolic and degenerative disorders. Recent Advances: Successful mitochondrial adaptive responses in the context of hypertriglyceridemia and dietary bioactive polyunsaturated fatty acids contribute to increase body energy expenditure and reduce oxidative stress, thus allowing several cell types to cope with metabolic challenges and stresses. These responses include mitochondrial redox signaling, mild uncoupling, and changes in network dynamic behavior. Critical Issues: Mitochondrial bioenergetics and redox changes in a lipid overload context are relatively well characterized. However, the turning point between adaptive and maladaptive mitochondrial responses remains a critical issue to be elucidated. In addition, the relationship between changes in fusion/fission machinery and mitochondrial function is less well understood. Future Directions: The effective mitochondrial responses described here support the research for new drug design and diet or nutraceutical formulations targeting mitochondrial mild uncoupling and effective quality control as putative strategies for cardiometabolic diseases. Antioxid. Redox Signal. 36, 953-968.
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Hipertrigliceridemia , Mitocondrias , Respiración de la Célula , Metabolismo Energético , Humanos , Hipertrigliceridemia/metabolismo , Lípidos/farmacología , Mitocondrias/metabolismoRESUMEN
Chronic high-glucose levels induce the generation of reactive oxygen species leading to mitochondrial dysfunction, which is one of the pathological triggers in the development of diabetes. This study investigated the alkaloid composition of two fruits of the genus Solanum, fruta-do-lobo (Solanum lycocarpum) and juá-açu (Solanum oocarpum), and their capacity to protect against oxidative damage and defective insulin secretion induced by chronic high-glucose levels. LC-MS and molecular network of fruit crude extracts reveals that juá-açu and fruta-do-lobo contain kukoamines and glycoalkaloids, respectively. Two purification processes were used to enrich those alkaloids. Fruta-do-lobo extract rich in glycoalkaloids showed a strong cytotoxicity effect, however the juá-açu enriched extract was able to protect mitochondrial functionality against glucotoxicity and stimulate insulin secretion even under conditions of hyperglycemia. These results are promising and suggest that juá-açu is a potential source of bioactive compounds for adjuvant/co-adjuvant therapy for diabetes.
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Alcaloides , Solanum , Alcaloides/farmacología , Frutas , Secreción de Insulina , MitocondriasRESUMEN
Chronic opioid use changes brain chemistry in areas related to reward processes, memory, decision-making, and addiction. Both neurons and astrocytes are affected, ultimately leading to dependence. Passiflora incarnata L. (Passifloraceae) is the basis of frequently used herbals to manage anxiety and insomnia, with proven central nervous system depressant effects. Anti-addiction properties of P. incarnata have been reported. The aim of this study was to investigate the effect of a commercial extract of Passiflora incarnata (Sintocalmy®, Aché Laboratory) in the naloxone-induced jumping mice model of morphine withdrawal. In addition, glial fibrillary acidic protein (GFAP) and S100 calcium-binding protein B (S100B) levels were assessed in the frontal cortex and hippocampus, and DNA damage was verified on blood cells. In order to improve solubilization a Sintocalmy methanol extract (SME) was used. SME is mainly composed by flavonoids isovitexin and vitexin. The effects of SME 50, 100 and 200 mg/kg (i.p.) were evaluated in the naloxone-induced withdrawal syndrome in mice. SME 50 and SME 100 mg/kg decreased naloxone-induced jumping in morphine-dependent mice without reducing locomotor activity. No alterations were found in GFAP levels, however SME 50 mg/kg prevented the S100B increase in the frontal cortex and DNA damage. This study shows anti-addiction effects for a commercial standardized extract of P. incarnata and suggests the relevance of proper clinical assessment.
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Ansiolíticos/uso terapéutico , Morfina/efectos adversos , Extractos Vegetales/uso terapéutico , Síndrome de Abstinencia a Sustancias/tratamiento farmacológico , Animales , Daño del ADN/efectos de los fármacos , Proteína Ácida Fibrilar de la Glía/metabolismo , Locomoción/efectos de los fármacos , Masculino , Ratones , Dependencia de Morfina/tratamiento farmacológico , Naloxona/uso terapéutico , Passiflora , Subunidad beta de la Proteína de Unión al Calcio S100/metabolismoRESUMEN
Endothelial dysfunction precedes atherosclerosis and is an independent predictor of cardiovascular events. Cholesterol levels and oxidative stress are key contributors to endothelial damage, whereas high levels of plasma high-density lipoproteins (HDL) could prevent it. Cholesteryl ester transfer protein (CETP) is one of the most potent endogenous negative regulators of HDL-cholesterol. However, whether and to what degree CETP expression impacts endothelial function, and the molecular mechanisms underlying the vascular effects of CETP on endothelial cells, have not been addressed. Acetylcholine-induced endothelium-dependent relaxation of aortic rings was impaired in human CETP-expressing transgenic mice, compared to their non-transgenic littermates. However, endothelial nitric oxide synthase (eNOS) activation was enhanced. The generation of superoxide and hydrogen peroxide was increased in aortas from CETP transgenic mice, while silencing CETP in cultured human aortic endothelial cells effectively decreased oxidative stress promoted by all major sources of ROS: mitochondria and NOX2. The endoplasmic reticulum stress markers, known as GADD153, PERK, and ARF6, and unfolded protein response effectors, were also diminished. Silencing CETP reduced endothelial tumor necrosis factor (TNF) α levels, intercellular cell adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) expression, diminishing monocyte adhesion. These results support the notion that CETP expression negatively impacts endothelial cell function, revealing a new mechanism that might contribute to atherosclerosis.
Asunto(s)
Proteínas de Transferencia de Ésteres de Colesterol/metabolismo , Células Endoteliales/metabolismo , Endotelio Vascular/patología , Endotelio Vascular/fisiopatología , Estrés Oxidativo , Animales , Caveolinas/metabolismo , Moléculas de Adhesión Celular/metabolismo , Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Proteínas de Transferencia de Ésteres de Colesterol/genética , Estrés del Retículo Endoplásmico , Activación Enzimática , Humanos , Ratones Transgénicos , NADPH Oxidasas/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Fosforilación , ARN Mensajero/genética , ARN Mensajero/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Células THP-1 , VasodilataciónRESUMEN
OBJECTIVE: The systemic function of CETP has been well characterized. CETP plasma activity reduces HDL cholesterol and thus increases the risk of atherosclerosis. Here, we investigated whether CETP expression modulate adiposity. METHODS: Body adiposity and energy metabolism related assays and gene/protein expression were compared in CETP transgenic and non-transgenic mice and in hamsters treated with CETP neutralizing antibody. RESULTS: We found that transgenic mice expressing human CETP present less white adipose tissue mass and lower leptinemia than nontransgenic (NTg) littermates. No differences were found in physical activity, food intake, fat fecal excretion, lipogenesis or exogenous lipid accumulation in adipose depots. Nonetheless, adipose lipolysis rates and whole-body energy expenditure were elevated in CETP mice. In accordance, lipolysis-related gene expression and protein content were increased in visceral and brown adipose tissue (BAT). In addition, we verified increased BAT temperature and oxygen consumption. These results were confirmed in two other animal models: 1) hamsters treated with CETP neutralizing antibody and 2) an independent line of transgenic mice expressing simian CETP. CONCLUSIONS: These findings reveal a novel anti-adipogenic role for CETP.