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1.
Biomimetics (Basel) ; 8(7)2023 Nov 07.
Article in English | MEDLINE | ID: mdl-37999172

ABSTRACT

Plant diversity includes over 300,000 species, and leaf structure is one of the main targets of selection, being highly variable in shape and size. On the other hand, the optimization of antenna design has no unique solution to satisfy the current range of applications. We analyzed the foliar geometries of 100 plant species and applied them as a biomimetic design template for microstrip patch antenna systems. From this set, a subset of seven species were further analyzed, including species from tropical and temperate forests across the phylogeny of the Angiosperms. Foliar geometry per species was processed by image processing analyses, and the resultant geometries were used in simulations of the reflection coefficients and the radiation patterns via finite differences methods. A value below -10 dB is set for the reflection coefficient to determine the operation frequencies of all antenna elements. All species showed between 3 and 15 operational frequencies, and four species had operational frequencies that included the 2.4 and 5 GHz bands. The reflection coefficients and the radiation patterns in most of the designs were equal or superior to those of conventional antennas, with several species showing multiband effects and omnidirectional radiation. We demonstrate that plant structures can be used as a biomimetic tool in designing microstrip antenna for a wide range of applications.

2.
Anim Reprod Sci ; 242: 107001, 2022 Jul.
Article in English | MEDLINE | ID: mdl-35660169

ABSTRACT

The aim of this study was to determine the effect of completely or partially replacing fresh foods from the broodstock diet with an experimental diet. During a 40-day period, three dietary treatments were tested on Litopeaneus vannamei broodstock. As part of the first dietary treatment, denoted as "FF", broodstock shrimp were fed only fresh frozen food (squid, polychaete, mussel and Artemia biomass). The second treatment denoted as "ED" was 100% an artificial experimental diet. The third treatment, denoted as MD, comprised both the experimental diet and the fresh-frozen food (only squid and mussel were used). In terms of fertile spawns, females with ≥ 1 spawn, females with ≥ 2 spawn, and fecundity, the MD treatment did not differ significantly from the FF treatment. Fecundity was lowest among females receiving the ED treatment. MD treatment demonstrated equivalent fertility in females, and sperm rate in males to that of the FF treatment. The highest normal sperm rate was found in the ED and MD treatments. As a result, a combination of fresh food and the experimental diet resulted in a more balanced reproduction performance.


Subject(s)
Penaeidae , Animal Feed/analysis , Animals , Diet/veterinary , Frozen Foods , Male
3.
Clin Neurol Neurosurg ; 216: 107223, 2022 May.
Article in English | MEDLINE | ID: mdl-35413637

ABSTRACT

PURPOSE: The presence of verbal auditory hallucinations is often associated with psychotic disorders and rarely is considered as an ictal phenomena. The aim of this paper is to describe the anatomical structures involved in the genesis of this ictal symptom during epileptic seizures and direct cortical stimulation using stereo encephalography (SEEG). METHOD: The case is of a 31-year-old right-handed female, bilateral speech representation, schizophrenia and with drug-resistant epilepsy and focal aware sensory seizures characterized by ictal verbal auditory hallucinations. She was implanted with depth electrodes, and she was monitored using SEEG recordings. RESULTS: She had focal aware sensory seizures characterized by verbal auditory hallucinations, with the following features: hearing numerous voices (both male and/or female), talking at the same time (not able to distinguish how many). The voices were inside her head, consisted of negative content, and lasted up to two minutes. Some of her focal aware sensory seizures evolved to focal motor seizures and rarely progressed to bilateral tonic clonic seizures. Her neurological examination, her brain MRI and her interictal SPECT were unremarkable. Her PET scan identified mild hypo metabolism over the right temporal and right frontal lobes. Her neuropsychological evaluation showed language laterality undetermined but her functional MRI showed bilateral language representation. On her video-EEG, three seizures were captured with a right posterior temporal onset. A subsequent SEEG showed thirteen typical seizures originating from the posterior temporal neocortical region. The cortical stimulation of the right posterior temporo-parietal neocortical region and right amygdala triggered her typical phenomena, which was multiple voices, inside her head, speaking in the second person, negative content, unable to identify gender, in English, and no side lateralization. CONCLUSION: Verbal auditory hallucinations should be analyzed carefully because they can be part of the seizure presentation. Our case supports the localization of these hallucinations in the right posterior neocortical temporal regions.

4.
Anim Reprod Sci ; 228: 106749, 2021 May.
Article in English | MEDLINE | ID: mdl-33865200

ABSTRACT

The aim of this study was to evaluate egg production and quality of females of the Pacific white shrimp, Litopenaeus vannamei, in which there was or was not unilateral eyestalk ablation after there was pre-maturation culturing in biofloc or clear-water systems. Acylglycerides, cholesterol, glucose and total soluble protein were determined for the hepatopancreas, ovaries, hemolymph and eggs. Females cultured using the biofloc system had a larger number of eggs released per spawning and per gram of spawning specimen body weight. The number of total spawning's per week was comparable among treatments. Females cultured in the biofloc system in which there was no eyestalk ablation had that greatest concentrations of nutrient reserves in the hepatopancreas (P < 0.05) with the females cultured in the biofloc and clear-water system that had eye stalk ablation having the next most abundant nutrient reserves. There were the least concentrations of nutrient reserves in females with eyestalk ablation cultured in the clear-water system (P < 0.05). There, however, were no difference in nutrient reserve concentrations in the hemolymph and ovaries. In the eggs, there was the same trend among treatments as the hepatopancreas nutrient reserves, indicating that both eyestalk ablation and pre-maturation culture conditions (i.e., either biofloc or clear-water) affected the quality of eggs in L. vannamei.


Subject(s)
Aquaculture , Ovum/physiology , Penaeidae/physiology , Animals , Female , Hemolymph/physiology , Hepatopancreas/physiology , Ovary/metabolism
5.
J Clin Med ; 8(12)2019 Dec 01.
Article in English | MEDLINE | ID: mdl-31805674

ABSTRACT

Ulcerative colitis is a relatively frequent, chronic disease that impacts significantly the patient's quality of life. Although many therapeutic options are available, additional approaches are needed because many patients either do not respond to current therapies or show significant side effects. Cardiotrophin-1 (CT-1) is a cytokine with potent cytoprotective, anti-inflammatory, and antiapoptotic properties. The purpose of this study was to assess if the administration of CT-1 could reduce colon damage in mice with experimental colitis was induced with 5% dextran sulfate sodium (DSS) in the drinking water. Half of the mice received an i.v. dose of CT-1 (200 µg/kg) 2 h before and 2 and 4 days after DSS administration. Animals were followed during 7 days after DSS administration. The severity of colitis was measured by standard scores. Colon damage was assessed by histology and immunohistochemistry. Inflammatory mediators were measured by Western blot and PCR. CT-1 administration to DSS-treated mice ameliorated both the clinical course (disease activity index), histological damage, inflammation (colon expression of TNF-α, IL-17, IL-10, INF IFN-γ, and iNOS), and apoptosis. Our results suggest that CT-1 administration before induction of colitis improves the clinical course, tissue damage, and inflammation in DSS-induced colitis in mice.

6.
Clin Sci (Lond) ; 132(9): 985-1001, 2018 05 23.
Article in English | MEDLINE | ID: mdl-29572384

ABSTRACT

Cardiotrophin-1 (CT-1) holds potent anti-inflammatory, cytoprotective, and anti-apoptotic effects in the liver, kidneys, and heart. In the present study, the role of endogenous CT-1 and the effect of exogenous CT-1 were evaluated in experimental ulcerative colitis. Colitis was induced in CT-1 knockout and wild-type (WT) mice by administration of dextran sulphate sodium (DSS) in the drinking water during 7 days. CT-1 knockout mice showed higher colon damage and disease severity than WT mice. In addition, CT-1 (200 µg/kg/day, iv) or vehicle (as control) was administered during 3 days to WT, colitic mice, starting on day 4 after initiation of DSS. Disease activity index (DAI), inflammatory markers (tumor necrosis factor α (TNF-α), INFγ, IL-17, IL-10, inducible nitric oxide synthase (iNOS)), colon damage, apoptosis (cleaved caspase 3), nuclear factor κB (NFκB) and STAT-3 activation, and bacterial translocation were measured. Compared with mice treated with DSS, mice also treated with exogenous CT-1 showed lower colon damage, DAI, plasma levels of TNFα, colon expression of TNF-α, INFγ, IL-17, iNOS and cleaved caspase 3, higher NFκB and signal transducer and activator of transcription 3 (STAT3) pathways activation, and absence of bacterial translocation. We conclude that endogenous CT-1 plays a role in the defense and repair response of the colon against ulcerative lesions through an anti-inflammatory and anti-apoptotic effect. Supplementation with exogenous CT-1 ameliorates disease symptoms, which opens a potentially new therapeutic strategy for ulcerative colitis.


Subject(s)
Colitis, Ulcerative/drug therapy , Colitis, Ulcerative/metabolism , Cytokines/blood , Cytokines/therapeutic use , Animals , Colitis, Ulcerative/chemically induced , Cytokines/genetics , Dextran Sulfate , Drug Evaluation, Preclinical , Male , Mice , Mice, Knockout
7.
Comput Biol Med ; 89: 170-180, 2017 10 01.
Article in English | MEDLINE | ID: mdl-28810184

ABSTRACT

Heart sound analysis plays an important role in the auscultative diagnosis process to detect the presence of cardiovascular diseases. In this paper we propose a novel parametric heart sound model that accurately represents normal and pathological cardiac audio signals, also known as phonocardiograms (PCG). The proposed model considers that the PCG signal is formed by the sum of two parts: one of them is deterministic and the other one is stochastic. The first part contains most of the acoustic energy. This part is modeled by the Matching Pursuit (MP) algorithm, which performs an analysis-synthesis procedure to represent the PCG signal as a linear combination of elementary waveforms. The second part, also called residual, is obtained after subtracting the deterministic signal from the original heart sound recording and can be accurately represented as an autoregressive process using the Linear Predictive Coding (LPC) technique. We evaluate the proposed heart sound model by performing subjective and objective tests using signals corresponding to different pathological cardiac sounds. The results of the objective evaluation show an average Percentage of Root-Mean-Square Difference of approximately 5% between the original heart sound and the reconstructed signal. For the subjective test we conducted a formal methodology for perceptual evaluation of audio quality with the assistance of medical experts. Statistical results of the subjective evaluation show that our model provides a highly accurate approximation of real heart sound signals. We are not aware of any previous heart sound model rigorously evaluated as our proposal.


Subject(s)
Algorithms , Cardiovascular Diseases/physiopathology , Heart Sounds , Models, Cardiovascular , Signal Processing, Computer-Assisted , Humans , Phonocardiography
8.
Biochim Biophys Acta ; 1862(9): 1801-14, 2016 09.
Article in English | MEDLINE | ID: mdl-27321931

ABSTRACT

Transforming growth factor beta 1 (TGF-ß1) is one of the most studied cytokines involved in renal tubulo-interstitial fibrosis, which is characterized by myofibroblast abundance and proliferation, and high buildup of extracellular matrix in the tubular interstitium leading to organ failure. Endoglin (Eng) is a 180-kDa homodimeric transmembrane protein that regulates a great number of TGF-ß1 actions in different biological processes, including ECM synthesis. High levels of Eng have been observed in experimental models of renal fibrosis or in biopsies from patients with chronic kidney disease. In humans and mice, two Eng isoforms are generated by alternative splicing, L-Eng and S-Eng that differ in the length and composition of their cytoplasmic domains. We have previously described that L-Eng overexpression promotes renal fibrosis after unilateral ureteral obstruction (UUO). However, the role of S-Eng in renal fibrosis is unknown and its study would let us analyze the possible function of the cytoplasmic domain of Eng in this process. For this purpose, we have generated a mice strain that overexpresses S-Eng (S-ENG(+)) and we have performed an UUO in S-ENG(+) and their wild type (WT) control mice. Our results indicate that obstructed kidney of S-ENG(+) mice shows lower levels of tubulo-interstitial fibrosis, less inflammation and less interstitial cell proliferation than WT littermates. Moreover, S-ENG(+) mice show less activation of Smad1 and Smad2/3 pathways. Thus, S-Eng overexpression reduces UUO-induced renal fibrosis and some associated mechanisms. As L-Eng overexpression provokes renal fibrosis we conclude that Eng-mediated induction of renal fibrosis in this model is dependent on its cytoplasmic domain.


Subject(s)
Endoglin/genetics , Endoglin/metabolism , Kidney/metabolism , Kidney/pathology , Nephritis/prevention & control , Ureteral Obstruction/metabolism , Animals , Cell Proliferation , Collagen Type I/metabolism , Disease Models, Animal , Fibronectins/metabolism , Fibrosis , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Inbred CBA , Mice, Transgenic , Models, Biological , Myofibroblasts/metabolism , Myofibroblasts/pathology , Nephritis/metabolism , Nephritis/pathology , Protein Isoforms/genetics , Protein Isoforms/metabolism , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Signal Transduction , Smad Proteins/metabolism , Transforming Growth Factor beta/metabolism , Up-Regulation , Ureteral Obstruction/complications , Ureteral Obstruction/pathology
10.
Toxicol Lett ; 241: 9-18, 2016 Jan 22.
Article in English | MEDLINE | ID: mdl-26581635

ABSTRACT

Sunitinib (Su) is currently approved for treatment of several malignances. However, along with the benefits of disease stabilization, cardiovascular toxicities have also been increasingly recognized. The aim of this study was to analyze which mechanisms are involved in the cardiotoxicity caused by Su, as well as to explore the potential cardioprotective effects of l-carnitine (LC). To this end, four groups of Wistar rats were used: (1) control; (2) rats treated with 400mg LC/kg/day; (3) rats treated with 25mg Su/kg/day; and (4) rats treated with LC+Su simultaneously. In addition, cultured rat cardiomyocytes were treated with an inhibitor of nuclear factor kappa B (NF-κB), in order to examine the role of this transcription factor in this process. An elevation in the myocardial expression of pro-inflammatory cytokines, together with an increase in the mRNA expression of NF-κB, was observed in Su-treated rats. These results were accompanied by an increase in the expression of pro-fibrotic factors, nitrotyrosine and NOX 2 subunit of NADPH oxidase; and by a decrease in that of collagen degradation factor. Higher blood pressure and heart rate levels were also found in Su-treated rats. All these alterations were inhibited by co-administration of LC. Furthermore, cardiotoxic effects of Su were blocked by NF-κB inhibition. Our results suggest that: (i) inflammatory and fibrotic processes are involved in the cardiac toxicity observed following treatment with Su; (ii) these processes might be mediated by the transcription factor NF-κB; (iii) LC exerts a protective effect against arterial hypertension, cardiac inflammation and fibrosis, which are all observed after Su treatment.


Subject(s)
Antineoplastic Agents/toxicity , Cardiotonic Agents/pharmacology , Carnitine/pharmacology , Heart Diseases/chemically induced , Heart Diseases/prevention & control , Indoles/antagonists & inhibitors , Indoles/toxicity , Myocarditis/chemically induced , Myocarditis/prevention & control , Pyrroles/antagonists & inhibitors , Pyrroles/toxicity , Animals , Blood Pressure/drug effects , Cardiotoxicity , Cytokines/biosynthesis , Endomyocardial Fibrosis/chemically induced , Endomyocardial Fibrosis/pathology , Endomyocardial Fibrosis/prevention & control , Gene Expression/drug effects , Heart Diseases/pathology , Male , Myocarditis/pathology , Myocytes, Cardiac/drug effects , NF-kappa B/metabolism , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Rats , Rats, Wistar , Sunitinib
11.
Cell Mol Life Sci ; 73(8): 1715-39, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26646071

ABSTRACT

The circulatory system is walled off by different cell types, including vascular mural cells and podocytes. The interaction and interplay between endothelial cells (ECs) and mural cells, such as vascular smooth muscle cells or pericytes, play a pivotal role in vascular biology. Endoglin is an RGD-containing counter-receptor for ß1 integrins and is highly expressed by ECs during angiogenesis. We find that the adhesion between vascular ECs and mural cells is enhanced by integrin activators and inhibited upon suppression of membrane endoglin or ß1-integrin, as well as by addition of soluble endoglin (SolEng), anti-integrin α5ß1 antibody or an RGD peptide. Analysis of different endoglin mutants, allowed the mapping of the endoglin RGD motif as involved in the adhesion process. In Eng (+/-) mice, a model for hereditary hemorrhagic telangectasia type 1, endoglin haploinsufficiency induces a pericyte-dependent increase in vascular permeability. Also, transgenic mice overexpressing SolEng, an animal model for preeclampsia, show podocyturia, suggesting that SolEng is responsible for podocytes detachment from glomerular capillaries. These results suggest a critical role for endoglin in integrin-mediated adhesion of mural cells and provide a better understanding on the mechanisms of vessel maturation in normal physiology as well as in pathologies such as preeclampsia or hereditary hemorrhagic telangiectasia.


Subject(s)
Antigens, CD/metabolism , Cell Adhesion/physiology , Endothelium, Vascular/metabolism , Myocytes, Smooth Muscle/metabolism , Podocytes/metabolism , Receptors, Cell Surface/metabolism , Animals , Antigens, CD/genetics , Cell Line, Tumor , Disease Models, Animal , Endoglin , Female , Human Umbilical Vein Endothelial Cells/metabolism , Humans , Integrin beta1/genetics , Jurkat Cells , Male , Mice , Mice, Inbred C57BL , Mice, Nude , Mice, Transgenic , Muscle, Smooth, Vascular/cytology , Muscle, Smooth, Vascular/metabolism , Myocytes, Smooth Muscle/cytology , Neovascularization, Pathologic/metabolism , Pericytes/metabolism , Pre-Eclampsia/genetics , Pre-Eclampsia/pathology , Pregnancy , Protein Binding , RNA Interference , RNA, Small Interfering , Receptors, Cell Surface/genetics , Retina/metabolism , Telangiectasia, Hereditary Hemorrhagic/genetics , Telangiectasia, Hereditary Hemorrhagic/pathology
12.
Nat Med ; 21(9): 989-97, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26236989

ABSTRACT

Progressive kidney fibrosis contributes greatly to end-stage renal failure, and no specific treatment is available to preserve organ function. During renal fibrosis, myofibroblasts accumulate in the interstitium of the kidney, leading to massive deposition of extracellular matrix and organ dysfunction. The origin of myofibroblasts is manifold, but the contribution of an epithelial-to-mesenchymal transition (EMT) undergone by renal epithelial cells during kidney fibrosis is still debated. We show that the reactivation of Snai1 (encoding snail family zinc finger 1, known as Snail1) in mouse renal epithelial cells is required for the development of fibrosis in the kidney. Damage-mediated Snail1 reactivation induces a partial EMT in tubular epithelial cells that, without directly contributing to the myofibroblast population, relays signals to the interstitium to promote myofibroblast differentiation and fibrogenesis and to sustain inflammation. We also show that Snail1-induced fibrosis can be reversed in vivo and that obstructive nephropathy can be therapeutically ameliorated in mice by targeting Snail1 expression. These results reconcile conflicting data on the role of the EMT in renal fibrosis and provide avenues for the design of novel anti-fibrotic therapies.


Subject(s)
Epithelial-Mesenchymal Transition , Kidney/pathology , Transcription Factors/physiology , Animals , Fibrosis , Folic Acid/toxicity , Inflammation/etiology , Male , Mice , Mice, Inbred C57BL , Renal Insufficiency, Chronic/etiology , Snail Family Transcription Factors , Ureteral Obstruction/complications
13.
PLoS One ; 9(10): e110365, 2014.
Article in English | MEDLINE | ID: mdl-25313562

ABSTRACT

Transforming growth factor-ß (TGF-ß) plays a pivotal role in renal fibrosis. Endoglin, a 180 KDa membrane glycoprotein, is a TGF-ß co-receptor overexpressed in several models of chronic kidney disease, but its function in renal fibrosis remains uncertain. Two membrane isoforms generated by alternative splicing have been described, L-Endoglin (long) and S-Endoglin (short) that differ from each other in their cytoplasmic tails, being L-Endoglin the most abundant isoform. The aim of this study was to assess the effect of L-Endoglin overexpression in renal tubulo-interstitial fibrosis. For this purpose, a transgenic mouse which ubiquitously overexpresses human L-Endoglin (L-ENG+) was generated and unilateral ureteral obstruction (UUO) was performed in L-ENG+ mice and their wild type (WT) littermates. Obstructed kidneys from L-ENG+ mice showed higher amounts of type I collagen and fibronectin but similar levels of α-smooth muscle actin (α-SMA) than obstructed kidneys from WT mice. Smad1 and Smad3 phosphorylation were significantly higher in obstructed kidneys from L-ENG+ than in WT mice. Our results suggest that the higher increase of renal fibrosis observed in L-ENG+ mice is not due to a major abundance of myofibroblasts, as similar levels of α-SMA were observed in both L-ENG+ and WT mice, but to the higher collagen and fibronectin synthesis by these fibroblasts. Furthermore, in vivo L-Endoglin overexpression potentiates Smad1 and Smad3 pathways and this effect is associated with higher renal fibrosis development.


Subject(s)
Antigens, CD/genetics , Gene Expression , Kidney Diseases/etiology , Kidney Diseases/pathology , Receptors, Cell Surface/genetics , Ureteral Obstruction/complications , Animals , Collagen/metabolism , Disease Models, Animal , Endoglin , Extracellular Matrix/metabolism , Fibronectins , Fibrosis , Humans , Kidney Diseases/metabolism , Mice , Mice, Transgenic , Myofibroblasts/metabolism , Myofibroblasts/pathology , Signal Transduction/drug effects , Smad Proteins/metabolism , Transforming Growth Factor beta/metabolism
14.
Biomed Res Int ; 2014: 124902, 2014.
Article in English | MEDLINE | ID: mdl-25101263

ABSTRACT

Tubulointerstitial fibrosis is a major feature of chronic kidney disease. Unilateral ureteral obstruction (UUO) in rodents leads to the development of renal tubulointerstitial fibrosis consistent with histopathological changes observed in advanced chronic kidney disease in humans. The purpose of this study was to assess the effect of inhibiting angiotensin II receptors or Ras activation on early renal fibrotic changes induced by UUO. Animals either received angiotensin II or underwent UUO. UUO animals received either losartan, atorvastatin, and farnesyl transferase inhibitor (FTI) L-744,832, or chaetomellic acid A (ChA). Levels of activated Ras, phospho-ERK1/2, phospho-Akt, fibronectin, and α-smooth muscle actin were subsequently quantified in renal tissue by ELISA, Western blot, and/or immunohistochemistry. Our results demonstrate that administration of angiotensin II induces activation of the small GTPase Ras/Erk/Akt signaling system, suggesting an involvement of angiotensin II in the early obstruction-induced activation of renal Ras. Furthermore, upstream inhibition of Ras signalling by blocking either angiotensin AT1 type receptor or by inhibiting Ras prenylation (atorvastatin, FTI o ChA) reduced the activation of the Ras/Erk/Akt signaling system and decreased the early fibrotic response in the obstructed kidney. This study points out that pharmacological inhibition of Ras activation may hold promise as a future strategy in the prevention of renal fibrosis.


Subject(s)
Angiotensin II/administration & dosage , Fibrosis/metabolism , Kidney Diseases/metabolism , Kidney/metabolism , Monomeric GTP-Binding Proteins/metabolism , Angiotensin II/metabolism , Animals , Atorvastatin , Disease Models, Animal , Fibrosis/drug therapy , Fibrosis/physiopathology , Heptanoic Acids/administration & dosage , Humans , Kidney Diseases/drug therapy , Kidney Diseases/physiopathology , Mice , Monomeric GTP-Binding Proteins/antagonists & inhibitors , Pyrroles/administration & dosage , Receptor, Angiotensin, Type 1/metabolism , Signal Transduction/drug effects , Ureteral Obstruction/diet therapy , Ureteral Obstruction/metabolism , Ureteral Obstruction/physiopathology
15.
Am J Hypertens ; 27(3): 460-70, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24413708

ABSTRACT

BACKGROUND: The development of renal fibrosis is a consequence of arterial hypertension. L-carnitine plays an essential role in the ß-oxidation of fatty acids, and we have previously demonstrated hypotensive, antioxidant, and anti-inflammatory effects of L-carnitine in arterial hypertension. This work aims to analyze the effect of L-carnitine on renal fibrosis and to explore the participation of peroxisome-proliferator activated receptor (PPAR)-γ in this effect. METHODS: Four groups or rats were used: control, treated with L-carnitine, treated with L-NAME, and treated with L-carnitine + L-NAME. Cultured rat kidney cells were also used to examine the role of PPAR-γ in L-carnitine effect. RESULTS: An increase in the expression of collagen, transforming growth factor beta 1 (TGF-ß1), connective tissue growth factor (CTGF), Nox2, and Nox4 was found in the kidney of L-NAME-treated rats. Hypertensive rats presented with an expansion of renal fibrotic areas, which was also accompanied by overexpression of proinflammatory cytokines, interleukin (IL)-1ß, and IL-6. A reduction in the expression of PPAR-γ and in that of anti-inflammatory IL-10 was found in the kidney of these rats. Simultaneous treatment with L-carnitine attenuated the renal fibrosis (which correlated with a reduction of plasma TGF-ß1 levels) and the pro-oxidative and proinflammatory status reported in L-NAME groups, with a concomitant increase in the expression of PPAR-γ. Furthermore, the antifibrotic effect of L-carnitine could be blocked by PPAR-γ inhibition. CONCLUSIONS: This study confirms the efficacy of L-carnitine against hypertension-associated renal fibrosis from in vivo and in vitro studies and suggests that the L-carnitine effect occurs in a PPAR-γ-dependent manner.


Subject(s)
Carnitine/pharmacology , Hypertension/drug therapy , Kidney Diseases/prevention & control , Kidney Tubules, Proximal/drug effects , PPAR gamma/drug effects , Animals , Cells, Cultured , Collagen/metabolism , Connective Tissue Growth Factor/metabolism , Cytoprotection , Disease Models, Animal , Enzyme Inhibitors , Fibrosis , Hypertension/chemically induced , Hypertension/metabolism , Hypertension/pathology , Inflammation Mediators/metabolism , Interleukin-10/metabolism , Interleukin-1beta/metabolism , Interleukin-6/metabolism , Kidney Diseases/etiology , Kidney Diseases/metabolism , Kidney Diseases/pathology , Kidney Tubules, Proximal/metabolism , Kidney Tubules, Proximal/pathology , Male , Membrane Glycoproteins/metabolism , NADPH Oxidase 2 , NADPH Oxidase 4 , NADPH Oxidases/metabolism , NG-Nitroarginine Methyl Ester , PPAR gamma/metabolism , Rats , Rats, Wistar , Transforming Growth Factor beta1/metabolism , Up-Regulation
16.
Biochem Pharmacol ; 85(7): 937-44, 2013 Apr 01.
Article in English | MEDLINE | ID: mdl-23295156

ABSTRACT

Cardiac fibrosis is a pathogenic factor in a variety of cardiovascular diseases and is characterized by an abnormal accumulation of extracellular matrix protein that leads to cardiac dysfunction. l-Carnitine (LC) plays an essential role in the ß-oxidation of long-chain fatty acids in lipid metabolism. We have previously demonstrated the beneficial effects of LC in hypertensive rats. The aim of this study was to analyze the effect of LC on arterial hypertension-associated cardiac fibrosis and to explore the mechanisms of LC action. To this end, four groups of rats were used: Wistar (control), rats treated with 400mg/kg/day of LC, rats treated with 25mg/kg/day of l-NAME (to induce hypertension), and rats treated with LC+l-NAME simultaneously. We found an elevation in the myocardial expression of profibrotic factors (TGF-ß1 and CTGF), types I and III of collagen, and NADPH oxidase subunits (NOX2 and NOX4), in hypertensive rats when compared with normotensive ones. In addition, an increase in myocardial fibrosis was also found in the l-NAME group. These results were accompanied by a down-regulation of PPAR-γ in the heart of hypertensive animals. When hypertensive rats were treated with LC, all these alterations were reversed. Moreover, a significant negative correlation was observed between myocardial interstitial fibrosis and mRNA expression of PPAR-γ. In conclusion, the reduction of cardiac fibrosis and the down-regulation of NOX2, NOX4, TGF-ß1 and CTGF induced by LC might be, at least in part, mediated by an upregulation of PPAR-γ, which leads to a reduction on hypertension-related cardiac fibrosis.


Subject(s)
Antihypertensive Agents/pharmacology , Carnitine/pharmacology , Hypertension/drug therapy , Myocardium/pathology , PPAR gamma/metabolism , Animals , Antihypertensive Agents/therapeutic use , Carnitine/chemistry , Carnitine/therapeutic use , Collagen Type I/metabolism , Collagen Type II/metabolism , Connective Tissue Growth Factor/metabolism , Fibrosis , Hypertension/chemically induced , Hypertension/pathology , Male , Membrane Glycoproteins/metabolism , Myocardium/metabolism , NADPH Oxidase 2 , NADPH Oxidase 4 , NADPH Oxidases/metabolism , NG-Nitroarginine Methyl Ester , Rats , Rats, Wistar , Transforming Growth Factor beta1/metabolism
17.
PLoS One ; 7(3): e32516, 2012.
Article in English | MEDLINE | ID: mdl-22427849

ABSTRACT

BACKGROUND: The immunosuppressive mammalian target of rapamycin (mTOR) inhibitors are widely used in solid organ transplantation, but their effect on kidney disease progression is controversial. mTOR has emerged as one of the main pathways regulating cell growth, proliferation, differentiation, migration, and survival. The aim of this study was to analyze the effects of delayed inhibition of mTOR pathway with low dose of everolimus on progression of renal disease and TGFß expression in the 5/6 nephrectomy model in Wistar rats. METHODS: This study evaluated the effects of everolimus (0.3 mg/k/day) introduced 15 days after surgical procedure on renal function, proteinuria, renal histology and mechanisms of fibrosis and proliferation. RESULTS: Everolimus treated group (EveG) showed significantly less proteinuria and albuminuria, less glomerular and tubulointerstitial damage and fibrosis, fibroblast activation cell proliferation, when compared with control group (CG), even though the EveG remained with high blood pressure. Treatment with everolimus also diminished glomerular hypertrophy. Everolimus effectively inhibited the increase of mTOR developed in 5/6 nephrectomy animals, without changes in AKT mRNA or protein abundance, but with an increase in the pAKT/AKT ratio. Associated with this inhibition, everolimus blunted the increased expression of TGFß observed in the remnant kidney model. CONCLUSION: Delayed mTOR inhibition with low dose of everolimus significantly prevented progressive renal damage and protected the remnant kidney. mTOR and TGFß mRNA reduction can partially explain this anti fibrotic effect. mTOR can be a new target to attenuate the progression of chronic kidney disease even in those nephropathies of non-immunologic origin.


Subject(s)
Kidney/drug effects , Nephrectomy/adverse effects , Proteinuria/drug therapy , Sirolimus/analogs & derivatives , TOR Serine-Threonine Kinases/antagonists & inhibitors , Transforming Growth Factor beta/metabolism , Analysis of Variance , Animals , Blotting, Western , Chromatography, High Pressure Liquid , Creatinine/blood , Creatinine/urine , Everolimus , Immunohistochemistry , Proteinuria/etiology , Rats , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Sirolimus/pharmacology , Spectrophotometry
18.
Kidney Int ; 77(10): 861-9, 2010 May.
Article in English | MEDLINE | ID: mdl-20164825

ABSTRACT

The antidiabetic drug metformin can diminish apoptosis induced by oxidative stress in endothelial cells and prevent vascular dysfunction even in nondiabetic patients. Here we tested whether it has a beneficial effect in a rat model of gentamicin toxicity. Mitochondrial analysis, respiration intensity, levels of reactive oxygen species, permeability transition, and cytochrome c release were assessed 3 and 6 days after gentamicin administration. Metformin treatment fully blocked gentamicin-mediated acute renal failure. This was accompanied by a lower activity of N-acetyl-beta-D-glucosaminidase, together with a decrease of lipid peroxidation and increase of antioxidant systems. Metformin also protected the kidney from histological damage 6 days after gentamicin administration. These in vivo markers of kidney dysfunction and their correction by metformin were complemented by in vitro studies of mitochondrial function. We found that gentamicin treatment depleted respiratory components (cytochrome c, NADH), probably due to the opening of mitochondrial transition pores. These injuries, partly mediated by a rise in reactive oxygen species from the electron transfer chain, were significantly decreased by metformin. Thus, our study suggests that pleiotropic effects of metformin can lessen gentamicin nephrotoxicity and improve mitochondrial homeostasis.


Subject(s)
Gentamicins/pharmacology , Hypoglycemic Agents/pharmacology , Metformin/pharmacology , Mitochondria/drug effects , Mitochondria/metabolism , Acetylglucosaminidase/metabolism , Acetylglucosaminidase/pharmacology , Animals , Antioxidants/metabolism , Antioxidants/pharmacology , Apoptosis/drug effects , Cytochrome c Group , Cytochromes c/metabolism , Cytochromes c/pharmacology , Electron Transport/drug effects , Gentamicins/metabolism , Hypoglycemic Agents/metabolism , Kidney/metabolism , Kidney Diseases/metabolism , Kidney Diseases/pathology , Lipid Peroxidation/drug effects , Male , Metformin/metabolism , Mitochondria/physiology , Oxidation-Reduction , Oxidative Stress/drug effects , Permeability , Rats , Reactive Oxygen Species/metabolism , Reactive Oxygen Species/pharmacology
19.
Kidney Int ; 77(6): 509-18, 2010 Mar.
Article in English | MEDLINE | ID: mdl-20032959

ABSTRACT

Tubulointerstitial fibrosis is characterized by the presence of myofibroblasts that contribute to extracellular matrix accumulation. These cells may originate from resident fibroblasts, bone-marrow-derived cells, or renal epithelial cells converting to a mesenchymal phenotype. Ras GTPases are activated during renal fibrosis and play crucial roles in regulating both cell proliferation and TGF-beta-induced epithelial-mesenchymal transition. Here we set out to assess the contribution of Ras to experimental renal fibrosis using the well-established model of unilateral ureteral obstruction. Fifteen days after obstruction, both fibroblast proliferation and inducers of epithelial-mesenchymal transition were lower in obstructed kidneys of H-ras knockout mice and in fibroblast cell lines derived from these mice. Interestingly, fibronectin, collagen I accumulation, overall interstitial fibrosis, and the myofibroblast population were also lower in the knockout than in the wild-type mice. As expected, we found lower levels of activated Akt in the kidneys and cultured fibroblasts of the knockout. Whether Ras inhibition will turn out to prevent progression of renal fibrosis will require more direct studies.


Subject(s)
Fibroblasts/metabolism , Genes, ras , Kidney/pathology , Sequence Deletion , Ureteral Obstruction/metabolism , Animals , Cell Line , Cell Proliferation , Collagen/metabolism , Epithelial Cells/metabolism , Fibronectins/metabolism , Fibrosis/metabolism , Glomerulonephritis/metabolism , Glomerulonephritis/pathology , Male , Mice , Mice, Knockout , Muscle, Smooth/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Transforming Growth Factor beta/metabolism , Ureteral Obstruction/pathology
20.
Cytotherapy ; 11(8): 1041-51, 2009.
Article in English | MEDLINE | ID: mdl-19929468

ABSTRACT

BACKGROUND AIMS: The aim of this study was to compare prospectively the vasculogenic capacity of two cell sources, monocytes and CD133+ cells. METHODS: Cells were obtained from healthy donors by adherence or magnetic selection. Animals studies were performed in a model of hind limb ischemia and different groups were established according to type and number of cells infused. Revascularization was measured by sequential blood flow analysis using a laser Doppler device and by assessing capillary density in the ischemic muscles. In order to locate the infused cells, immunofluorescence and immunocytochemistry techniques were performed and analyzed by light and confocal microscopy. RESULTS: During the study period there was a significant improvement in both limb perfusion and capillary density in mice treated with either human monocytes or CD133+ cells (P<0.05) compared with non-treated mice. No cells were detected as incorporated into the vessels when 1 x 10(5) cells were used but with higher doses (1 x 10(6)) a few human cells were observed integrated into the vessels in both groups of treated mice. Supernatants of both cell types showed vascular endothelial growth factor (VEGF), epidermal growth factor (EGF) and platelet-derived growth factor- AB (PDGF-AB) expression. CONCLUSIONS: Treatment with human monocytes or CD133+ cells improves blood perfusion and capillary density in a murine model and both cell types seem to stimulate vasculogenesis in a fairly similar way.


Subject(s)
Antigens, CD/metabolism , Glycoproteins/metabolism , Hindlimb/blood supply , Hindlimb/pathology , Ischemia/pathology , Monocytes/cytology , Neovascularization, Physiologic , Peptides/metabolism , AC133 Antigen , Angiogenesis Inducing Agents/metabolism , Animals , Capillaries/pathology , Cell Movement , Disease Models, Animal , Enzyme-Linked Immunosorbent Assay , Humans , Immunophenotyping , Laser-Doppler Flowmetry , Mice , Microscopy, Confocal , Muscles/pathology , Perfusion , Phenotype , Regional Blood Flow , Staining and Labeling
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