RESUMO
PURPOSE: The use of sex steroids by trans people has been of paramount importance regarding body changes during gender transition. The objective of this study was to assess the effects of an injectable steroid combination frequently used by transwomen, namely estradiol enanthate with dihydroxyprogesterone acetophenide (E2EN/DHPA), on blood pressure and metabolic outcomes using an animal model. METHODS: Two-month-old male Wistar rats were orchiectomized or sham-operated and divided into groups: (1) Sham treated with sesame oil vehicle (SG), (2) sham treated with E2EN/DHPA (SP), (3) orchiectomized rats treated with vehicle (OG), and (4) orchiectomized rats treated with E2EN/DHPA (OP), with all groups treated every 10 days for 5 months. We evaluated systolic blood pressure (SBP), body weight (BW), abdominal circumference, nasoanal length (NAL), food and water intake (FI, WI), lipid profile (triglycerides, LDL, and HDL), serum C-reactive protein (CRP), plasma concentrations of urea (URpl) and creatinine (CRpl), 24 h urinary volume (V24 h), sodium and potassium excretion (UNa+, UK+), and proteinuria. RESULTS: E2EN/DHPA administration reduced BW (SP 324.5 ± 31.1; OP 291.7 ± 41.3 g) and NAL (SP 24.5 ± 0.4; OP 24.6 ± 1.0 cm), without changing blood pressure, but increased URpl concentration (SP 55.0 ± 4.8; OP 42.5 ± 8.8 mg/dL) and CRpl (SP 0.47 ± 0.05; OP 0.46 ± 0.04 mg/dL), sodium (SP 3.1 ± 0.8; OP 3.3 ± 0.4 µEq/min/kg), potassium (SP 0.91 ± 0.22; OP 0.94 ± 0.22 µEq/min/kg) excretions and urinary volume (SP 15.5 ± 2.1; OP 16.4 ± 2.9 mL/24 h). CONCLUSION: Cross-sex hormone therapy with E2EN/DHPA significantly modified body characteristics in male rats, producing a feminizing change without altering blood pressure or generating harmful metabolic parameters, but larger translational studies are still needed.
Assuntos
Progestinas , Roedores , Animais , Pressão Sanguínea/fisiologia , Peso Corporal , Estrogênios/farmacologia , Humanos , Masculino , Potássio/farmacologia , Progestinas/farmacologia , Ratos , Ratos Wistar , SódioRESUMO
P2X7 receptor promotes inflammatory response and neuropathic pain. New drugs capable of impairing inflammation and pain-reducing adverse effects extracted from plant extracts have been studied. Physalis angulate L. possesses traditional uses and exhibits antiparasitic, anti-inflammatory, antimicrobial, antinociceptive, antimalarial, antileishmanial, immunosuppressive, antiasthmatic. diuretic, and antitumor activities. The most representative phytochemical constituents identified with medicinal importance are the physalins and withanolides. However, the mechanism of anti-inflammatory action is scarce. Although some physalins and withanolides subtypes have anti-inflammatory activity, only four physalins subtypes (B, D, F, and G) have further studies. Therefore, we evaluated the crude ethanolic extract enriched with physalins B, D, F, and G from P. angulata leaves, a pool containing the physalins B, D, F, G, and the physalins individually, as P2X7 receptor antagonists. For this purpose, we evaluated ATP-induced dye uptake, macroscopic currents, and interleukin 1-ß (IL-1ß) in vitro. The crude extract and pool dose-dependently inhibited P2X7 receptor function. Thus, physalin B, D, F, and G individually evaluated for 5'-triphosphate (ATP)-induced dye uptake assay, whole-cell patch-clamp, and cytokine release showed distinct antagonist levels. Physalin D displayed higher potency and efficacy than physalin B, F, and G for all these parameters. In vivo mice model as ATP-induced paw edema was potently inhibited for physalin D, in contrast to physalin B, F, and G. ATP and lipopolysaccharide (LPS)-induced pleurisy in mice were reversed for physalin D treatment. Molecular modeling and computational simulation predicted the intermolecular interactions between the P2X7 receptor and physalin derivatives. In silico results indicated physalin D and F as a potent allosteric P2X7 receptor antagonist. These data confirm physalin D as a promisor source for developing a new P2X7 receptor antagonist with anti-inflammatory action.
Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Physalis/química , Extratos Vegetais/farmacologia , Secoesteroides/farmacologia , Lesão Pulmonar Aguda/fisiopatologia , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Simulação por Computador , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Masculino , Camundongos , Modelos Moleculares , Extratos Vegetais/administração & dosagem , Folhas de Planta , Antagonistas do Receptor Purinérgico P2X/administração & dosagem , Antagonistas do Receptor Purinérgico P2X/isolamento & purificação , Antagonistas do Receptor Purinérgico P2X/farmacologia , Receptores Purinérgicos P2X7/efeitos dos fármacos , Secoesteroides/isolamento & purificaçãoRESUMO
Anaphylactic shock can be defined as an acute syndrome, and it is the most severe clinical manifestation of allergic diseases. Anaphylactoid reactions are similar to anaphylactic events but differ in the pathophysiological mechanism. Nitric oxide (NO) inhibitors during anaphylaxis suggest that NO might decrease the signs and symptoms of anaphylaxis but exacerbate associated vasodilation. Therefore, blocking the effects of NO on vascular smooth muscle by inhibiting the guanylate cyclase (GC) would be a reasonable strategy. This study aimed to investigate the effects of NO/cGMP pathway inhibitors methylene blue (MB), Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME), and indigo carmine (IC) in shock induced by compound 48/80 (C48/80) in rats. The effect was assessed by invasive blood pressure measurement. Shock was initiated by C48/80 intravenous bolus injection 5 min before (prophylactic) or after (treatment) the administration of the inhibitors MB (3 mg/kg), L-NAME (1 mg/kg), and IC (3 mg/kg). Of the groups that received drugs as prophylaxis for shock, only the IC group did not present the final systolic blood pressure (SBP) better than the C48/80 group. Regarding shock treatment with the drugs tested, all groups had the final SBP similar to the C48/80group. Altogether, our results suggested that inhibition of GC and NO synthase in NO production pathway was not sufficient to revert hypotension or significantly improve survival.
Assuntos
Anafilaxia/tratamento farmacológico , GMP Cíclico/antagonistas & inibidores , Inibidores Enzimáticos/administração & dosagem , Músculo Liso Vascular/efeitos dos fármacos , Óxido Nítrico/antagonistas & inibidores , Animais , Modelos Animais de Doenças , Índigo Carmim/administração & dosagem , Masculino , Azul de Metileno/administração & dosagem , NG-Nitroarginina Metil Éster/administração & dosagem , Ratos , Ratos WistarRESUMO
Melanoma is a form of skin cancer with high mortality owing to its fast progression and metastatic capacity. The treatments available nowadays are only palliative in advanced stages of the disease. Thus, alternative therapies for cancer treatment are in demand, and molecules from natural sources, such as polysaccharides, could represent new possible therapeutic approaches. Polysaccharides of freshwater and marine algae with biological activities, such as antitumor properties, are greatly reported in the scientific literature. In the present study, a sulfated heterorhamnan obtained from the green seaweed Gayralia brasiliensis (Gb1 fraction) was chemically characterized and its biological activities in the B16-F10 murine melanoma cell line were evaluated. The Gb1 polysaccharidic fraction tested concentrations presented low or absence of cytotoxicity to B16-F10 cells and neither cell proliferation nor cell cycle were altered. Interestingly, Gb1 treatment decreased B16-F10 cells migration and invasion capabilities and CD44 labeling, showing to be a promising compound for further in vitro and in vivo antitumor studies.
Assuntos
Clorófitas/química , Desoxiaçúcares/farmacologia , Mananas/farmacologia , Melanoma/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Movimento Celular , Desoxiaçúcares/toxicidade , Mananas/toxicidade , Camundongos , Invasividade Neoplásica , SulfatosRESUMO
Anaphylactic shock can be defined as an acute syndrome, and it is the most severe clinical manifestation of allergic diseases. Anaphylactoid reactions are similar to anaphylactic events but differ in the pathophysiological mechanism. Nitric oxide (NO) inhibitors during anaphylaxis suggest that NO might decrease the signs and symptoms of anaphylaxis but exacerbate associated vasodilation. Therefore, blocking the effects of NO on vascular smooth muscle by inhibiting the guanylate cyclase (GC) would be a reasonable strategy. This study aimed to investigate the effects of NO/cGMP pathway inhibitors methylene blue (MB), Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME), and indigo carmine (IC) in shock induced by compound 48/80 (C48/80) in rats. The effect was assessed by invasive blood pressure measurement. Shock was initiated by C48/80 intravenous bolus injection 5 min before (prophylactic) or after (treatment) the administration of the inhibitors MB (3 mg/kg), L-NAME (1 mg/kg), and IC (3 mg/kg). Of the groups that received drugs as prophylaxis for shock, only the IC group did not present the final systolic blood pressure (SBP) better than the C48/80 group. Regarding shock treatment with the drugs tested, all groups had the final SBP similar to the C48/80group. Altogether, our results suggested that inhibition of GC and NO synthase in NO production pathway was not sufficient to revert hypotension or significantly improve survival.
Assuntos
Animais , Masculino , Ratos , GMP Cíclico/antagonistas & inibidores , Inibidores Enzimáticos/administração & dosagem , Anafilaxia/tratamento farmacológico , Músculo Liso Vascular/efeitos dos fármacos , Óxido Nítrico/antagonistas & inibidores , Ratos Wistar , NG-Nitroarginina Metil Éster/administração & dosagem , Modelos Animais de Doenças , Índigo Carmim/administração & dosagem , Azul de Metileno/administração & dosagemRESUMO
Purinergic receptors are widespread in the human organism and are involved in several physiological functions like neurotransmission, nociception, platelet aggregation, etc. In the immune system, they may regulate the expression and release of pro-inflammatory factors as well as the activation and death of several cell types. It is already described the participation of some purinergic receptors in the inflammation and pathological processes, such as a few neglected tropical diseases (NTDs) which affect more than 1 billion people in the world. Although the high social influence those diseases represent endemic countries, most of them do not have an efficient, safe or affordable drug treatment. In that way, this review aims to discuss the current literature involving purinergic receptor and immune response to NTDs pathogens, which may contribute in the search for new therapeutic possibilities.
Assuntos
Doenças Negligenciadas/tratamento farmacológico , Receptores Purinérgicos/metabolismo , Medicina Tropical/métodos , Animais , Humanos , Imunidade , Inflamação , Terapia de Alvo Molecular/métodos , Doenças Negligenciadas/imunologia , Doenças Negligenciadas/patologia , Transdução de Sinais/efeitos dos fármacosRESUMO
Objectives The objective of this paper is to perform an ultrasonography (US) analysis of hands and wrists in two groups of patients with systemic lupus erythematosus (SLE), with and without Jaccoud's arthropathy, matched by age and disease duration and to correlate them with levels of CXCL13 clinical features, laboratory tests and disease activity score. Methods Sixty-four patients with SLE were enrolled, 32 with and 32 without Jaccoud's arthropathy. Each patient underwent physical examination, laboratory tests (including CXCL13 by ELISA) and bilateral US. Synovial hypertrophy, tenosynovitis and erosions were evaluated according to a semiquantitative grading system with a 0-3 rating. US findings were correlated with serum levels of CXCL13, other serological parameters and disease activity index. Results Synovitis was found in 25/64 patients (39%) and tenosynovitis in 14/64 (22%). These findings were more frequent in SLE patients with Jaccoud's arthropathy, particularly tenosynovitis ( p = 0.002) and synovitis ( p = 0.01). Median serum level of CXCL13 was 20.16 pg/ml in the whole population (23.21 pg/ml in the Jaccoud's arthropathy group and 11.48 pg/ml in the group without). There was an association between the presence of disease activity and high level of CXCL13 ( p = 0.004). However, no association was found between high levels of CXCL13 and "arthritis" in SLEDAI, swollen joints on physical examination or synovitis on US. Conclusions US findings in joints of SLE patients with Jaccoud's arthropathy confirm that synovitis and tenosynovitis are common in these patients. In addition, serum level of CXCL13 is associated with disease activity in SLE but does not seem to be a biomarker for arthritis in these patients.
Assuntos
Quimiocina CXCL13/sangue , Articulações dos Dedos/diagnóstico por imagem , Artropatias/diagnóstico por imagem , Lúpus Eritematoso Sistêmico/sangue , Articulação Metacarpofalângica/diagnóstico por imagem , Ultrassonografia , Adulto , Biomarcadores/sangue , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Artropatias/sangue , Artropatias/imunologia , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/imunologia , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Fatores de Risco , Índice de Gravidade de Doença , Sinovite/sangue , Sinovite/diagnóstico por imagem , Sinovite/imunologia , Tenossinovite/sangue , Tenossinovite/diagnóstico por imagem , Tenossinovite/imunologiaRESUMO
The objective was to evaluate the effect of in ovo feeding with glycerol on post-hatch development in broiler chicks. A total of 408 fertile eggs were divided into six experimental groups consisting of five 0.9% saline solutions containing various concentrations of glycerol (12.5, 25.0, 37.5 and 50.0 nmol/ml), and a placebo group (inoculation with saline only) and a control group (without inoculation). Inoculations were performed at 17 days of incubation for the evaluation of hatchability, embryo mortality, body and viscera weights, intestinal epithelium morphometry, blood glucose and liver glycerol kinase activity of chicks at hatching. Inoculation of solutions containing glycerol did not influence body weight at hatching and relative weights of liver, pancreas, intestine and breast. There was a quadratic effect of glycerol levels on the weights of yolk residue and gizzard and on blood glucose, and an increasing linear effect on spleen and heart weights. Higher duodenum and ileum villous height and deeper jejunum and ileum crypts were obtained with 50.0 nmol/ml of glycerol. A linear increasing effect was also observed in liver glycerol kinase activity; however, lower blood glucose was observed with 37.5 and 50 nmol/ml of glycerol. It is therefore concluded that glycerol may be used at doses of 25 nmol/ml as a substrate in in ovo feeding of broiler chickens. However, further studies must be conducted not only to establish an optimal dose but also to evaluate the combination of this substrate with other nutrients used in the in ovo feeding.
Assuntos
Galinhas/crescimento & desenvolvimento , Glicerol/administração & dosagem , Animais , Embrião de Galinha , Relação Dose-Resposta a Droga , Injeções , Intestinos/anatomia & histologia , Intestinos/efeitos dos fármacos , Fígado/anatomia & histologia , Fígado/efeitos dos fármacos , Músculo Esquelético/anatomia & histologia , Músculo Esquelético/efeitos dos fármacos , Óvulo , Pâncreas/anatomia & histologia , Pâncreas/efeitos dos fármacosRESUMO
Artificial lights are essential for controlling the reproductive tract development of birds during puberty and therefore influence reproductive quality. The aim of this study was to evaluate the effect of different light sources on reproductive anatomic and physiological characteristics of female Japanese quail (Coturnix coturnix japonica). A total of 270 birds from one day of age were housed in a masonry shed divided into six rooms with light isolation. Each room was equipped with a different type of light bulb and contained seven cages with five birds in each. The light bulbs tested were: incandescent; compact fluorescent; and light-emitting diode (LED) in the colors white, blue, red and green. The experimental design was completely randomized with six treatments and seven replications of individual birds each. The anatomic and physiological condition of the birds was evaluated at four, eight and 12 weeks of age. The white LED bulb advanced (P<0.05) the sexual maturity by one week, resulted (P<0.05) in higher live weights and greater weight and relative percentage of ovarian stroma, oviduct and ovarian tissue at eight weeks of age. Higher plasma concentrations of estradiol and lipids were also observed (P<0.05) at eight weeks under the white LED bulb. At 12 weeks of age, the magnum and isthmus folding characteristics were better (P<0.05) with the red LED bulb. In conclusion, the photostimulation with the white LED bulb was more efficient at activating the reproductive cycle, hastening the onset of sexual maturity and increasing the development of reproductive organs after puberty.
Assuntos
Coturnix/anatomia & histologia , Luz , Animais , Cor , Coturnix/fisiologia , Feminino , Genitália Feminina/anatomia & histologia , Genitália Feminina/crescimento & desenvolvimento , Genitália Feminina/fisiologia , Genitália Feminina/efeitos da radiação , Ovário/crescimento & desenvolvimento , Ovário/efeitos da radiação , Oviductos/crescimento & desenvolvimento , Oviductos/efeitos da radiação , Maturidade Sexual/efeitos da radiaçãoRESUMO
Ion channels allow for rapid ion diffusion through the plasma membrane. In some conditions, ion channels induce changes in the critical plasma membrane permeability that permit 900-Da solutes to enter cells. This process is known as the pore phenomenon. Some transient receptor potential (TRP) channel subtypes have been highlighted such as the P2X7 receptor, plasma membrane VDAC-1 channel, and pannexin hemichannels. The TRP ion channels are considered multimodal transducers that respond to several kinds of stimuli. In addition, many TRP channel subtypes are involved in physiological and pathophysiological processes such as inflammation, pain, and cancer. The TRPA1, TRPM8, and TRPV1-4 subtypes have been shown to promote large-molecular-weight solute uptake, including impermeable fluorescent dyes, QX-314 hydrophilic lidocaine derivative, gabapentin, and antineoplastic drugs. This review discusses the current knowledge of TRP-associated pores and encourages scientists to study their features and explore them as novel therapeutic tools.
Assuntos
Permeabilidade da Membrana Celular , Canais Iônicos de Abertura Ativada por Ligante/metabolismo , Potenciais da Membrana , Canais de Ânion Dependentes de Voltagem/metabolismo , Animais , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Transporte de Íons , Proteínas de Neoplasias/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Dor/tratamento farmacológico , Dor/metabolismoRESUMO
Metabolic acidosis has profound effects on vascular tone. This study investigated the in vivo effects of acute metabolic acidosis (AMA) and chronic metabolic acidosis (CMA) on hemodynamic parameters and endothelial function. CMA was induced by ad libitum intake of 1% NH4Cl for 7 days, and AMA was induced by a 3-h infusion of 6 M NH4Cl (1 mL/kg, diluted 1:10). Phenylephrine (Phe) and acetylcholine (Ach) dose-response curves were performed by venous infusion with simultaneous venous and arterial blood pressure monitoring. Plasma nitrite/nitrate (NOx) was measured by chemiluminescence. The CMA group had a blood pH of 7.15±0.03, which was associated with reduced bicarbonate (13.8±0.98 mmol/L) and no change in the partial pressure of arterial carbon dioxide (PaCO2). The AMA group had a pH of 7.20±0.01, which was associated with decreases in bicarbonate (10.8±0.54 mmol/L) and PaCO2 (47.8±2.54 to 23.2±0.74 mmHg) and accompanied by hyperventilation. Phe or ACh infusion did not affect arterial or venous blood pressure in the CMA group. However, the ACh infusion decreased the arterial blood pressure (ΔBP: -28.0±2.35 mm Hg [AMA] to -4.5±2.89 mmHg [control]) in the AMA group. Plasma NOx was normal after CMA but increased after AMA (25.3±0.88 to 31.3±0.54 µM). These results indicate that AMA, but not CMA, potentiated the Ach-induced decrease in blood pressure and led to an increase in plasma NOx, reinforcing the effect of pH imbalance on vascular tone and blood pressure control.
Assuntos
Acetilcolina/administração & dosagem , Acidose/fisiopatologia , Pressão Sanguínea/efeitos dos fármacos , Endotélio Vascular/fisiopatologia , Hipotensão/induzido quimicamente , Desequilíbrio Ácido-Base/metabolismo , Acidose/induzido quimicamente , Acidose/metabolismo , Doença Aguda , Animais , Bicarbonatos/sangue , Pressão Sanguínea/fisiologia , Determinação da Pressão Arterial , Dióxido de Carbono/análise , Doença Crônica , Endotélio Vascular/metabolismo , Hemodinâmica/fisiologia , Hiperventilação/metabolismo , Luminescência , Masculino , Nitratos/sangue , Óxido Nítrico/metabolismo , Nitritos/sangue , CoelhosRESUMO
Metabolic acidosis has profound effects on vascular tone. This study investigated the in vivo effects of acute metabolic acidosis (AMA) and chronic metabolic acidosis (CMA) on hemodynamic parameters and endothelial function. CMA was induced by ad libitum intake of 1% NH4Cl for 7 days, and AMA was induced by a 3-h infusion of 6 M NH4Cl (1 mL/kg, diluted 1:10). Phenylephrine (Phe) and acetylcholine (Ach) dose-response curves were performed by venous infusion with simultaneous venous and arterial blood pressure monitoring. Plasma nitrite/nitrate (NOx) was measured by chemiluminescence. The CMA group had a blood pH of 7.15±0.03, which was associated with reduced bicarbonate (13.8±0.98 mmol/L) and no change in the partial pressure of arterial carbon dioxide (PaCO2). The AMA group had a pH of 7.20±0.01, which was associated with decreases in bicarbonate (10.8±0.54 mmol/L) and PaCO2 (47.8±2.54 to 23.2±0.74 mmHg) and accompanied by hyperventilation. Phe or ACh infusion did not affect arterial or venous blood pressure in the CMA group. However, the ACh infusion decreased the arterial blood pressure (ΔBP: -28.0±2.35 mm Hg [AMA] to -4.5±2.89 mmHg [control]) in the AMA group. Plasma NOx was normal after CMA but increased after AMA (25.3±0.88 to 31.3±0.54 μM). These results indicate that AMA, but not CMA, potentiated the Ach-induced decrease in blood pressure and led to an increase in plasma NOx, reinforcing the effect of pH imbalance on vascular tone and blood pressure control.
Assuntos
Animais , Masculino , Coelhos , Acetilcolina/administração & dosagem , Acidose/fisiopatologia , Pressão Sanguínea/efeitos dos fármacos , Endotélio Vascular/fisiopatologia , Hipotensão/induzido quimicamente , Doença Aguda , Desequilíbrio Ácido-Base/metabolismo , Acidose/induzido quimicamente , Acidose/metabolismo , Determinação da Pressão Arterial , Bicarbonatos/sangue , Pressão Sanguínea/fisiologia , Doença Crônica , Dióxido de Carbono/análise , Endotélio Vascular/metabolismo , Hemodinâmica/fisiologia , Hiperventilação/metabolismo , Luminescência , Nitratos/sangue , Óxido Nítrico/metabolismo , Nitritos/sangueRESUMO
Erythropoietin (EPO) has been well characterized as a renal glycoprotein hormone regulating red blood cell production by inhibiting apoptosis of erythrocyte progenitors in hematopoietic tissues. EPO exerts regulatory effects in cardiac and skeletal muscles. Duchenne muscular dystrophy is a lethal degenerative disorder of skeletal and cardiac muscle. In this study, we tested the possible therapeutic beneficial effect of recombinant EPO (rhEPO) in dystrophic muscles in mdx mice. Total strength was measured using a force transducer coupled to a computer. Gene expression for myostatin, transforming growth factor-β1 (TGF-β1), and tumor necrosis factor-α (TNF-α) was determined by quantitative real time polymerase chain reaction. Myostatin expression was significantly decreased in quadriceps from mdx mice treated with rhEPO (rhEPO=0.60±0.11, control=1.07±0.11). On the other hand, rhEPO had no significant effect on the expression of TGF-β1 (rhEPO=0.95±0.14, control=1.05±0.16) and TNF-α (rhEPO=0.73±0.20, control=1.01±0.09). These results may help to clarify some of the direct actions of EPO on skeletal muscle.
Assuntos
Animais , Masculino , Regulação para Baixo/efeitos dos fármacos , Eritropoetina/uso terapêutico , Expressão Gênica/efeitos dos fármacos , Distrofia Muscular de Duchenne/tratamento farmacológico , Miostatina/metabolismo , Proteínas Recombinantes/uso terapêutico , Modelos Animais de Doenças , Distrofina/deficiência , Camundongos Endogâmicos mdx , Força Muscular/efeitos dos fármacos , Músculo Esquelético/metabolismo , Distrofia Muscular de Duchenne/metabolismo , Miostatina/genética , Fenótipo , Reação em Cadeia da Polimerase em Tempo Real , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Erythropoietin (EPO) has been well characterized as a renal glycoprotein hormone regulating red blood cell production by inhibiting apoptosis of erythrocyte progenitors in hematopoietic tissues. EPO exerts regulatory effects in cardiac and skeletal muscles. Duchenne muscular dystrophy is a lethal degenerative disorder of skeletal and cardiac muscle. In this study, we tested the possible therapeutic beneficial effect of recombinant EPO (rhEPO) in dystrophic muscles in mdx mice. Total strength was measured using a force transducer coupled to a computer. Gene expression for myostatin, transforming growth factor-ß1 (TGF-ß1), and tumor necrosis factor-α (TNF-α) was determined by quantitative real time polymerase chain reaction. Myostatin expression was significantly decreased in quadriceps from mdx mice treated with rhEPO (rhEPO = 0.60 ± 0.11, control = 1.07 ± 0.11). On the other hand, rhEPO had no significant effect on the expression of TGF-ß1 (rhEPO = 0.95 ± 0.14, control = 1.05 ± 0.16) and TNF-α (rhEPO = 0.73 ± 0.20, control = 1.01 ± 0.09). These results may help to clarify some of the direct actions of EPO on skeletal muscle.
Assuntos
Regulação para Baixo/efeitos dos fármacos , Eritropoetina/uso terapêutico , Expressão Gênica/efeitos dos fármacos , Distrofia Muscular de Duchenne/tratamento farmacológico , Miostatina/metabolismo , Proteínas Recombinantes/uso terapêutico , Animais , Modelos Animais de Doenças , Distrofina/deficiência , Masculino , Camundongos Endogâmicos mdx , Força Muscular/efeitos dos fármacos , Músculo Esquelético/metabolismo , Distrofia Muscular de Duchenne/metabolismo , Miostatina/genética , Fenótipo , Reação em Cadeia da Polimerase em Tempo Real , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The P2X7 receptor (P2X7R), an ATP-gated cation channel, is expressed predominantly in leukocytes. Activation of P2X7R has been implicated in the formation of a cytolytic pore (i.e., a large conductance channel) that allows the passage of molecules up to 900 Da in macrophages. At least two hypotheses have been presented to explain the conversion of a nonselective cation channel to a cytolytic pore. One hypothesis suggests that the pore is a separate molecular structure activated by P2X7R, and the second asserts that this is an intrinsic property of P2X7R (pore dilation). Based on connexin knockout and hemichannel antagonist studies, some groups have concluded that connexins and pannexins, the hemichannel-forming proteins in vertebrates, are fundamental components of the large conductance channel associated with P2X7R. Dye uptake and electrophysiology experiments were used to evaluate the efficacy and specificity of some hemichannel antagonists under conditions known to open the large conductance channel associated with P2X7R. Hemichannel antagonists and interference RNA (RNAi) targeting pannexin-1 did not affect P2X7R macroscopic currents [ATP, 1,570±189 pA; ATP+100 µM carbenoxolone (CBX), 1,498±100 pA; ATP+1 mM probenecid (Prob), 1,522±9 pA] or dye uptake in a FACS assay (ATP, 63±5%; ATP+100 µM CBX, 51.51±8.4%; ATP+1 mM Prob, 57.7±4.3%) in mouse macrophages. These findings strongly suggest that the high-permeability pore evident after prolonged P2X7R activation does not occur through connexin or pannexin hemichannels in murine macrophages. Another membrane protein may be involved in P2X7R pore formation.
Assuntos
Conexinas/fisiologia , Macrófagos Peritoneais/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Receptores Purinérgicos P2X7/fisiologia , Trifosfato de Adenosina/farmacologia , Animais , Linhagem Celular , Células Cultivadas , Masculino , Camundongos , Antagonistas do Receptor Purinérgico P2X/farmacologia , Ratos , Ratos WistarRESUMO
The congenital muscular dystrophies (CMD) are heterogeneous muscular diseases with early and dystrophic pattern on muscle biopsy. Many different subtypes have been genetically identified and most phenotypes not yet identified belong to the merosin-positive (MP) CMD subgroup. OBJECTIVE: To analyze the immunohistochemical expression of the main proteins of the dystrophin-glycoproteins associated complex in muscle biopsy of patients with different CMD phenotypes, for investigating a possible correlation with clinical and histopathological data. METHOD: Fifty-nine patients with CMD had clinical, histopathological and immunohistochemical data evaluated: 32 had MP-CMD, 23 CMD with merosin deficiency (MD-CMD), one Ullrich phenotype and three Walker-Warburg disease. RESULTS: Dystrophin and dysferlin were normal in all; among the patients with MD-CMD, merosin deficiency was partial in nine who showed the same clinical severity as those with total deficiency; the reduced expression of alpha-sarcoglycan (SG) and alpha-dystroglycan (DG) showed statistically significant correlation with severe MD-CMD phenotype. CONCLUSION: There is a greater relationship between merosin and the former proteins; among MP-CMD patients, no remarkable immunohistochemical/phenotypical correlations were found, although the reduced expression of beta-DG had showed statistically significant correlation with severe phenotype and marked fibrosis on muscular biopsy.
A distrofia muscular congênita (DMC) é doença muscular heterogênea, de início precoce e padrão histopatológico de distrofia. Diversos subtipos foram geneticamente identificados e os fenótipos ainda não identificados pertencem em geral ao subgrupo de DMC merosina-positiva (MP). OBJETIVO: Analisar a expressão imuno-histoquímica das principais proteínas do complexo distrofina-glicoproteínas associadas na biópsia muscular de pacientes com diferentes fenótipos de DMC, a fim de investigar uma eventual correlação com o quadro clínico e histopatológico. MÉTODO: Cinqüenta e nove pacientes com DMC foram avaliados clinicamente e sua biópsia muscular, histopatologica e imuno-histoquimicamente: 32 eram MP, 23 merosina-deficiente (MD), um mostrava fenótipo Ullrich e três síndrome de Walker-Warburg. RESULTADOS: Distrofina e disferlina foram normais em todos; nove pacientes MD apresentavam déficit parcial de merosina, porém com a mesma gravidade clínica daqueles com deficiência total. CONCLUSÃO: A hipoexpressão de a-sarcoglicana (SG) and a-distroglycan (DG) se correlacionou estatisticamente com o grave fenótipo MD, assim indicando maior correlação entre a merosina e as referidas proteínas; entre os pacientes MP, apesar da hipoexpressão de b-DG ter se correlacionado significativamente com fenótipo e histopatologia mais grave, não houve correlação clínica/imuno-histoquímica valorizável.
Assuntos
Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Complexo de Proteínas Associadas Distrofina/metabolismo , Distrofias Musculares/metabolismo , Laminina/deficiência , Brasil , Distribuição de Qui-Quadrado , Complexo de Proteínas Associadas Distrofina/genética , Distrofias Musculares/congênito , Seguimentos , Fenótipo , Índice de Gravidade de Doença , Sarcoglicanas/metabolismoRESUMO
Ullrich congenital muscular dystrophy (UCMD), due to mutations in the collagen VI genes, is an autosomal recessive form of CMD, commonly associated with distal joints hyperlaxity and severe course. A mild or moderate involvement can be occasionally observed. OBJECTIVE: To evaluate the clinical picture of CMD patients with Ullrich phenotype who presented decreased or absent collagen VI immunoreactivity on muscular biopsy. RESULTS: Among 60 patients with CMD, two had no expression of collagen V and their clinical involvement was essentially different: the first (3 years of follow-up) has mild motor difficulty; the second (8 years of follow-up) never acquired walking and depends on ventilatory support. A molecular study, performed by Pan et al. at the Thomas Jefferson University, demonstrated in the first a known mutation of Bethlem myopathy in COL6A1 and in the second the first dominantly acting mutation in UCMD and the first in COL6A1, previously associated only to Bethlem myopathy, with benign course and dominant inheritance. CONCLUSION: Bethlem myopathy should be considered in the differential diagnosis of UCMD, even in patients without fingers contractures; overlap between Ullrich and Bethlem phenotypes can be supposed.
A distrofia muscular congênita (DMC) com hiperextensibilidade articular distal (fenótipo Ullrich) associa-se a mutações nos genes do colágeno VI e corresponde a um grave quadro congênito de herança autossômica recessiva e curso progressivo, ocasionalmente mostrando menor gravidade. OBJETIVO: Avaliar o quadro clínico dos pacientes com DMC tipo Ullrich que apresentam imunoexpressão baixa ou ausente do colágeno VI na biópsia muscular. RESULTADOS: Entre 60 pacientes com DMC, dois mostravam imunomarcação negativa do colágeno VI. Mostravam-se clinicamente essencialmente diferentes: o primeiro, com 8 anos de idade e três de seguimento mostra leve dificuldade motora; o segundo, com 14 anos de idade e 8 de seguimento, não deambula e apresenta insuficiência respiratória. O estudo molecular, realizado na Thomas Jefferson University por Pan et al., revelou no primeiro, no gene COL6A1, mutação típica da miopatia de Bethlem, que tem curso benigno e herança autossômica dominante; e no segundo a primeira mutação de efeito dominante e do gene COL6A1, previamente associado apenas à miopatia de Bethlem. CONCLUSÃO: A miopatia de Bethlem deve constar no diagnóstico diferencial da DMC tipo Ullrich, mesmo na ausência das típicas contraturas dos dedos; pode existir sobreposição dos fenótipos Ullrich e Bethlem.
Assuntos
Adolescente , Criança , Pré-Escolar , Humanos , Masculino , Colágeno Tipo VI/deficiência , Distrofias Musculares/genética , Heterogeneidade Genética , Biópsia , Colágeno Tipo VI/genética , Diagnóstico Diferencial , Distrofias Musculares/congênito , Distrofias Musculares/patologia , Seguimentos , Imuno-Histoquímica , Instabilidade Articular/genética , Instabilidade Articular/patologia , FenótipoRESUMO
Lyme disease is an infectious disease caused by spirochete Borrelia burgdorferi transmitted by Ixodid tick bite. The geographic distribution of the disease is universal, but the disease has not been identified definitely in South America yet. We report a probable case of Lyme disease in a woman, living in Jaguaré slum (São Paulo), who showed characteristics skin lesions of erythema chronicum migrans, with fever, weakness, headache, muscular pain, cough, arthralgia and sensitive radicular neuropathy in the left arm. The sequential serology made by ELISA method, using Borrelia burgdorferi whole sonicated antigen from Dr. Allen C. Steere laboratory, showed high titers of IgM antibody (1:1600). Because of the persistence of high IgM response for two months, we decided to treat the patient with tetracycline 2g/day during 10 days and the sorology became negative two months. The western blotting confirmed ELISA results showing presence of five bands (IgM). This report fulfills CDC criteria for Lyme disease diagnosis.