RESUMO
INTRODUCTION: Type 1 diabetes mellitus (DM) causes marked skeletal muscle atrophy. Mesenchymal stromal cells (MSC) are an attractive therapy to avoid diabetic complications because of their ability to modify the microenvironment at sites of tissue injury. The objective of this study was to evaluate the effects of MSC transplantation on muscle adaptation caused by diabetes. METHODS: DM was induced by streptozotocin (STZ), and the diabetic animals received systemic MSC transplantation. The von Frey test and footprint analysis were used to assess sensation and sensory motor performance, respectively. Tibialis anterior muscles were investigated by morphology; molecular markers atrogin-1/muscle RING-finger protein-1, nuclear factor κB/p38 mitogen-activated protein kinase, tumor necrosis-like weak inducer of apoptosis/fibroblast growth factor-inducible 14, myostatin, myogenic differentiation 1, and insulin-like growth factor 1 were also assessed. RESULTS: MSC transplantation improved sensation and walking performance and also decreased muscle fibrosis in DM rats by modulating atrogenes but did not prevent muscle atrophy. DISCUSSION: MSCs can reduce muscle and functional complications that result from type 1 DM in rats. Muscle Nerve 58: 583-591, 2018.
Assuntos
Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Transplante de Células-Tronco Mesenquimais , Músculo Esquelético/patologia , Doenças Musculares/patologia , Distúrbios Somatossensoriais/fisiopatologia , Animais , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 1/complicações , Modelos Animais de Doenças , Fibrose , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatologia , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Doenças Musculares/etiologia , Doenças Musculares/metabolismo , Doenças Musculares/fisiopatologia , Proteína MyoD/metabolismo , Miostatina/metabolismo , NF-kappa B/metabolismo , Ratos , Ratos Wistar , Proteínas Ligases SKP Culina F-Box/metabolismo , Transdução de Sinais , Receptor de TWEAK/metabolismo , Tato/fisiologia , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Caminhada , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Knowledge of the signalling pathways involved in various diseases has enabled advances in the understanding of pathophysiological, diagnostic and therapeutic models of several inflammatory and autoimmune diseases. Systemic lupus erythematosus is a widely studied autoimmune disease that can affect multiple organs, with a major impact on morbidity and mortality when it involves the kidneys. Over the past 10 years, interest in the role of the TWEAK/Fn14 signalling pathway in lupus nephritis, as well as other clinical settings, has increased. By reviewing the literature, this article assesses the role of this pathway in lupus nephritis, underlines the importance of TWEAK in urine (uTWEAK) as a biomarker of the disease and stresses the favourable results published in the literature from the inhibition of the TWEAK/Fn14 pathway as a therapeutic target in experimental animal models, demonstrating its potential application in other settings. Results of ongoing clinical trials and future research will give us a better understanding of the real benefit of blocking this pathway in the clinical course of several conditions.
Assuntos
Nefrite Lúpica/etiologia , Transdução de Sinais/fisiologia , Receptor de TWEAK/fisiologia , HumanosRESUMO
OBJECTIVE: The aim of this work was to investigate the effects of electrical stimulation (ES) of denervated muscles of rat in neuromuscular performance, muscle atrophy, and fibrosis formation. DESIGN: Wistar rats were divided into normal (N), 7- or 15-day denervation (D7d and D15d), D7d or D15d plus ES (DES7d and DES15d, respectively). Sciatic nerves were crushed causing muscle denervation. Two hundred muscle contractions were electrically induced daily by surface electrodes, considering muscle chronaxie. Sciatic functional index was used to determine neuromuscular performance during walking. The muscle fiber cross-sectional area and percentage of connective tissue were assessed by light microscopy. Molecular markers of extracellular matrix production and remodeling were evaluated. Metalloproteinase (MMP) activity was assessed by zymography, and TWEAK, Fn14, myostatin, and transforming growth factor (TGF)-ß gene expressions were determined by real-time PCR. RESULTS: Electrical stimulation impaired natural recovery of walking at 15 days. In addition, ES induced fibrosis and accentuated muscle atrophy in denervated muscles. Although ES reduced the accumulation of TWEAK and myostatin expressions, it up-regulated Fn14 and TGF-ß in a time-dependent manner. Electrical stimulation also increased the activity of MMP-2 compared to the other groups (P < 0.05). CONCLUSIONS: Electrical stimulation applied to denervated muscles induced muscle fibrosis and atrophy, as well as loss of performance. The TWEAK/Fn14 system, TGF-beta/myostatin pathway, and MMP activity seem to be involved in these deleterious changes.
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Cronaxia , Estimulação Elétrica , Denervação Muscular , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Citocina TWEAK , Regulação para Baixo , Fibrose/etiologia , Metaloproteinase 2 da Matriz/metabolismo , Proteínas de Membrana/metabolismo , Modelos Animais , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Atrofia Muscular/etiologia , Miostatina/metabolismo , Ratos Wistar , Receptores do Fator de Necrose Tumoral/metabolismo , Receptor de TWEAK , Fator de Crescimento Transformador beta/metabolismo , Fatores de Necrose Tumoral/metabolismo , Regulação para CimaRESUMO
Chronic inflammation develops in the retinal microvasculature under sustained hyperglycemia and is implicated in the pathogenesis of diabetic retinopathy. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor Fn14 have been reported to promote pro-inflammatory cytokines, which are involved in the pathogenesis of proliferative diabetic retinopathy (PDR). It is therefore possible that the TWEAK/Fn14 pathway can play a regulatory role in PDR. In the present study, we examined the expression of TWEAK and Fn14 in vitreous fluid from PDR patients. To confirm the correlation between the TWEAK expression and clinical pathological characteristics of PDR, we investigated the regulatory role of the TWEAK/Fn14 pathway in cell proliferation and collagen synthesis in retinal ARPE-19 cells. The results demonstrated that vitreous fluid from patients with PDR had higher levels of TWEAK and Fn14 than that from T2DM patients without PDR, thus suggesting an important regulatory role of TWEAK/Fn14 signaling in the pathogenesis of PDR. Furthermore, overexpression of TWEAK in ARPE-19 cells also promoted proliferation of and collagen synthesis in these retinal cells. It is possible that TWEAK/Fn14 upregulation in PDR may contribute to PDR progression by promoting the proliferation or fibrosis of retinal cells.
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Colágeno/metabolismo , Retinopatia Diabética/metabolismo , Receptores do Fator de Necrose Tumoral/metabolismo , Retina/metabolismo , Fatores de Necrose Tumoral/metabolismo , Apoptose/genética , Apoptose/fisiologia , Linhagem Celular , Proliferação de Células/fisiologia , Citocina TWEAK , Diabetes Mellitus Tipo 2/metabolismo , Retinopatia Diabética/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Receptores do Fator de Necrose Tumoral/genética , Retina/patologia , Receptor de TWEAK , Fatores de Necrose Tumoral/genética , Corpo Vítreo/metabolismoRESUMO
The NF-kB (nuclear factor kB) pathway is involved in the proliferation of many cell types. To explore the mechanism of the NF-kB signaling pathway underlying the oval cell proliferation during rat liver regeneration, the Rat Genome 230 2.0 Array was used to detect expression changes of NF-kB signaling pathway-related genes in oval cells. The results revealed that the expression levels of many genes in the NF-kB pathway were significantly changed. This included 48 known genes and 16 homologous genes, as well as 370 genes and 85 homologous genes related to cell proliferation. To further understand the biological significance of these changes, an expression profile function was used to analyze the potential biological processes. The results showed that the NF-kB pathway promoted oval cell proliferation mainly through three signaling branches; the tumor necrosis factor alpha branch (TNF-a pathway), the growth factor branch, and the chemokine branch. An integrated statistics method was used to define the key genes in the NF-kB pathway. Seven genes were identified to play vital roles in the NF-kB pathway. To confirm these results, the protein content, including two key genes (TNF and FGF11) and two non-key genes (CCL2 and TNFRSF12A), were analyzed using two-dimensional gel electrophoresis and MALDI-TOF/TOF mass spectrometry. The results were generally consistent with those of the array data. To conclude, three branches and seven key genes were involved in the NF-kB signaling pathway that regulates oval cell proliferation during rat liver regeneration.
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Proliferação de Células , Regeneração Hepática , Fígado/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais , Animais , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Fígado/citologia , Fígado/fisiologia , NF-kappa B/genética , Ratos , Receptores do Fator de Necrose Tumoral/genética , Receptores do Fator de Necrose Tumoral/metabolismo , Receptor de TWEAK , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
TWEAK and APRIL are important members of the TNF superfamily, which play a crucial role in several diseases. Here, we describe the identification of grass carp (Ctenopharyngodon idella) homologs of TWEAK and APRIL (designated gcTWEAK and gcAPRIL, respectively) and their response to Aeromonas hydrophila and Aquareovirus infection. The gcTWEAK cDNA sequence contains 2273 bases with an open reading frame of 753 bases encoding 250-amino acid residues. The gcTWEAK protein contains a predicted transmembrane domain, a putative furin protease cleavage site, 3 conserved cysteine residues, and a typical TNF homology domain. The gcAPRIL cDNA sequence contains 1408 bases with an open reading frame of 747 bases encoding 248-amino acid residues. The gcAPRIL protein contains a predicted transmembrane domain, a putative furin protease cleavage site, 2 conserved cysteine residues, and a typical TNF homology domain corresponding to other, known APRIL homologs. Reverse transcription-polymerase chain reaction analysis shows that both gcTWEAK and gcAPRIL transcripts are predominantly expressed in the skin, spleen, and head kidney, and they are significantly upregulated in most immune tissues by A. hydrophila and Aquareovirus infections. Our results demonstrate that liver is the most responsive tissue against bacterial infection, whereas gill is the most responsive tissue against viral infection. The association of increased gcTWEAK and gcAPRIL expression after bacterial and viral infections suggests that they play a potentially important role in the immune system of fish.