SUELI MIEKO OBA SHINJO
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Neurologia, Faculdade de Medicina
LIM/15 - Laboratório de Investigação em Neurologia, Hospital das Clínicas, Faculdade de Medicina
LIM/15 - Laboratório de Investigação em Neurologia, Hospital das Clínicas, Faculdade de Medicina
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- Exercise training attenuates skeletal muscle fat infiltration and improves insulin pathway of patients with immune-mediated necrotizing myopathies and dermatomyositis(2023) OLIVEIRA, Diego Sales de; BORGES, Isabela Bruna Pires; MARIE, Suely Kazue Nagahashi; LERARIO, Antonio Marcondes; OBA-SHINJO, Sueli Mieko; SHINJO, Samuel KatsuyukiObjectives: This study aims to evaluate the effects of exercise training on intramuscular lipid content and genes related to insulin pathway in patients with systemic autoimmune myopathies (SAMs). Patients and methods: Between January 2016 and May 2019, a total of seven patients with dermatomyositis (DM; 3 males, 4 females; mean age: 49.8 & PLUSMN;2.3 years; range, 43 to 54 years), six with immune mediated necrotizing myopathy (IMNM; 3 males, 3 females; mean age: 58.5 & PLUSMN;10.6 years; range, 46 to 74 years), and 10 control individuals (CTRL group; 4 males, 6 females; mean age: 48.7 & PLUSMN;3.9 years; range, 41 to 56 years) were included. The muscle biopsy before and after the intervention was performed to evaluate the intramuscular lipid content. Patients underwent a combined exercise training program for 12 weeks. Skeletal muscle gene expression was analyzed and the DM versus CTRL group, DM pre-and post-, and IMNM pre-and post-intervention were compared. Results: The DM group had a higher intramuscular lipid content in type II muscle fibers compared to the CTRL group. After the intervention, there was a reduction of lipid content in type I and II fibers in DM and IMNM group. The CTRL group showed a significantly higher expression of genes related to insulin and lipid oxidation pathways (AMPK$2, AS160, INSR, PGC1-a, PI3K, and RAB14) compared to the DM group. After exercise training, there was an increase gene expression related to insulin pathway and lipid oxidation in DM group (AMPK$2, AS160, INSR, PGC1-a, PI3K, and RAB14) and in IMNM group (AKT2, AMPK$2, RAB10, RAB14, and PGC1-a). Conclusion: Exercise training attenuated the amount of fat in type I and II muscle fibers in patients with DM and IMNM and increased gene expression related to insulin pathways and lipid oxidation in DM and IMNM. These results suggest that exercise training can improve the quality and metabolic functions of skeletal muscle in these diseases.
- Comparison between treatment naive juvenile and adult dermatomyositis muscle biopsies: difference of inflammatory cells phenotyping(2018) SHINJO, Samuel Katsuyuki; SALLUM, Adriana Maluf Elias; OBA-SHINJO, Sueli Mieko; SILVA, Marilda Guimaraes; SILVA, Clovis Artur; MARIE, Suely Kazue NagahashiBackground: Different inflammatory cells (i.e., CD4, CD8, CD20 and CD68) are involved in pathogenesis of DM muscle. In this context, the aim of this study was to assess and compare these inflammatory cell phenotyping in muscle samples of treatment naive juvenile and adult patients with dermatomyositis. Methods: This is a cross-sectional study, in which 28 untreated juvenile and 28 adult untreated dermatomyositis patients were included. Immunohistochemical analysis was performed on serial frozen muscle sections. Inflammatory cell phenotyping was analyzed quantitatively in endomysium, perimysium, and perivascular (endomysium and perimysium) area. Results: Mean age at disease onset was 73 and 42.0 years in juvenile and adult dermatomyositis, respectively. Both groups had comparable time duration from symptom's onset to biopsy performance. CD4 and CD8 positive cells distributions were similar in both groups in all analyzed area, except for more predominance of CD4 in perimysium at juvenile muscle biopsies. The CD20 and CD68 positive cells were predominantly observed in adult muscle biopsy sections, when compared to juvenile samples, except for similar distribution of CD20 in perivascular endomysium, and CD68 in perimysium. Conclusions: These data show that the differences between juvenile and adult dermatomyositis may be restricted not only to patients' age, but also to different inflammatory cell distribution, particularly, in new-onset disease. Further studies are necessary to confirm the present study data and to analyze meaning of the different inflammatory cell phenotyping distribution finding in these both diseases.
conferenceObject Overexpression of Ankyrin Repeat Domain Containing Protein 1 Gene (ANKRD1) in Polymyositis Muscle Biopsies Is Correlated to Hypoxia.(2014) SHINJO, Samuel Katsuyuki; OBA-SHINJO, Sueli Mieko; UNO, Miyuki; MARIE, Suely Kazue Nagahashi- The expression of gene ANKRD1 correlates with hypoxia status in muscle biopsies of treatment-näive adult dermatomyositis(2017) SHINJO, Samuel Katsuyuki; OBA-SHINJO, Sueli Mieko; UNO, Miyuki; MARIE, Suely Kazue NagahashiOBJECTIVES. The ANKRD1 gene codes for the ankyrin repeat domain containing protein 1 and has an important role in myogenesis and possibly also in angiogenesis. Microvasculopathy is a cornerstone and an early pathological marker of change in dermatomyositis, leading to hypoxia and muscle perifascicular atrophy. These alterations could upregulate genes involved in myogenesis and angiogenesis such as ANKRD1. Therefore, we analyzed ANKRD1 expression in muscle biopsies of dermatomyositis and correlated with other hypoxia parameters and with histological changes. METHODS. Total RNA was extracted from frozen muscle biopsies samples of 29 dermatomyositis patients. A control group consisted of 20 muscle biopsies from adult patients with non-inflammatory myopathy diseases. The gene coding for hypoxia-inducible factor 1, alpha subunit (HIF1A), was analyzed to estimate the degree of hypoxia. ANKRD1 and HIF1A transcript expression levels were determined by quantitative real time PCR. RESULTS. Significantly higher ANKRD1 and HIF1A expression levels were observed in dermatomyositis relative to the control group (P<0.001, both genes). In addition, ANKRD1 and HIF1A were coexpressed (r=0.703, P=0.001) and their expression levels correlated positively to perifascicular atrophy (r=0.420, P=0.023 and r=0.404, P=0.030, respectively). CONCLUSIONS. Our results demonstrate ANKRD1 overexpression in dermatomyositis correlated to HIF1A expression and perifascicular atrophy. ANKRD1 involvement in myogenesis and angiogenesis mechanisms indicates that further investigation is worthwhile.
- Overexpression of Ankyrin Repeat Domain Containing Protein 1 Gene (ANKRD1) in Dermatomyositis Muscle Biopsies Is Correlated to Hypoxia and Perifascicular Atrophy(2012) SHINJO, Samuel K.; OBA-SHINJO, Sueli M.; UNO, Miyuki; MARIE, Suely K. N.Background/Purpose: ANKRD1 codes for ankyrin repeat domain containing protein 1, which belongs to the muscle ankyrin repeat protein family involved in a mechano-signaling pathway that links myofibrillar stress response to muscle gene expression. In addition, ANKRD1 has an important role in transcriptional regulation, myofibrillar assembly, cardio-genesis, myogenesis and also possibly in angiogenesis. Microvasculopathy is considered as a cornerstone and early pathological change in dermatomyositis (DM), leading to hypoxia, capillary necrosis and muscle perifascicular atrophy. These alterations could upregulate genes involved in myogenesis and angiogenesis like ANKRD1. Therefore, we analyzed ANKRD1 expression in muscle biopsies of DM patients and correlated with other hypoxia parameters. Methods: RNA was extracted from frozen muscle biopsies samples of 30 untreated adult DM patients (Bohan and Peter’s criteria, 1975). As a control group, we analyzed 20 muscle biopsies with no histological change from untreated adult patients with non-inflammatory myopathy diseases. The gene coding for hypoxia-inducible factor 1, alpha subunit (HIF1A) was analyzed to estimate hypoxia degree. The ANKRD1 and HIF1A transcript expression levels were determined by quantitative real time PCR using Sybr Green method. Perifascicular atrophy was analyzed histologically by semi-quantitative method of HE stained biopsies. Expression and localization of ANKRD1 and HIF1a in muscle biopsies was accessed by immunohistochemistry. Results: Higher ANKRD1 and HIF1A expressions levels were observed in DM relative to control group (p<0.001 and p<0.001). In addition, the expression levels of both genes were correlated (r=0.703, P=0.001). We also observed a positive correlation of both genes to perifascicular atrophy (r=0.420, p=0.023 and r=0.404, p=0.030, respectively). However, ANKRD1 and HIF1A expression levels did not correlate to demographic, clinical and laboratory features (p>0.05). Immunohistochemistry showed that ANKRD1 and HIF1a were expressed mainly by atrophic muscle perifascicular cells. Conclusion: Our results demonstrated ANKRD1 is overexpressed, correlated to HIF1A in perifascicular atrophic fibers of DM muscle specimens. ANKRD1 involvement in myogenesis and angiogenesis mechanism will be further investigated.
- Effect of atorvastatin on muscle tissues of dermatomyositis and antisynthetase syndrome patients with dyslipidemia(2024) BORGES, Isabela Bruna Pires; OBA-SHINJO, Sueli Mieko; LERARIO, Antonio Marcondes; MARIE, Suely Kazue Nagahashi; SHINJO, Samuel KatsuyukiIntroduction: In a recent study, we have shown that atorvastatin is clinically safe for dermatomyositis (DM) and antisynthetase syndrome (ASS) patients with dyslipidemia. Herein, we showed in an unprecedented way, the safety of atorvastatin on the muscular tissues of these patients.Methods: Transcriptome analysis was performed on samples of the vastus lateralis muscle obtained at baseline and after 12 weeks of atorvastatin (20 mg/day) intervention in DM or ASS patients with dyslipidemia [6DM and 5ASS received atorvastatin, and 2DM and 3ASS received placebo]. The results were analyzed considering differences in expression fold change before and after treatment. Histological and histochemical analyses were also performed.Results: In both groups, no significant changes were observed in genes related to the mitochondrial, oxidative, insulin, lipid, and fibrogenic pathways. Histological analysis showed a slight variability in the fiber size that was preserved after the intervention. In addition, the mosaic of muscle fibers was preserved in the internal architecture of the fibers and all histological regions. No fiber necrosis or atrophy, focal failures, subsarcolemmal accumulation, lipids, areas of fibrosis, or alterations in mitochondrial activity were observed. All muscle fibers were labeled for MHC I.Conclusion: Atorvastatin did not promote significant changes in the expression of genes related to mitochondrial, oxidative, insulin, lipid, and fibrogenic pathways in the muscle tissues of DM and ASS patients with dyslipidemia. Atorvastatin did not also promote histological and histochemical changes in muscle tissues. Our results reinforce the safety of the administration of atorvastatin to treat dyslipidemia in patients with DM and ASS.
article 7 Citação(ões) na Scopus Serum interleukin-17A level is associated with disease activity of adult patients with dermatomyositis and polymyositis(2019) SILVA, M. G.; OBA-SHINJO, S. M.; MARIE, S. K. N.; SHINJO, S. K.Objective To assess serum interleukin (IL)-17A levels in patients with dermatomyositis (DM) and polymyositis (PM) and correlate them with the demographic, clinical, laboratory and therapeutic data of these diseases. Methods This was a cross-sectional, single-centre study that included defined DM and PM patients who were age-, gender- and ethnicity-matched to healthy individuals. Serum IL-17A analysis, as well as analysis for other cytokines (IL-6, TNF alpha and IFN gamma), was performed by multiplex immunoassay. The disease status parameters were based on the International Myositis Assessment and Clinical Studies Group (IMACS) set scores. Results Eighty DM, 32 PM patients and 104 healthy individuals were enrolled. Mean age of patients with DM and PM was 46.0 and 47.7, respectively, with a predominance of women and white ethnicity in both groups. Overall, clinical, laboratory, therapeutic, and current disease status were similar among patients with DM and PM. Median serum IL-17A level was higher in patients with PM and DM than the control group (0.73 vs. 0.49 vs. 0.35 pg/mL, respectively; p<0.050) and higher in PM when compared to DM (p<0.001). In DM, serum IL-17A levels were associated with cumulative cutaneous lesions, IMACS parameters, and serum IL-6 and IFN gamma levels. In PM, serum IL-17A levels correlated with patients' current age, IMACS parameters and serum TNF alpha and IFN gamma levels. Conclusion Serum IL-17A levels are not only increased, but also associated with disease activity in patients with DM and PM. Our data strongly suggest that IL-17A may be a biomarker of disease activity for these systemic autoimmune myopathies.- Angiotensin-converting enzyme insertion/deletion gene polymorphism is associated with dermatomyositis(2015) SHINJO, Samuel K.; UNO, Miyuki; OBA-SHINJO, Sueli M.; MARIE, Suely K. N.Background and objective: The cornerstone of dermatomyositis (DM) pathogenesis involves vascular disturbance that leads to hypoxia, capillary necrosis and muscle perifascicular atrophy. Hence, the hypothesis is that the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) gene polymorphism could be associated with susceptibility to DM. Method: A single centre, case control study that genotyped ACE gene in 88 DM and 99 healthy individuals. The ACE gene polymorphism was determined by melting curve analysis of real-time polymerase chain reaction products using SYBR Green. Results: The DM and the control subjects had a comparable mean age, gender frequency and ethnicity. The frequency of the D allele was higher in DM than in the control individuals (63.6% vs 55.6%, respectively). The DM had more ACE D/D and less ACE I/D genotype when compared to the control individuals, whereas the ACE I/I genotype distribution was similar in both case and control groups. Moreover, after sex-age-adjusted analysis, the ACE D/D genotype was strongly associated with DM disease (odds ratio (OR) 2.44, 95% confidence interval (CI): 1.17-4.37), in contrast to ACE I/D genotype (OR 0.51, 95% CI: 0.28-0.93). Conclusions: Homozygous ACE D/D was associated significantly with the DM risk. Further investigations are required to clarify and to confirm the association of these genes with DM susceptibility.
- A Brazilian family with inclusion body myopathy associated with Paget's disease of bone and frontotemporal dementia linked to the VCP pGly97Glu mutation(2018) SHINJO, Samuel Katsuyuki; OBA-SHINJO, Sueli Mieko; LERARIO, Antonio Marcondes; MARIE, Suely Kazue NagahashiThe objective of this study is to report a Brazilian patient and his family with inclusion body myopathy associated with Paget's disease of bone and frontotemporal dementia (IBMPFD). A systematic review of the literature on the valosin-containing protein (VCP) mutation was also performed. The proband (patient) was initially treated as a case of possible refractory polymyositis with Paget's disease and later as an inclusion body myopathy. However, after admission to our service, and considering his personal and familial antecedents, whole exome sequencing was performed revealing valosin-containing protein (VCP) c.290G > A (p.Gly97Glu) mutation in the patient and his nine family members. The clinical presentation of the patient and his family was characterized by different degrees and evaluations of IBMPFD. According to the literature, only one family (Chinese) has this same VCP mutation concomitantly with different IBMPFD phenotype manifestations. The present study shows that IBMPFD should be considered as a differential diagnosis in patients with inflammatory myopathies associated to bone disease and/or cognitive impairment. Moreover, the study expands the genotypic spectrum of missense mutations of VCP gene in a Brazilian family with variable phenotypes.
- Exercise Training Attenuates Ubiquitin-Proteasome Pathway and Increases the Genes Related to Autophagy on the Skeletal Muscle of Patients With Inflammatory Myopathies(2021) BORGES, Isabela Bruna Pires; OLIVEIRA, Diego Sales de; MARIE, Suely Kazue Nagahashi; LENARIO, Antonio Marcondes; OBA-SHINJO, Sueli Mieko; SHINJO, Samuel KatsuyukiBackground/Objective: The aim of this study was to evaluate the effects of exercise training on the ubiquitin-proteasome system (UPS) and genes related to autophagy on the skeletal muscle of patients with dermatomyositis (DM) and immune-mediated necrotizing myopathies (IMNMs). Methods: Seven DM patients and 6 IMNM patients were treated for 12 weeks with a twice-weekly aerobic and resistance training exercise program. Aerobic capacity, muscle strength, and expression of genes in the skeletal muscle related to UPS and to autophagy were evaluated at the baseline and after the intervention. Moreover, only at the baseline, 10 healthy control individuals were also evaluated. Results: The age of DM and IMNM patients was 49.8 and 58.5 years, respectively. Genes related to UPS were upregulated, whereas genes related to autophagy and antioxidative systems were downregulated only in the DM group when compared with control group. After completion of the exercise training program, several genes related to UPS were downregulated, whereas genes related to autophagy, mitochondrial pathways, and antioxidative systems were upregulated in both the DM and IMNM groups. Conclusions: Exercise training can increase genes related to autophagy, mitophagy, and lysosomal biogenesis in the skeletal muscle of patients. These results suggest an increase in the recycling of damaged proteins and organelles, which may also contribute to the performance and endurance of skeletal muscles in these patients. Furthermore, in patients with myositis, exercise training led to a decrease in genes related to UPS and an increase in genes related to antioxidative capacity. Therefore, this may also contribute to an attenuation of skeletal muscle loss and of the deleterious effects of oxidative stress on the skeletal muscle of these patients.