JOSE PINHATA OTOCH
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Cirurgia, Faculdade de Medicina - Docente
DVCLCIR-62, Hospital Universitário
LIM/26 - Laboratório de Pesquisa em Cirurgia Experimental, Hospital das Clínicas, Faculdade de Medicina - Líder
DVCLCIR-62, Hospital Universitário
LIM/26 - Laboratório de Pesquisa em Cirurgia Experimental, Hospital das Clínicas, Faculdade de Medicina - Líder
18 resultados
Resultados de Busca
Agora exibindo 1 - 10 de 18
- Lipases and lipid droplet-associated protein expression in subcutaneous white adipose tissue of cachectic patients with cancer(2017) SILVERIO, Renata; LIRA, Fabio S.; OYAMA, Lila M.; NASCIMENTO, Claudia M. Oller do; OTOCH, Jose P.; ALCANTARA, Paulo S. M.; BATISTA JR., Miguel L.; SEELAENDER, MariliaBackground: Cancer cachexia is a multifactorial metabolic syndrome characterized by marked loss of adipose tissue and skeletal muscle. Fat loss from adipose tissue in cancer cachexia is partly the result of increased lipolysis. Despite the growing amount of studies focused on elucidating the mechanisms through which lipolysis-related proteins regulate the lipolytic process, there are scarce data concerning that profile in the adipose tissue of cancer cachectic patients. Considering its fundamental importance, it was our main purpose to characterize the expression of the lipolysis-related proteins in the white adipose tissue of cachectic cancer patients. Methods: Patients from the University Hospital were divided into three groups: control, cancer cachexia (CC), and weight-stable cancer patients (WSC). To gain greater insight into adipose tissue wasting during cancer cachexia progression, we have also analyzed an experimental model of cachexia (Walker 256 carcinosarcoma). Animals were divided into: control, intermediate cachexia (IC) and terminal cachexia (TC). Subcutaneous white adipose tissue of patients and epidydimal white adipose tissue of animals were investigated regarding molecular aspects by determining the protein content and gene expression of hormone-sensitive lipase (HSL), adipose triglyceride lipase (ATGL), comparative gene identification-58 (CGI-58), perilipin 1, leptin, adiponectin, visfatin, and tumour necrosis factor alpha (TNF-alpha). Results: We found augmented lipolysis in CC associated with increased HSL expression, as well as upregulation of ATGL expression and reduction in perilipin 1 content. In IC, there was an imbalance in the secretion of pro-and anti-inflammatory factors. The alterations at the end-stage of cachexia were even more profound, and there was a reduction in the expression of almost all proteins analyzed in the animals. Conclusions: Our findings show that cachexia induces important morphological, molecular, and humoral alterations in the white adipose tissue, which are specific to the stage of the syndrome.
- High levels of modified ceramides are a defining feature of murine and human cancer cachexia(2020) MORIGNY, Pauline; ZUBER, Julia; HAID, Mark; KALTENECKER, Doris; RIOLS, Fabien; LIMA, Joanna D. C.; SIMOES, Estefania; OTOCH, Jose Pinhata; SCHMIDT, Soeren Fisker; HERZIG, Stephan; ADAMSKI, Jerzy; SEELAENDER, Marilia; DIAZ, Mauricio Berriel; ROHM, MariaBackground Cancer cachexia (CCx) is a multifactorial energy-wasting syndrome reducing the efficiency of anti-cancer therapies, quality of life, and survival of cancer patients. In the past years, most studies focused on the identification of tumour and host-derived proteins contributing to CCx. However, there is still a lack of studies addressing the changes in bioactive lipids. The aim of this study was to identify specific lipid species as a hallmark of CCx by performing a broad range lipid analysis of plasma from well-established CCx mouse models as well as cachectic and weight stable cancer patients. Methods Plasma from non-cachectic (PBS-injected mice, NC26 tumour-bearing mice), pre-cachectic and cachectic mice (C26 and LLC tumour-bearing mice, Apc(Min/+)mutant mice), and plasma from weight stable and cachectic patients with gastrointestinal cancer, were analysed using the Lipidyzer (TM) platform. In total, 13 lipid classes and more than 1100 lipid species, including sphingolipids, neutral and polar glycerolipids, were covered by the analysis. Correlation analysis between specific lipid species and readouts of CCx were performed. Lipidomics data were confirmed by gene expression analysis of metabolic organs to analyse enzymes involved in sphingolipid synthesis and degradation. Results A decrease in several lysophosphatidylcholine (LPC) species and an increase in numerous sphingolipids including sphingomyelins (SMs), ceramides (CERs), hexosyl-ceramides (HCERs) and lactosyl-ceramides (LCERs), were mutual features of CCx in both mice and cancer patients. Notably, sphingolipid levels gradually increased during cachexia development. Key enzymes involved in ceramide synthesis were elevated in liver but not in adipose, muscle, or tumour tissues, suggesting that ceramide turnover in the liver is a major contributor to elevated sphingolipid levels in CCx. LPC(16:1), LPC(20:3), SM(16:0), SM(24:1), CER(16:0), CER(24:1), HCER(16:0), and HCER(24:1) were the most consistently affected lipid species between mice and humans and correlated negatively (LPCs) or positively (SMs, CERs and HCERs) with the severity of body weight loss. Conclusions High levels of sphingolipids, specifically ceramides and modified ceramides, are a defining feature of murine and human CCx and may contribute to tissue wasting and skeletal muscle atrophy through the inhibition of anabolic signals. The progressive increase in sphingolipids during cachexia development supports their potential as early biomarkers for CCx.
- Peritumoural adipose tissue pro-inflammatory cytokines are associated with tumoural growth factors in cancer cachexia patients(2018) PINTO NETO, Nelson Inacio; MURARI, Ariene Soares de Pinho; OYAMA, Lila Missae; OTOCH, Jose Pinhata; ALCANTARA, Paulo Sergio Martins; TOKESHI, Flavio; FIGUEREDO, Raquel Galvao; ALVES, Michele Joana; LIMA, Joanna Darck Carola Correia; MATOS-NETO, Emidio Marques de; SEELAENDER, Marilia; NASCIMENTO, Claudia Maria Oller doBackground Cancer cachexia (CC) is a multifactorial syndrome, often irreversible, that affects patients with cancer influenced, in part, by the inflammatory condition. Peritumoural adipose tissue produces adipokines and angiogenic, apoptotic, and growth factors; given the possible crosstalk between the peritumoural adipose tissue and tumour, these may play an important role in cancer biology and carcinogenesis. Methods Results The aim of this study was to evaluate the factors produced by peritumoural adipose tissue in a cohort of 16 colorectal cancer patients with either weight-stable cancer (WSC; n = 7) or CC (n = 9). The study was approved by the Ethics Research Committee (972.914). Samples of peritumoural adipose tissue were analysed for concentrations of TNF-alpha, IL-1 beta, STAT-1, STAT-3, RANTES, IL-1Ra, IP-10, IL-15, MCP-1, IFN-alpha, GCSF, FADD, and TGF-beta. The cytokines and proteins were measured using Multiplex. Correlations between the proteins and cytokines were evaluated. TNF-alpha, STAT-1, and FADD, a factor involved in apoptosis, were significantly higher in CC group than in the WSC group. In the peritumoural adipose tissue of the CC group, RANTES showed a significant positive correlation with IL-1Ra and IP-10 and a negative correlation with IFN-alpha; and GCSF showed significant negative correlations with IL-1Ra, IP-10, IL-15, and MCP-1 and a positive correlation with IFN-alpha. In the peritumoural adipose tissue of the WSC group, no significant correlations were detected between RANTES, GCSF, IL-3, FADD, and STAT-1 and the cytokines/chemokines analysed. Conclusions These results indicated that inflammatory and tumorigenic pathways were altered in peritumoural adipose tissue in CC. Furthermore, inflammatory cytokines were correlated with growth factors in the peritumoural adipose tissue of cachectic patients, suggesting that inflammatory cytokines modulated the proliferative environment closely linked to the tumour.
- Post-COVID-19 condition: systemic inflammation and low functional exercise capacity(2024) CASTRO, Gabriela Salim de; GAMA, Leonardo R.; RAMOS, Alexandre Ferreira; SILVA, Guilherme Gatti da; TEIXEIRA, Alexandre Abilio de Souza; CUNHA-NETO, Edecio; SOUZA, Heraldo Possolo de; MARIE, Suely K.; TALIB, Leda L.; COELHO, Veronica; KALIL, Jorge; ARAUJO, Adriana Ladeira de; RITTO, Ana Paula; BELON, Alessandro Rodrigo; SANTOS, Amanda Soares; BARRERE, Ana Paula Noronha; SAWAMURA, Marcio V. Y.; LAMAS, Celina Almeida; BALDI, Bruno Guedes; CARVALHO, Carlos R. R.; KULIKOWSKI, Leslie Domenici; DAMIANO, Rodolfo Furlan; IMAMURA, Marta; ROSA NETO, Jose Cesar; LIRA, Fabio S.; OTOCH, Jose Pinhata; MIGUEL, Euripedes Constantino; BATTISTELLA, Linamara; FORLENZA, Orestes V.; BUSATTO, Geraldo; SEELAENDER, MariliaIntroduction Post-COVID-19 condition (PCC) is characterised by a plethora of symptoms, with fatigue appearing as the most frequently reported. The alterations that drive both the persistent and post-acute disease newly acquired symptoms are not yet fully described. Given the lack of robust knowledge regarding the mechanisms of PCC we have examined the impact of inflammation in PCC, by evaluating serum cytokine profile and its potential involvement in inducing the different symptoms reported.Methods In this cross-sectional study, we recruited 227 participants who were hospitalised with acute COVID-19 in 2020 and came back for a follow-up assessment 6-12 months after hospital discharge. The participants were enrolled in two symptomatic groups: Self-Reported Symptoms group (SR, n = 96), who did not present major organ lesions, yet reported several debilitating symptoms such as fatigue, muscle weakness, and persistent loss of sense of smell and taste; and the Self-Reported Symptoms and decreased Pulmonary Function group (SRPF, n = 54), composed by individuals with the same symptoms described by SR, plus diagnosed pulmonary lesions. A Control group (n = 77), with participants with minor complaints following acute COVID-19, was also included in the study. Serum cytokine levels, symptom questionnaires, physical performance tests and general clinical data were obtained in the follow-up assessment.Results SRPF presented lower IL-4 concentration compared with Control (q = 0.0018) and with SR (q = 0.030), and lower IFN-alpha 2 serum content compared with Control (q = 0.007). In addition, SRPF presented higher MIP-1 beta serum concentration compared with SR (q = 0.029). SR presented lower CCL11 (q = 0.012 and q = 0.001, respectively) and MCP-1 levels (q = 0.052 for both) compared with Control and SRPF. SRPF presented lower G-CSF compared to Control (q = 0.014). Female participants in SR showed lower handgrip strength in relation to SRPF (q = 0.0082). Male participants in SR and SRPF needed more time to complete the timed up-and-go test, as compared with men in the Control group (q = 0.0302 and q = 0.0078, respectively). Our results indicate that different PCC symptom profiles are accompanied by distinct inflammatory markers in the circulation. Of particular concern are the lower muscle function findings, with likely long-lasting consequences for health and quality of life, found for both PCC phenotypes.
- Adipose tissue fibrosis in human cancer cachexia: the role of TGF beta pathway(2017) ALVES, Michele Joana; FIGUEREDO, Raquel Galvao; AZEVEDO, Flavia Figueiredo; CAVALLARO, Diego Alexandre; PINTO NETO, Nelson Inacio; LIMA, Joanna Darck Carola; MATOS-NETO, Emidio; RADLOFF, Katrin; RICCARDI, Daniela Mendes; CAMARGO, Rodolfo Gonzalez; ALCANTARA, Paulo Sergio Martins De; OTOCH, Jose Pinhata; BATISTA JUNIOR, Miguel Luiz; SEELAENDER, MariliaBackground: Cancer cachexia is a multifactorial syndrome that dramatically decreases survival. Loss of white adipose tissue (WAT) is one of the key characteristics of cachexia. WAT wasting is paralleled by microarchitectural remodeling in cachectic cancer patients. Fibrosis results from uncontrolled ECM synthesis, a process in which, transforming growth factor-beta (TGF beta) plays a pivotal role. So far, the mechanisms involved in adipose tissue (AT) re-arrangement, and the role of TGF beta in inducing AT remodeling in weight-losing cancer patients are poorly understood. This study examined the modulation of ECM components mediated by TGF beta pathway in fibrotic AT obtained from cachectic gastrointestinal cancer patients. Methods: After signing the informed consent form, patients were enrolled into the following groups: cancer cachexia (CC, n = 21), weight-stable cancer (WSC, n = 17), and control (n = 21). The total amount of collagen and elastic fibers in the subcutaneous AT was assessed by histological analysis and by immunohistochemistry. TGF beta isoforms expression was analyzed by Multiplex assay and by immunohistochemistry. Alpha-smooth muscle actin (aSMA), fibroblast-specific protein (FSP1), Smad3 and 4 were quantified by qPCR and/or by immunohistochemistry. Interleukin (IL) 2, IL5, IL8, IL13 and IL17 content, cytokines known to be associated with fibrosis, was measured by Multiplex assay. Results: There was an accumulation of collagen and elastic fibers in the AT of CC, as compared with WSC and controls. Collagens type I, III, VI, and fibronectin expression was enhanced in the tissue of CC, compared with both WSC and control. The pronounced expression of aSMA in the surrounding of adipocytes, and the increased mRNA content for FSP1 (20-fold) indicate the presence of activated myofibroblasts; particularly in CC. TGF beta 1 and TGF beta 3 levels were up-regulated by cachexia in AT, as well in the isolated adipocytes. Smad3 and Smad4 labeling was found to be more evident in the fibrotic areas of CC adipose tissue. Conclusions: Cancer cachexia promotes the development of AT fibrosis, in association with altered TGF beta signaling, compromising AT organization and function.
- Cancer Cachexia and MicroRNAs(2015) CAMARGO, Rodolfo Gonzalez; RIBEIRO, Henrique Quintas Teixeira; GERALDO, Murilo Vieira; MATOS-NETO, Emidio; NEVES, Rodrigo Xavier; CARNEVALI JR., Luiz Carlos; DONATTO, Felipe Fedrizzi; ALCANTARA, Paulo S. M.; OTTOCH, Jose P.; SEELAENDER, MariliaCancer cachexia is a paraneoplastic syndrome compromising quality of life and survival, mainly characterized by involuntary weight loss, fatigue, and systemic inflammation. The syndrome is described as a result of tumor-host interactions characterized by an inflammatory response by the host to the presence of the tumor. Indeed, systemic inflammation is considered a pivotal feature in cachexia progression and maintenance. Cytokines are intimately related to chronic systemic inflammation and the mechanisms underlying the release of these factors are not totally elucidated, the etiology of cachexia being still not fully understood. Therefore, the understanding of cachexia-related mechanisms, as well as the establishment of markers for the syndrome, is very relevant. MicroRNAs (miRNAs) are a class of noncoding RNAs interfering with gene regulation. Different miRNA expression profiles are associated with different diseases and inflammatory processes. miRNAs modulate adipose and skeletal muscle tissue metabolism in cancer cachexia and also tumor and tissue derived inflammation. Therefore, we propose a possible role for miRNAs in the modulation of the host inflammatory response during cachexia. Moreover, the establishment of a robust body of evidence in regard to miRNAs and the mechanisms underlying cachexia is mandatory, and shall contribute to the improvement of its diagnosis and treatment.
- Human Cachexia Induces Changes in Mitochondria, Autophagy and Apoptosis in the Skeletal Muscle(2019) CASTRO, Gabriela S. de; SIMOES, Estefania; LIMA, Joanna D. C. C.; ORTIZ-SILVA, Milene; FESTUCCIA, William T.; TOKESHI, Flivio; ALCANTARA, Paulo S.; OTOCH, Jose P.; COLETTI, Dario; SEELAENDER, MariliaCachexia is a wasting syndrome characterized by the continuous loss of skeletal muscle mass due to imbalance between protein synthesis and degradation, which is related with poor prognosis and compromised quality of life. Dysfunctional mitochondria are associated with lower muscle strength and muscle atrophy in cancer patients, yet poorly described in human cachexia. We herein investigated mitochondrial morphology, autophagy and apoptosis in the skeletal muscle of patients with gastrointestinal cancer-associated cachexia (CC), as compared with a weight-stable cancer group (WSC). CC showed prominent weight loss and increased circulating levels of serum C-reactive protein, lower body mass index and decreased circulating hemoglobin, when compared to WSC. Electron microscopy analysis revealed an increase in intermyofibrillar mitochondrial area in CC, as compared to WSC. Relative gene expression of Fission 1, a protein related to mitochondrial fission, was increased in CC, as compared to WSC. LC3 II, autophagy-related (ATG) 5 and 7 essential proteins for autophagosome formation, presented higher content in the cachectic group. Protein levels of phosphorylated p53 (Ser46), activated caspase 8 (Asp384) and 9 (Asp315) were also increased in the skeletal muscle of CC. Overall, our results demonstrate that human cancer-associated cachexia leads to exacerbated muscle-stress response that may culminate in muscle loss, which is in part due to disruption of mitochondrial morphology, dysfunctional autophagy and increased apoptosis. To the best of our knowledge, this is the first report showing quantitative morphological alterations in skeletal muscle mitochondria in cachectic patients.
- Activation of the Adipose Tissue NLRP3 Inflammasome Pathway in Cancer Cachexia(2021) JESUS, Joyce de Cassia Rosa de; MURARI, Ariene Soares de Pinho; RADLOFF, Katrin; MORAES, Ruan Carlos Macedo de; FIGUEREDO, Raquel Galvao; PESSOA, Ana Flavia Marcal; ROSA-NETO, Jose Cesar; MATOS-NETO, Emidio Marques; ALCANTARA, Paulo S. M.; TOKESHI, Flavio; MAXIMIANO, Linda Ferreira; BIN, Fang Chia; FORMIGA, Fernanda Bellotti; OTOCH, Jose P.; SEELAENDER, MariliaBackground Cachexia is a paraneoplastic syndrome that accompanies and compromises cancer treatment, especially in advanced stages, affecting the metabolism and function of several organs. The adipose tissue is the first to respond to the presence of the tumor, contributing to the secretion of factors which drive the systemic inflammation, a hallmark of the syndrome. While inflammation is a defensive innate response, the control mechanisms have been reported to be disrupted in cachexia. On the other hand, little is known about the role of NLRP3 inflammasome in this scenario, a multiprotein complex involved in caspase-1 activation and the processing of the cytokines IL-1 beta and IL-18. Aim based on the evidence from our previous study with a rodent model of cachexia, we examined the activation of the NLRP3 inflammasome pathway in two adipose tissue depots obtained from patients with colorectal cancer and compared with that another inflammatory pathway, NF-kappa B. Results For CC we found opposite modulation in ScAT and PtAT for the gene expression of TLR4, Caspase-1 (cachectic group) and for NF-kappa B p50, NF-kappa B p65, IL-1 beta. CD36, expression was decreased in both depots while that of NLRP3 and IL-18 was higher in both tissues, as compared with controls and weight stable patients (WSC). Caspase-1 basal protein levels in the ScAT culture supernatant were higher in WSC and (weight stable patients) CC, when compared to controls. Basal ScAT explant culture medium IL-1 beta and IL-18 protein content in ScAT supernatant was decreased in the WSC and CC as compared to CTL explants. Conclusions The results demonstrate heterogeneous responses in the activation of genes of the NLRP3 inflammasome pathway in the adipose tissue of patients with cancer cachexia, rendering this pathway a potential target for therapy aiming at decreasing chronic inflammation in cancer.
conferenceObject ADIPOSE TISSUE EXTRACELLULAR MATRIX REMODELLING IN CANCER CACHEXIA(2015) ALVES, Michele; NETO, Emidio Matos; MAXIMILIANO, Linda; ALCANTARA, Paulo; OTOCH, Jose; BATISTA, Miguel; SEELAENDER, Marilia- Cachexia-associated adipose tissue morphological rearrangement in gastrointestinal cancer patients(2016) BATISTA JR., Miguel L.; HENRIQUES, Felipe S.; NEVES, Rodrigo X.; OLIVAN, Mireia R.; MATOS-NETO, Emidio M.; ALCANTARA, Paulo S. M.; MAXIMIANO, Linda F.; OTOCH, Jose P.; ALVES, Michele J.; SEELAENDER, MariliaBackground and aimsCachexia is a syndrome characterized by marked involuntary loss of body weight. Recently, adipose tissue (AT) wasting has been shown to occur before the appearance of other classical cachexia markers. We investigated the composition and rearrangement of the extracellular matrix, adipocyte morphology and inflammation in the subcutaneous AT (scAT) pad of gastrointestinal cancer patients. MethodsSurgical biopsies for scAT were obtained from gastrointestinal cancer patients, who were signed up into the following groups: cancer cachexia (CC, n=11), weight-stable cancer (WSC, n=9) and weight-stable control (non-cancer) (control, n=7). The stable weight groups were considered as those with no important weight change during the last year and body mass index <25kg/m(2). Subcutaneous AT fibrosis was quantified and characterized by quantitative PCR, histological analysis and immunohistochemistry. ResultsThe degree of fibrosis and the distribution and collagen types (I and III) were different in WSC and CC patients. CC patients showed more pronounced fibrosis in comparison with WSC. Infiltrating macrophages surrounding adipocytes and CD3 Ly were found in the fibrotic areas of scAT. Subcutaneous AT fibrotic areas demonstrated increased monocyte chemotactic protein 1 (MCP-1) and Cluster of Differentiation (CD)68 gene expression in cancer patients. ConclusionsOur data indicate architectural modification consisting of fibrosis and inflammatory cell infiltration in scAT as induced by cachexia in gastrointestinal cancer patients. The latter was characterized by the presence of macrophages and lymphocytes, more evident in the fibrotic areas. In addition, increased MCP-1 and CD68 gene expression in scAT from cancer patients may indicate an important role of these markers in the early phases of cancer.