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BACKGROUND: The Ec peptide (PEc) that defines the IGF-1Ec isoform, is associated with prostate cancer progression by inducing proliferation, metastases, and tumour repair. On these grounds, an anti-PEc monoclonal antibody (MAb) was developed. Our objective is to examine the effects of this antibody on prostate cancer and its possible side effects. METHODS: The effects of the obtained MAb were examined in cancer and non-cancerous cell lines (unmodified and modified either to overexpress or silence PEc) and in tumours in SCID mice injected with unmodified prostate cancer cells. The investigation was obtained with respect to cellular proliferation, migration, invasion, toxicity to tumours, effects on the cell cycle, immune response activation, effects on mesenchymal stem cell mobilisation leading to tumour repair, tissue distribution, and toxicity to mice. RESULTS: Anti-PEc MAb treatment led to a significant decrease in cellular proliferation, migration, and invasion compared to the untreated cell lines (p < 0.0005 in every case). Mechanistically, these effects were associated with the downregulation of pERK1/2 and vimentin and the upregulation of E-Cadherin. In vivo, anti-PEc MAb treatment was associated with a significant decrease in tumour size and metastases rate (p < 0.0005 in every case) by reversing the tumours mesenchymal phenotype. It also inhibited host stem cell mobilisation towards the tumour, leading to apoptosis. Anti-PEc MAb assessment in respect to distribution and toxicity, indicated its tumour specificity and lack of toxicity. CONCLUSIONS: These data indicate that the therapeutic targeting of PEc with the anti-PEc MAb may have considerable clinical benefit for prostate cancer patients.
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Anticorpos Monoclonais , Proliferação de Células , Camundongos SCID , Neoplasias da Próstata , Masculino , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/tratamento farmacológico , Animais , Humanos , Camundongos , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Fator de Crescimento Insulin-Like I/imunologiaRESUMO
Background: Peripheral myopathy consists a hallmark of heart failure (HF) and has been associated with poor prognosis. Inflammation has been suggested to dominate this pathology, while exercise training is typically associated with the induction of anti-inflammatory mechanisms. However, the current knowledge regarding the involvement of inflammation-related genes in the exercise training-induced muscle adaptations in HF patients is very limited. Given that high-intensity interval training (HIIT) alone or combined with strength training (COM) has gained ground in HF cardiac rehabilitation, this study aimed to investigate the local muscle expression of inflammatory and tissue remodeling factors in HF patients, who underwent 3 months of these training schemes. In addition, we examined whether these exercise training-induced gene expression responses are associated with changes in exercise capacity in those patients. Methods: Thirteen male patients with chronic HF (age: 51 ± 13 y; body mass index (BMI): 27 ± 4 kg/ m 2 ) were randomly assigned to a 3-month exercise program consisted of either HIIT (N = 6) or COM training (N = 7). Muscle tissue biopsies were obtained from vastus lateralis pre- and post-training and transcriptional changes in interleukin 6 (IL-6), interleukin 8 (IL-8), tumor necrosis factor-1 alpha (TNF-1 α ), urokinase-type plasminogen activator (uPA), urokinase-type plasminogen activator receptor (uPAR), and transforming growth factor-beta 1 (TGF- ß 1) were quantified by RT-PCR. Results: An overall increase in the expression levels of selected inflammatory (IL-8, TNF-1 α ) and remodeling factors (uPAR) was found post-training (p < 0.05), while IL-6, uPA and TGF- ß 1 gene expression remained unchanged (p > 0.05). The observed alterations did not differ between training groups. Additionally, IL-8 changes were found to be correlated with the improvement in exercise capacity post-training (p < 0.05). Conclusions: This is the first study demonstrating an increase in intramuscular inflammatory and remodeling key factors induced by HIIT or COM training in HF patients. Combining these observations with our previous findings of improved muscle hypertrophy and capillarization post-training in these patients, the findings of the present study may suggest that inflammatory responses are part of an ongoing remodeling process in the exercising skeletal muscle. Clinical Trial Registration: NCT02387411.
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OBJECTIVES: Vitamin D deficiency has been observed in autoimmune rheumatic diseases, such as rheumatoid arthritis. The aim was to study vitamin D in patients with systemic lupus erythematosus (SLE) and its relationship with disease activity. METHODS: In a cohort of 45 patients with SLE, 41 females and 4 males, aged 47.07 ± 2.17 years (mean ± SEM), and range = 21-79 years, 25(OH)D3 levels were determined by electrochemiluminescence. C3 and C4 levels were also analyzed. SLE disease activity was estimated by SLEDAI-2K. Observations were also performed in a control group matched for age and sex. RESULTS: In this cohort of SLE patients, 25(OH)D3 levels were 40.36 ± 2.41 nmol/L (mean ± SEM) as opposed to 60.98 ± 4.28 nmol/L in the control group (p < 0.001, Student's t test). Vitamin D levels were related to C3 (p < 0.001, linear regression analysis), correlation coefficient 0.106, r2 = 0.011, and C4 (p < 0.001); correlation coefficient 0.316 and r2 = 0.100; and inversely related to disease activity (p < 0.001), correlation coefficient -0.572 and r2 = 0.327. 25(OH)D3 levels were 17.73 ± 1.20 nmol/L and 12.24 ± 0.93 nmol/L, in the groups without and with renal involvement, respectively (p = 0.001, Student's t test). CONCLUSIONS: Vitamin D levels are low in SLE patients and are inversely related to disease activity. Routine screening for vitamin D levels should be performed in SLE patients.
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Doenças Autoimunes , Lúpus Eritematoso Sistêmico , Deficiência de Vitamina D , Vitamina D/análise , Feminino , Grécia , Humanos , Masculino , Vitamina D/química , Deficiência de Vitamina D/epidemiologiaRESUMO
PURPOSE: To investigate whether preimplantation genetic testing for aneuploidy (PGT-A) improves the clinical outcome in patients with advanced maternal age (AMA), recurrent miscarriages (RM), and recurrent implantation failure (RIF). METHODS: Retrospective cohort study from a single IVF center and a single genetics laboratory. One hundred seventy-six patients undergoing PGT-A were assigned to three groups: an AMA group, an RM group, and a RIF group. Two hundred seventy-nine patients that did not undergo PGT-A were used as controls and subgrouped similarly to the PGT-A cohort. For the PGT-A groups, trophectoderm biopsy was performed and array comparative genomic hybridization was used for PGT-A. Clinical outcomes were compared with the control groups. RESULTS: In the RM group, we observed a significant decrease of early pregnancy loss rates in the PGT-A group (18.1% vs 75%) and a significant increase in live birth rate per transfer (50% vs 12.5%) and live birth rate per patient (36% vs 12.5%). In the RIF group, a statistically significant increase in the implantation rate per transfer (69.5% vs 33.3%) as well as the live birth rate per embryo transfer (47.8% vs 19%) was observed. In the AMA group, a statistically significant reduction in biochemical pregnancy loss was observed (3.7% vs 31.5%); however, live birth rates per embryo transfer and per patient were not significantly higher than the control group. CONCLUSION: Our results agree with recently published studies, which suggest caution in the universal application of PGT-A in women with infertility. Instead, a more personalized approach by choosing the right candidates for PGT-A intervention should be followed.
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Aborto Habitual , Diagnóstico Pré-Implantação , Aborto Habitual/diagnóstico , Aborto Habitual/genética , Aneuploidia , Hibridização Genômica Comparativa , Feminino , Fertilização in vitro/métodos , Testes Genéticos/métodos , Humanos , Gravidez , Taxa de Gravidez , Diagnóstico Pré-Implantação/métodos , Estudos RetrospectivosRESUMO
Hepatocellular carcinoma (HCC) may still develop in chronic hepatitis B (CHB) patients even under effective long-term oral antiviral therapy, but its pathogenesis in the setting of long-standing inhibition of viral replication has not been completely elucidated. We investigated whether species of circulating cell-free DNA (cfDNA) may be involved in the process of hepatocarcinogenesis in treated CHB patients. Serum samples were obtained from HBeAg-negative CHB patients with (HCC cases, n = 37) or without HCC development during the first 5 years of oral antiviral therapy (controls, n = 74). HCC cases and controls were matched 1:2 for age, sex and platelets. Determination of different circulating cfDNA species (before HCC diagnosis in HCC cases) including total cfDNA quantity, levels of Alu repeat DNA and RNase P coding DNA, copies of mitochondrial DNA and levels of 5-methyl-2'-deoxycytidine as an indicator of DNA methylation was performed. HCC cases compared with controls had higher median levels of Alu247 (123 vs 69 genomic equivalent, p = .042) and RNase P coding DNA (68 vs 15 genomic equivalent, p < .001). In contrast, median cfDNA concentration, Alu115 levels, Alu247/Alu115 ratio as an index of DNA integrity and mitochondrial DNA copies did not differ significantly between HCC cases and controls. Receiver operating characteristic curve analysis showed that levels RNase P coding DNA offered good prediction of subsequent HCC development (c-statistic: 0.80, p < .001). In conclusion, serum levels of RNase P coding DNA are increased years before HCC diagnosis and could be potentially helpful in the prediction of the HCC risk in treated HBeAg-negative CHB patients.
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Carcinoma Hepatocelular , DNA Tumoral Circulante , Hepatite B Crônica , Neoplasias Hepáticas , Antivirais/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/epidemiologia , Metilação de DNA , Vírus da Hepatite B/genética , Hepatite B Crônica/complicações , Hepatite B Crônica/tratamento farmacológico , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/epidemiologiaRESUMO
In recent years, cellular senescence has generated a lot of interest among researchers because of its involvement in both the normal aging process and common human diseases. During senescence, cells undergo alterations that include telomere shortening, nuclear area enlargement, and genomic and mitochondrial DNA damage, leading to irreversible cell cycle arrest, and secretion of proinflammatory cytokines. Evidence suggests that the complex process of senescence is involved in the development of a plethora of chronic diseases including metabolic and inflammatory disorders and tumorigenesis. Recently, several human and animal studies have emphasized the involvement of senescence in the pathogenesis and development of liver steatosis including the progression to nonalcoholic steatohepatitis (NASH) as characterized by the additional emergence of inflammation, hepatocyte ballooning, and liver fibrosis. The development of nonalcoholic fatty liver disease (NAFLD) and its progression to NASH are commonly accompanied by several pathophysiological events including metabolic dysregulation and inflammatory phenomena occurring within the liver that may contribute to or derive from cellular senescence, implying that the latter may be both a stimulus and a consequence of the disease. Conclusion: In this review, we summarize the current literature on the impact of cellular senescence in NAFLD/NASH and discuss the effectiveness and safety of novel senolytic drugs and therapeutic options available to delay or treat the disease. Finally, we identify the open questions and issues to be addressed in the near future.
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Senescência Celular , Hepatopatia Gordurosa não Alcoólica/etiologia , Animais , Pesquisa Biomédica/tendências , Senescência Celular/fisiologia , Progressão da Doença , Previsões , Humanos , Hepatopatia Gordurosa não Alcoólica/complicaçõesRESUMO
In Type 1 Diabetes Mellitus (T1DM), leukocyte infiltration of the pancreatic islets and the resulting immune-mediated destruction of beta cells precede hyperglycemia and clinical disease symptoms. In this context, the role of the pancreatic endothelium as a barrier for autoimmunity- and inflammation-related destruction of the islets is not well studied. Here, we identified Robo4, expressed on endothelial cells, as a regulator of pancreatic vascular endothelial permeability during autoimmune diabetes. Circulating levels of Robo4 were upregulated in mice subjected to the Multiple Low-Dose Streptozotocin (MLDS) model of diabetes. Upon MLDS induction, Robo4-deficiency resulted in increased pancreatic vascular permeability, leukocyte infiltration to the islets and islet apoptosis, associated with reduced insulin levels and faster diabetes development. On the contrary, in vivo administration of Slit2 in mice modestly delayed the emergence of hyperglycaemia and ameliorated islet inflammation in MLDS-induced diabetes. Thus, Robo4-mediated endothelial barrier integrity reduces insulitis and islet destruction in autoimmune diabetes. Our findings highlight the importance of the endothelium as gatekeeper of pancreatic inflammation during T1DM development and may pave the way for novel Robo4-related therapeutic approaches for autoimmune diabetes.
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Permeabilidade Capilar , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Células Endoteliais/metabolismo , Células Secretoras de Insulina/metabolismo , Receptores de Superfície Celular/metabolismo , Animais , Apoptose , Linhagem Celular , Células Cultivadas , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/patologia , Células Endoteliais/patologia , Humanos , Células Secretoras de Insulina/patologia , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Superfície Celular/sangue , Receptores de Superfície Celular/genéticaRESUMO
Cardiomyocytes possess the ability to respond to mechanical stimuli by reprogramming their gene expression. This study investigated the effects of different loading protocols on signaling and expression responses of myogenic, anabolic, inflammatory, atrophy and pro-apoptotic genes in cardiomyocyte-like H9C2 cells. Differentiated H9C2 cells underwent various stretching protocols by altering their elongation, frequency and duration, utilizing an in vitro cell tension system. The loading-induced expression changes of MyoD, Myogenin, MRF4, IGF-1 isoforms, Atrogin-1, Foxo1, Fuca and IL-6 were measured by Real Time-PCR. The stretching-induced activation of Akt and Erk 1/2 was also evaluated by Western blot analysis. Low strain (2.7% elongation), low frequency (0.25 Hz) and intermediate duration (12 h) stretching protocol was overall the most effective in inducing beneficial responses, i.e., protein synthesis along with the suppression of apoptosis, inflammation and atrophy, in the differentiated cardiomyocytes. These findings demonstrated that varying the characteristics of mechanical loading applied on H9C2 cells in vitro can regulate their anabolic/survival program.
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Apoptose/genética , Reprogramação Celular/genética , Hipertrofia/genética , Mecanotransdução Celular/genética , Miócitos Cardíacos/metabolismo , Animais , Morte Celular/genética , Linhagem Celular , Sobrevivência Celular/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Humanos , Hipertrofia/patologia , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Fator de Crescimento Insulin-Like I/genética , Sistema de Sinalização das MAP Quinases/genética , Proteínas Musculares/genética , Proteína MyoD/genética , Miócitos Cardíacos/patologia , Fatores de Regulação Miogênica/genética , Miogenina/genética , Ratos , Proteínas Ligases SKP Culina F-Box/genéticaRESUMO
Eccentric exercise has been extensively used as a model to study the contraction-induced muscle damage and its consequent processes. This study aimed at examining molecular responses associated with tissue remodelling, inflammation and angiogenesis in skeletal muscle during the recovery period after eccentric exercise in humans. Ten healthy men performed 50 maximal eccentric muscle actions with the knee extensors and muscle biopsies were collected from the vastus lateralis before and 6 h, 48 h and 120 h post eccentric exercise. Real Time-PCR was utilized to investigate alterations in gene expression of various tissue remodelling-, inflammation- and angiogenesis-related factors: uPA, uPA-R, TGF-ß1, MMP-9, TNF-α, IL-6, IL-8, VEGF, VEGFR-2, HIF-1a, Ang-1, Ang-2 and Tie-2. The uPA/uPA-R system exhibited a similar time-expression pattern increasing 6 h post exercise (p < 0.05), while the other tissue remodelling factors TGF-ß1 and MMP-9 did not change significantly over time. Transcriptional responses of inflammatory factors TNF-α and IL-8 increased significantly and peaked 6 h post eccentric exercise (p < 0.05), while IL-6 exhibited a similar, though not statistically significant, expression profile (p > 0.05). Similarly, the expression of angiopoietin receptor Tie-2 showed an early increase only at 6 h after the completion of exercise (p < 0.05), while the other angiogenic factors failed to reach statistical significance due a high interindividual variability in the gene expression responses. The early transcriptional upregulation of tissue remodelling, inflammation- and angiogenesis-related factors post eccentric exercise may indicate the acute intramuscular activation of these processes functionally related to muscle damage-induced adaptation.
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Exercício Físico/fisiologia , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiologia , Adulto , Indutores da Angiogênese/metabolismo , Citocinas/metabolismo , Expressão Gênica/genética , Voluntários Saudáveis , Humanos , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Masculino , Contração Muscular/fisiologia , Neovascularização Fisiológica/fisiologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The human blood plasma proteome profile has been an area of intensive investigation and differential scanning calorimetry (DSC) has come forward as a novel tool in analyzing plasma heat capacity changes to monitor various physiological responses in health and disease. This study used DSC to assess potential alterations in the plasma heat capacity profile of albumin and globulins during extremely demanding physical exercise. We monitored the changes in denaturation profiles of those plasma proteins for five consecutive days of an extraordinary exercise training schedule in 14 young male Special Forces volunteers, as well as after a 30-day recovery period. The major effect of the prolonged intense exercise was the continuous upward shift of the albumin peak by 2°-3 °C on the initial days of exercise, with a tendency to plateau circa the 5th day of exercise. In addition, some redistribution of the denaturational enthalpy was observed upon exercise, where the globulins peak increased relative to the albumin peak. Noteworthy, the alterations in the plasma proteome denaturational profiles were not persistent, as virtually full recovery of the initial status was observed after 30 days of recovery. Our findings indicate that 5 days of exhaustive physical exercise of highly trained individuals enhanced the thermal stability of plasma albumin shifting its denaturational transition to higher temperatures. We surmise that these effects may be a result of increased blood oxygenation during the prolonged intense exercise and, consequently, of albumin oxidation as part of the overall adaptation mechanisms of the body to extreme physical and/or oxidative stress.
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Proteínas Sanguíneas/metabolismo , Exercício Físico , Temperatura Alta , Adaptação Fisiológica , Adulto , Varredura Diferencial de Calorimetria , Grécia , Humanos , Masculino , Militares , Desnaturação Proteica , Voluntários , Adulto JovemRESUMO
The pathogenetic mechanisms involved in the progression of non-alcoholic fatty liver disease (NAFLD) have not been completely elucidated, while the significance of circulating cell-free DNA (cf-DNA) species has been rarely evaluated in NAFLD. Herein, we assessed the serum levels of cf-DNA species in NAFLD patients and investigated their potential associations with patients' characteristics and severity of liver disease. Forty-nine adult patients with NAFLD of any stage were included in this cohort study. Cf-DNA was isolated from patients' sera and the levels of several distinct cf-DNA species including total cf-DNA, gene-coding cf-DNA, Alu repeat sequences, mitochondrial DNA copies and 5-methyl-2'-deoxycytidine were determined. Cirrhotic compared to non-cirrhotic patients had significantly lower serum levels of cf-DNA and RNAse P coding DNA as well as higher expression of 5-methyl-2'-deoxycytidine. After adjustment for the significant clinico-epidemiological factors, lower serum levels of cf-DNA or RNAse P were independently associated with the presence of cirrhosis. Serum levels of total and gene-coding DNA are associated with the presence of cirrhosis in NAFLD patients regardless of clinical or epidemiological parameters and may therefore be used as a screening tool for NAFLD progression.
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Ácidos Nucleicos Livres/sangue , Cirrose Hepática/fisiopatologia , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Índice de Gravidade de Doença , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Ácidos Nucleicos Livres/genética , Estudos de Coortes , Grécia/epidemiologia , Humanos , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/genética , Fatores de Risco , Adulto JovemRESUMO
The process of myogenesis gradually deteriorates as the skeletal muscle ages, contributing to muscle mass loss. The aim of this study is to investigate the effect of senescence/aging on skeletal myogenesis, in vitro. A model of multiple cell divisions of C2C12 myoblasts was used to replicate cell senescence. Control and aged myoblasts were investigated during myogenesis, i.e., at days 0, 2, and 6of differentiation. SA-ß-gal activity and comet assay were used as markers of aging and DNA damage. Flow cytometry was performed to characterize potential differences in cell cycle between control and aged cells. Alterations in the mRNA and/or protein expression of myogenic regulatory factors (MRFs), IGF-1 isoforms, apoptotic, atrophy, inflammatory, metabolic and aging-related factors were evaluated. Compared with the control cells, aged myoblasts exhibited G0/G1 cell cycle arrest, DNA damage, increased SA-ß-gal activity, and increased expression of aging-related factors p16 and p21 during differentiation. Moreover, aged myoblasts showed a reduction in the expression of MRFs and metabolic/anabolic factors, along with an increased expression of apoptotic, atrophy and inflammatory factors. A diminished differentiation capacity characterized the aged myoblasts which, in combination with the induction of apoptotic and atrophy factors, indicated a disrupted myogenic lineage in the senescent muscle cells.
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Senescência Celular , Desenvolvimento Muscular , Animais , Linhagem Celular , Camundongos , Mioblastos/metabolismo , Fatores de Regulação Miogênica/metabolismoRESUMO
Developmental arrest of the preimplantation embryo is a multifactorial condition, characterized by lack of cellular division for at least 24 hours, hindering the in vitro fertilization cycle outcome. This systematic review aims to present the molecular drivers of developmental arrest, focusing on embryonic and parental factors. A systematic search in PubMed/Medline, Embase and Cochrane-Central-Database was performed in January 2021. A total of 76 studies were included. The identified embryonic factors associated with arrest included gene variations, mitochondrial DNA copy number, methylation patterns, chromosomal abnormalities, metabolic profile and morphological features. Parental factors included, gene variation, protein expression levels and infertility etiology. A valuable conclusion emerging through critical analysis indicated that genetic origins of developmental arrest analyzed from the perspective of parental infertility etiology and the embryo itself, share common ground. This is a unique and long-overdue contribution to literature that for the first time presents an all-inclusive methodological report on the molecular drivers leading to preimplantation embryos' arrested development. The variety and heterogeneity of developmental arrest drivers, along with their inevitable intertwining relationships does not allow for prioritization on the factors playing a more definitive role in arrested development. This systematic review provides the basis for further research in the field.
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Blastocisto/patologia , Embrião de Mamíferos/patologia , Desenvolvimento Embrionário , Fertilização in vitro , HumanosRESUMO
Senescence is considered to be a cardinal player in several chronic inflammatory and metabolic pathologies. The two dominant mechanisms of senescence include replicative senescence, predominantly depending on age-induced telomere shortening, and stress-induced senescence, triggered by external or intracellular harmful stimuli. Recent data indicate that hepatocyte senescence is involved in the development of nonalcoholic fatty liver disease (NAFLD). However, previous studies have mainly focused on age-related senescence during NAFLD, in the presence or absence of obesity, while information about whether the phenomenon is characterized by replicative or stress-induced senescence, especially in non-aged organisms, is scarce. Herein, we subjected young mice to two different diet-induced NAFLD models which differed in the presence of obesity. In both models, liver fat accumulation and increased hepatic mRNA expression of steatosis-related genes were accompanied by hepatic senescence, indicated by the increased expression of senescence-associated genes and the presence of a robust hybrid histo-/immunochemical senescence-specific staining in the liver. Surprisingly, telomere length and global DNA methylation did not differ between the steatotic and the control livers, while malondialdehyde, a marker of oxidative stress, was upregulated in the mouse NAFLD livers. These findings suggest that senescence accompanies NAFLD emergence, even in non-aged organisms, and highlight the role of stress-induced senescence during steatosis development independently of obesity.
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Senescência Celular , Fígado/patologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/metabolismo , Animais , Metilação de DNA , Dieta Hiperlipídica , Feminino , Hepatócitos/metabolismo , Resistência à Insulina , Peroxidação de Lipídeos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo , RNA Mensageiro/metabolismo , Telômero/metabolismo , Telômero/ultraestruturaRESUMO
PURPOSE OF REVIEW: Heart failure (HF) is a structural or functional cardiac abnormality which leads to failure of the heart to deliver oxygen commensurately with the requirements of the tissues and it may progress to a generalized wasting of skeletal muscle, fat tissue, and bone tissue (cardiac cachexia). Clinically, dyspnea, fatigue, and exercise intolerance are some typical signs and symptoms that characterize HF patients. This review focused on the phenotypic characteristics of HF-induced skeletal myopathy as well as the mechanisms of muscle wasting due to HF and highlighted possible therapeutic strategies for skeletal muscle wasting in HF. RECENT FINDINGS: The impaired exercise capacity of those patients is not attributed to the reduced blood flow in the exercising muscles, but rather to abnormal metabolic responses, myocyte apoptosis and atrophy of skeletal muscle. Specifically, the development of skeletal muscle wasting in chronic HF is characterized by structural, metabolic, and functional abnormalities in skeletal muscle and may be a result not only of reduced physical activity, but also of metabolic or hormonal derangements that favour catabolism over anabolism. In particular, abnormal energy metabolism, mitochondrial dysfunction, transition of myofibers from type I to type II, muscle atrophy, and reduction in muscular strength are included in skeletal muscle abnormalities which play a central role in the decreased exercise capacity of HF patients. Skeletal muscle alterations and exercise intolerance observed in HF are reversible by exercise training, since it is the only demonstrated intervention able to improve skeletal muscle metabolism, growth factor activity, and functional capacity and to reverse peripheral abnormalities.
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Metabolismo Energético , Exercício Físico/fisiologia , Insuficiência Cardíaca/complicações , Músculo Esquelético/fisiopatologia , Atrofia Muscular/etiologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Músculo Esquelético/metabolismo , Atrofia Muscular/fisiopatologiaRESUMO
PURPOSE: This systematic review including a meta-analytical approach aims to investigate the safety and efficacy of employing a double ovarian stimulation (DuoStim) and a subsequent double oocyte retrieval in the same menstrual cycle, in poor ovarian reserve (POR) patients. METHODS: A systematic search of literature was performed in the databases of PubMed/MEDLINE, Embase, and Cochrane Central Library up until March 2019. Both prospective and retrospective cohort studies considered suitable for inclusion reported on women with POR undergoing a DuoStim in the follicular (FPS) and luteal phase (LPS) of the same menstrual cycle. Following the systematic review of the literature, a meta-analytical approach was attempted. RESULTS: This study indicates that DuoStim is correlated with a higher number of retrieved oocytes, mature MII oocytes, and good-quality embryos in comparison to conventional stimulation. Additionally, LPS seems to be correlated with an equal or an even higher overall performance in comparison to FPS. CONCLUSION: DuoStim favors an enhanced clinical outcome in regard to the total number of yielded oocytes, mature oocytes, and available embryos, along with the quality of obtained embryos. Sourced data indicate that LPS is not correlated with a higher aneuploidy rate. This option may present as promising for the time-sensitive nature of POR patients' management, by enabling a higher oocyte yield during a single menstrual cycle.
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Infertilidade Feminina/terapia , Ciclo Menstrual , Recuperação de Oócitos/métodos , Oócitos/citologia , Oócitos/fisiologia , Reserva Ovariana , Indução da Ovulação/métodos , Feminino , HumanosRESUMO
PURPOSE: The aim of this study is to provide data on the practice of Luteal Phase Oocyte Retrieval (LuPOR). The authors assess cell-free DNA levels in follicular fluid (ff cfDNA) from poor responders undergoing natural cycles, and comparing it to respective data originating from follicular phase oocyte retrievals. METHODS: Forty-seven women were eligible for this prospective study. Participants were classified as poor responders based on Bologna criteria while being detected with a second follicular wave. Follicular fluid was collected and prepared for cfDNA extraction. Levels of cfDNA were quantified via Q-PCR employing the ALU115 and ALU247 primers. These primers are associated with apoptotic and necrotic events. Levels of ff cfDNA resulting from follicular phase oocyte retrieval (FoPOR) and LuPOR-performed in a single menstrual cycle were associated with the number and maturation status of yielded oocytes and the number and fertilization status of resulting zygotes. Survival rate following thawing of cryopreserved zygotes, along with the resulting number of cleavage stage and blastocyst stage embryos are provided. RESULTS: Mean levels of ALU115 were significantly lower during FoPOR when compared to LuPOR (0.79 ± 0.72 vs 1.46 ± 1.59 ng/µl, p = 0.02). Regarding the FoPOR group, a significant positive correlation of serum estradiol and ALU115 concentration (p = 0.04) was revealed. A significant negative correlation between serum estradiol and cfDNA integrity was observed both during FoPOR (p = 0.03) and LuPOR (p = 0.03). A significant lower number of retrieved (1.09 ± 0.28 vs 1.29 ± 0.58, p = 0.02) and MII oocytes (0.77 ± 0.55 vs 1.08 ± 0.61, p = 0.02) was observed when comparing the FoPOR to LuPOR groups respectively. The integrity of cfDNA was observed to be higher in FoPOR originating embryos that arrested either prior to cleavage (0.28 ± 0.13 vs 0.17 ± 0.10, p = 0.006) or prior to blastocyst formation (0.28 ± 0.12 vs 0.13 ± 0.06, p = 0.04). In the case of LuPOR originating embryos, cfDNA integrity was observed to be higher in embryos that arrested only prior to the blastocyst stage (0.27 ± 0.20 vs 0.11 ± 0.07, p = 0.008). Similarly, cfDNA integrity was observed to be lower in top quality blastocysts originating from FoPOR (0.07 ± 0.04 vs 0.17 ± 0.05, p = 0.03) and in top quality cleavage stage embryos (0.09 ± 0.06 vs 0.31 ± 0.22, p = 0.01) and blastocysts (0.06 ± 0.02 vs 0.14 ± 0.06, p = 0.02) originating from LuPOR. CONCLUSIONS: Our results indicate that ff originating from LuPOR presents with higher levels of cfDNA. The higher cfDNA levels are attributed to mainly apoptotic events, as the ALU247 levels and DNA integrity did not differ statistically significantly between FoPOR and LuPOR. The absolute mean level of ALU247 corresponding to necrotic events was higher in LuPOR. Regarding embryological data, cfDNA integrity was correlated with both number and quality of cleavage stage embryos in both FoPOR and LuPOR, along with blastocyst stage embryos in LuPOR. Necrotic events were associated with poorer blastocyst formation rate and blastocyst quality in LuPOR. As the comparison between FoPOR and LuPOR results to similar IVF laboratory data, the practice of LuPOR may stand as a promising approach for poor responders, while it merits further investigation.
Assuntos
Ácidos Nucleicos Livres/sangue , Fertilização in vitro , Fase Folicular/sangue , Infertilidade Feminina/sangue , Fase Luteal/sangue , Adulto , Elementos Alu/genética , Blastocisto/metabolismo , Ácidos Nucleicos Livres/química , Feminino , Líquido Folicular/química , Humanos , Infertilidade Feminina/patologia , Recuperação de Oócitos/métodos , Oócitos/crescimento & desenvolvimento , Oócitos/metabolismo , Folículo Ovariano/metabolismo , Indução da Ovulação/métodos , Adulto JovemRESUMO
Background and Objectives: Clinicians are called to overcome age-related challenges in decision making during In Vitro Fertilization (IVF) treatment. The aim of this study was to investigate the possible impact of a single calendar year difference among patients aged 34, 35 and 36 on IVF outcomes. Materials and Methods: Medical records between 2008 and 2019 were analyzed retrospectively. The study group consisted of women diagnosed with tubal factor infertility. Sample size was divided in three categories at 34, 35 and 36 years of age. Embryo transfer including two blastocysts was performed for every patient. Comparisons were performed regarding hormonal profile, response to stimulation, quality of transferred embryos, positive hCG test and clinical pregnancy rate. Results: A total of 706 women were eligible to participate. Two-hundred and forty-eight women were 34, 226 were 35 while the remaining 232 were 36 years old. Regarding the hormonal profile, the number of accumulated oocytes and the quality of embryos transferred, no statistically significant difference was documented between the three age groups. Women aged 34 and 35 years old indicated a significantly increased positive hCG rate in comparison to women aged 36 years old (p-value = 0.009, p-value = 0.023, respectively). Women aged 34 and 35 years old presented with a higher clinical pregnancy rate in comparison to those aged 36 years old (p-value = 0.04, p-value = 0.05, respectively). Conclusion: A calendar year difference between patients undergoing IVF treatment at 34 or 35 years of age does not appear to exert any influence regarding outcome. When treatment involves patients above the age of 35, then a single calendar year may exert considerable impact on IVF outcome. This observation indicates that age 35 may serve as a valid cut-off point regarding IVF outcome.
Assuntos
Fatores Etários , Fertilização in vitro/normas , Indução da Ovulação/estatística & dados numéricos , Adulto , Tomada de Decisões , Feminino , Fertilização in vitro/métodos , Fertilização in vitro/estatística & dados numéricos , Humanos , Oócitos , Indução da Ovulação/métodos , Indução da Ovulação/normas , Gravidez , Estudos RetrospectivosRESUMO
Background and Objectives: The evaluative strength of available bibliometric tools in the field of clinical embryology has never been examined in the literature. The aim is to bring insight regarding the identity of clinical embryology research, introducing concerns when solely relying on the methodology of bibliometric analysis. Methods: An all-inclusive analysis of the most bibliometrically highlighted scientific contributions regarding the cornerstones of clinical embryology was performed employing the Scopus, Web of Science (WoS) and PubMed databases, between 1978-2018. An analysis of the number of publications, respective citations and h-index, g-index, along with m-quotient is presented. The top 30 contributing authors for each distinctive area of research are listed. An attempt at visualizing the yearly published articles, clusters, and collaborations of authors, along with the geographic origin of publications, is also presented. Results: Combining all searches and keywords yielded 54,522 results. In the Scopus database, employing the keyword "In Vitro Fertilization" yielded 41,292 results. The publications of the top five authors in each research field were analytically presented and compared to the total number of publications for each respective field. The research field of Preimplantation Genetic Diagnosis/Screening/Testing was allocated the highest percentage of publications produced by the top five authors. Regarding journal bibliometrics, based on the year 2017 metrics, there are only 29 journals according to WoS that refer to "Reproductive Biology", ranking it 187th among 235 disciplines. The USA produced the highest number of publications (12,537). Conclusion: Results indicate an explosion of interest published in the literature regarding the field of clinical embryology. Further analysis on collaborations and the trends involved should be of added value as productivity between countries varies significantly. This may guide researchers, in vitro fertilization professionals, and prospective authors during literature search, while proving useful regarding manuscript design and concurring on keywords and abstract content.
Assuntos
Embriologia/métodos , Pesquisa/normas , Bibliometria , Embriologia/tendências , Mapeamento Geográfico , Humanos , Pesquisa/tendênciasRESUMO
Polycystic Kidney Disease (PKD), which is attributable to mutations in the PKD1 and PKD2 genes encoding polycystin-1 (PC1) and polycystin-2 (PC2) respectively, shares common cellular defects with cancer, such as uncontrolled cell proliferation, abnormal differentiation and increased apoptosis. Interestingly, PC1 regulates many signalling pathways including Jak/STAT, mTOR, Wnt, AP-1 and calcineurin-NFAT which are also used by cancer cells for sending signals that will allow them to acquire and maintain malignant phenotypes. Nevertheless, the molecular relationship between polycystins and cancer is unknown. In this study, we investigated the role of PC1 in cancer biology using glioblastoma (GOS3), prostate (PC3), breast (MCF7), lung (A549) and colorectal (HT29) cancer cell lines. Our in vitro results propose that PC1 promotes cell migration in GOS3 cells and suppresses cell migration in A549 cells. In addition, PC1 enhances cell proliferation in GOS3 cells but inhibits it in MCF7, A549 and HT29 cells. We also found that PC1 up-regulates mTOR signalling and down-regulates Jak signalling in GOS3 cells, while it up-regulates mTOR signalling in PC3 and HT29 cells. Together, our study suggests that PC1 modulates cell proliferation and migration and interacts with mTOR and Jak signalling pathways in different cancer cell lines. Understanding the molecular details of how polycystins are associated with cancer may lead to the identification of new players in this devastating disease.