1,720,971 research outputs found
Life-Long Hyperbilirubinemia Exposure and Bilirubin Priming Prevent In Vitro Metabolic Damage
No full textBackground: Unconjugated bilirubin (UCB) is more than the final product of heme catabolism. Mildly elevated systemic bilirubin concentrations, such as in Gilbert syndrome (GS), protect against various oxidative stress-mediated and metabolic diseases, including cardiovascular disease, type 2 diabetes mellitus, metabolic syndrome, cancer, and age-related disease. The Gunn rat is an animal model of hereditary hyperbilirubinemia widely used in assessing the effect of high serum bilirubin concentration in various organs. The present work aims to understand if life-long hyperbilirubinemia and bilirubin-priming might contribute to protection against atherosclerosis and diabetic nephropathy (DN) at the cellular level. Methods: Primary aortic endothelial cells and podocytes obtained from hyperbilirubinemic homozygous jj and normobilirubinemic heterozygous Nj Gunn rats were exposed to Palmitic Acid (PA) and Angiotensin II (Ang II), respectively, and the effects on cell viability and the activation of damage-related metabolic pathways evaluated. Results were validated on immortalized H5V and HK2 cells exposed to damage after UCB pretreatment. Results: In both primary cell models, cells obtained from jj Gunn rats showed as significantly higher than Nj Gunn rats at any dose of the toxic agent. Reduction in CHOP expression and IL-6 release was observed in jj primary aortic endothelial cells exposed to PA compared to Nj cells. The same occurred on H5V pretreated with Unconjugated bilirubin. Upon Ang II treatment, primary podocytes from jj Gunn rats showed lower DNA fragmentation, cleaved caspase-3, and cleaved PARP induction than primary podocytes from Nj Gunn rats. In HK2 cells, the induction by Ang II of HIF-1α and LOXl2 was significantly reduced by UCB pretreatment. Conclusion: Our data suggest that in models of atherosclerosis and DN life–long hyperbilirubinemia exposure or bilirubin-priming significantly contribute to decrease the injury by enhancing thecellular defensive response
Bilirubin disrupts calcium homeostasis in neonatal hippocampal neurons: a new pathway of neurotoxicity
Full text linkSevere hyperbilirubinemia leads to bilirubin encephalopathy in neonates, causing irreversible neurological sequelae. We investigated the nature of neuronal selective vulnerability to unconjugated bilirubin (UCB) toxicity. The maintenance of intracellular calcium homeostasis is crucial for neuron survival. Calcium release from endoplasmic reticulum (ER) during ER-stress can lead to apoptosis trough the activation of Caspase-12. By live calcium imaging we monitored the generation of calcium signals in dissociated hippocampal neurons and glial cells exposed to increasing UCB concentrations. We showed the ability of UCB to alter intracellular calcium homeostasis, inducing the appearance of repetitive intracellular calcium oscillations. The contribution of intracellular calcium stores and the induction and activation of proteins involved in the apoptotic calcium-dependent signaling were also assessed. Thapsigargin, a specific inhibitor of Sarco/endoplasmic reticulum ATPase (SERCA) pumps, significantly reduced the duration of Ca2+ oscillation associated with UCB exposure indicating that UCB strongly interfered with the reticulum calcium stores. On the contrary, in pure astrocyte cultures, spontaneous Ca2+ transient duration was not altered by UCB. The protein content of GRP78, AT6, CHOP, Calpain and Caspase-12 of neuronal cells treated with UCB for 24 h was at least twofold higher compared to controls. Calcium-dependent Calpain and Caspase-12 induction by UCB were significantly reduced by 50% and 98%, respectively when cells were pretreated with the ER-stress inhibitor 4-PBA. These results show the strong and direct interference of UCB with neuronal intracellular Ca2+dynamics, suggesting ER Ca2+ stores as a primary target of UCB toxicity with the activation of the apoptotic ER-stress-dependent pathway
Association of serum bilirubin level with metabolic syndrome and non-alcoholic fatty liver disease: A cross-sectional study of 1672 obese children
Full text linkAs in adults, obesity also plays a central role in the development of metabolic syndrome (MS) in children. Non-alcoholic fatty liver disease (NAFLD) is considered a manifestation of MS. Not only MS but also NAFLD seem to be inversely associated with serum bilirubin concentrations, an important endogenous tissue protector when only mild elevated. The aim of the study was to evaluate the association between serum bilirubin levels and the prevalence of MS and NAFLD in Italian obese children and adolescents. A retrospective cross-sectional study was performed in 1672 patients aged from 5 to 18 years. Clinical and laboratory parameters were assessed. NAFLD was measured by liver ultrasonography. The study was approved by the Ethical Committee of the Istituto Auxologico Italiano (research project code 1C021_2020, acronym BILOB). MS was present in 24% and fatty liver (FL) in 38% of this population. Bilirubin was not associated with FL and MS as a whole, but it was inversely associated only with selected components of MS, i.e., large WC, high blood pressure and high triglycerides. Our data suggest that bilirubin is not protective against MS and NAFLD in the presence of severe obesity
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
During apoptosis of tumor cells HMGA1a protein undergoes methylation: identification of the modification site by mass spectrometry.
No full textProgrammed cell death is characterized by posttranslational modifications of a limited and specific set of nuclear proteins. We demonstrate that during apoptosis of different types of tumor cells there is a monomethylation of the nuclear protein HMGA1a that is associated to its previously described hyperphosphorylation/dephosphorylation process. HMGA1a methylation is strictly related to the execution of programmed cell death and is a massive event that involves large amounts of the protein. In some tumor cells, HMGA1a protein is already methylated to an extent that depends on cell type. The degree of methylation in any case definitely increases during apoptosis. In the studied cell systems (human leukaemia, human prostate tumor, and rat thyroid transformed cells) among the low-molecular-mass HMG proteins, only HMGA1a was found to be methylated. A tryptic digestion map of HPLC-purified HMGA1a protein showed that methylation occurs at arginine 25 in the consensus G(24)R(25)G(26) that belongs to one of the DNA-binding AT-hooks of the protein. An increase of HMGA1a methylation could be related to heterochromatin and chromatin remodeling of apoptotic cells
UPREGULATION IN THE EXPRESSION OF MULTIDRUG RESISTANT PROTEIN MRP1 MRNA AND PROTEIN BY INCREASED BILIRUBIN PRODUCTION IN RAT.
No full textVariations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Importance of the correct assessment of bone fractures in the clinical management of metastatic castration-resistant prostate cancer treated with radium-223: A case report
No full textPatients who undergo radium-223 treatment for metastatic castration-resistant prostate cancer (mCRPC) generally have a long history of androgen deprivation therapy and/or steroid therapy, which leads to bone loss and causes osteoporosis. Notably, Osteoporosis in combination with metastatic bone disease increases the risk of bone fracture. An 84-year-old man with multi-metastatic bone CRPC underwent six administrations of intravenous radium-223, which induced a good biochemical and clinical response. However, two months following the treatment, the patient reported acute pain localized to the lumbar spine mimicking bone progression disease and presented with stable prostate-specific antigen levels. A prostate-specific membrane antigen-positron emission tomography scan showed no tracer uptake in that site, whereas a magnetic resonance imaging scan and subsequent vertebral biopsy confirmed the absence of cancer progression and showed the presence of vertebral crushing of L4-L5, which was probably due to an osteoporotic process. The patient had never received bisphosphonate therapy and refused it during alpha-emitting therapy with radium-223. The osteoporotic process, in association with metastatic bone disease, more easily leads to bone fractures that have an important impact on performance status, quality of life and prognosis quoad vitam in patients with advanced prostate cancer. Use of bisphosphonates or anti-RANKL antibody appears to be effective in improving bone mineral density. Notably, patients with multi-metastatic bone disease who undergo radium-223 therapy should be treated in conjunction with anti-osteoporotic therapy (bisphosphonates or anti-RANKL antibody) and adequate calcium and vitamin D supplementation. Early recognition and differentiation of osteoporotic processes when determining the progression of cancer-associated bone disease is crucial in evaluating the response to radium-223 therapy and, consequently, for further therapeutic decision making
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