Participação do estresse de retículo endoplasmático no processo de morte celular em neutrófilos de ratos diabéticos.
Bibliographic record
Abstract
Endoplasmic reticulum (ER) has been gaining evidence when it comes to cell death.This organelle may go under stress conditions due to changes in protein formation, lack of ATP, disturbances in calcium signaling and alterations in the redox state.The accumulation of unfolded proteins initiates the activation of the Unfolded Protein Response (UPR).Currently, it is well established that the ER stress response is due to activation of three ER components: Inositol-Requiring kinase 1α (IRE1α), double-stranded RNA-activated protein kinase-like ER kinase (PERK) and Activating transcription factor 6 (ATF6).The UPR may resolve the ER stress by upregulating genes responsible to maintain the ER homeostasis; or it can activate genes that lead to the cell death when the ER disbalance is not solved.Hyperglycemia, one of many symptoms observed is Diabetes, may cause ER stress in various types of cells, for instance, pancreatic β-cells, osteoblasts and cardiomiocytes.Thus, this study aims to investigate the possible involvement of the ER stress in the process of cell death in neutrophils from diabetic rats.ER stress was evaluated by the expression of key genes: GRP78 (Bip), IRE-1, PERK, ATF-6 by PCR real time; the content of proteins related to the PERK pathway: PERK, eIF2α, peIF2α, ATF4, CHOP and GADD34; the content o pJNK, a protein related to cell death that is activated by IRE1α pathway; the content of ATF6 and sXBP1 resulted from the IRE1α activity.Also, the gene expression of MAM proteins related to the association between ER and mitochondria, Mitofusin 2, GRP75 and PACS2, were evaluated.MAM is related to the ER homeostasis and is very importat for calcium and ATP exechange between these twoorganelles.Finally, activity of caspases 3 by spectrofluorimetry and ROS production by chemoluminescence, using luminol, were measured.We observed higher expression of GRP78 (Bip) in the control group and higher expression of IRE1α in the diabetic and control group when they were stimulated with PMA.However, increase in IRE1α was observed in the non-stimulated state only in the diabetic group.This same pattern was observed in CHOP gene expression.The content of peIF2α was higher in the control group without stimulus and the other proteins of the PERK pathway showed no alteration.Gene expression of the MAM proteins was higher in the control group when neutrophils were stimulated with PMA.CHOP content was increased in the diabetic group.Finally, Caspase 3 activity and the reason Bax/Bcl2 were higher in the diabetic group stimulated with PMA.In summary, our study found that neutrophils from diabetic rats when stimulated with PMA exhibit greater susceptibility to death due to activation of IRE1α and subsequent phosphorylation of JNK, reduced safety in mitochondria-ER interaction in the MAM compartment and increased caspase-3 activation.We also conclude that these changes were not altered by ROS, since the two groups, control and diabetic, have the same profile of these species production when stimulated with PMA.Control group seems to be protect against the ER stress by ROS production by higher expression of GRP78 and MAM proteins.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".