scholarly journals Hearing Impairment in a Mouse Model of Diabetes Is Associated with Mitochondrial Dysfunction, Synaptopathy, and Activation of the Intrinsic Apoptosis Pathway

2021 ◽  
Vol 22 (16) ◽  
pp. 8807
Author(s):  
Ah-Ra Lyu ◽  
Tae-Hwan Kim ◽  
Sun-Ae Shin ◽  
Eung-Hyub Kim ◽  
Yang Yu ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Mouse Model ◽  
Mitochondrial Dysfunction ◽  
Hearing Impairment ◽  
B Cell Lymphoma ◽  
Diabetic Mice ◽  
Intrinsic Apoptosis ◽  
Apoptosis Pathway ◽  
Intrinsic Apoptosis Pathway ◽  
The Impact

Although previous studies continuously report an increased risk of hearing loss in diabetes patients, the impact of the disease on the inner ear remains unexplored. Herein, we examine the pathophysiology of diabetes-associated hearing impairment and cochlear synaptopathy in a mouse model of diabetes. Male B6.BKS(D)-Leprdb/J (db/db, diabetes) and heterozygote (db/+, control) mice were assigned into each experimental group (control vs. diabetes) based on the genotype and tested for hearing sensitivity every week from 6 weeks of age. Each cochlea was collected for histological and biological assays at 14 weeks of age. The diabetic mice exerted impaired hearing and a reduction in cochlear blood flow and C-terminal-binding protein 2 (CtBP2, a presynaptic ribbon marker) expression. Ultrastructural images revealed severely damaged mitochondria from diabetic cochlea accompanied by a reduction in Cytochrome c oxidase subunit 4 (COX4) and CR6-interacting factor 1 (CRIF1). The diabetic mice presented significantly decreased levels of platelet endothelial cell adhesion molecule (PECAM-1), B-cell lymphoma 2 (BCL-2), and procaspase-9, but not procaspase-8. Importantly, significant changes were not found in necroptotic programmed cell death markers (receptor-interacting serine/threonine-protein kinase 1, RIPK1; RIPK3; and mixed lineage kinase domain-like pseudokinase, MLKL) between the groups. Taken together, diabetic hearing loss is accompanied by synaptopathy, microangiopathy, damage to the mitochondrial structure/function, and activation of the intrinsic apoptosis pathway. Our results imply that mitochondrial dysfunction is deeply involved in diabetic hearing loss, and further suggests the potential benefits of therapeutic strategies targeting mitochondria.

Taking control of the female fertile lifespan: a key role for Bcl-2 family proteins

2016 ◽  
Vol 28 (7) ◽  
pp. 864 ◽  
Author(s):  
Seng H. Liew ◽  
Kavitha Vaithiyanathan ◽  
Karla J. Hutt
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Female Fertility ◽  
Intrinsic Apoptosis ◽  
Apoptosis Pathway ◽  
Primordial Follicles ◽  
Intrinsic Apoptosis Pathway ◽  
Reproductive Life ◽  
The Relationship

Precisely how the length of the female fertile lifespan is regulated is poorly understood and it is likely to involve complex factors, one of which is follicle number. Indeed, the duration of female fertility appears to be intimately linked to the number of available oocytes, which are stored in the ovary as primordial follicles. There is mounting evidence implicating the intrinsic apoptosis pathway, which is controlled by members of the B-cell lymphoma-2 (BCL-2) family, as a key regulator of the number of primordial follicles established in the ovary at birth and maintained throughout reproductive life. Consequently, the pro- and anti-apoptotic BCL-2 family proteins are emerging as key determinants of the length of the female fertile lifespan. This review discusses the relationship between the intrinsic apoptosis pathway, follicle number and length of the female fertile lifespan.

scholarly journals Intrinsic Apoptosis Pathway in Fallopian Tube Epithelial Cells Induced by Cladribine

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Ewelina Wawryk-Gawda ◽  
Patrycja Chylińska-Wrzos ◽  
Marta Lis-Sochocka ◽  
Kamila Bulak ◽  
Barbara Jodłowska-Jędrych
Keyword(s):  
Epithelial Cells ◽  
P53 Protein ◽  
Female Rats ◽  
Intrinsic Apoptosis ◽  
Intrinsic Pathway ◽  
Apoptosis Pathway ◽  
Intrinsic Apoptosis Pathway ◽  
Oviduct Epithelial Cells ◽  
The Impact ◽  
Apoptotic Mechanism

Cladribine is a purine nucleoside analog which initiates the apoptotic mechanism within cells. Moreover, the available data confirms that cladribine, with the participation of the p53 protein, as well as the proapoptotic proteins from the Bcl-2 family, also induces the activation of the intrinsic apoptosis pathway. However, while there has been a lot of research devoted to the effect of cladribine on lymphatic system cells, little is known about the impact of cladribine on the reproductive system. The aim of our study was to evaluate apoptosis in oviduct epithelial cells sourced from 15 different female rats. In so doing, the sections were stained with caspases 3, 9, and 8. Results suggest that cladribine also induces apoptosis in the oviduct epithelial cells by way of the intrinsic pathway. Indeed, the discontinuing of the administration of cladribine leads to a reduction in the amount of apoptotic cells in the oviduct epithelium.

Polymorphisms in key regulator genes of the intrinsic apoptosis pathway in risk and clinical presentation of diffuse large B-cell lymphoma

2016 ◽  
Vol 35 (4) ◽  
pp. 911-913
Author(s):  
Angelo Borsarelli Carvalho Brito ◽  
Marcia Torresan Delamain ◽  
Cristiane de Oliveira ◽  
Carmino Antonio de Souza ◽  
José Vassallo ◽  
...  
Keyword(s):  
B Cell ◽  
Clinical Presentation ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Intrinsic Apoptosis ◽  
Apoptosis Pathway ◽  
Large B Cell Lymphoma ◽  
Intrinsic Apoptosis Pathway ◽  
Regulator Genes ◽  
Large B Cell

scholarly journals Targeting mitochondrial respiration and the BCL2 family in MYC-associated B-cell lymphoma

2020 ◽  
Author(s):  
Giulio Donati ◽  
Micol Ravà ◽  
Marco Filipuzzi ◽  
Paola Nicoli ◽  
Laura Cassina ◽  
...  
Keyword(s):  
Oxidative Phosphorylation ◽  
B Cell ◽  
Complex I ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
High Grade ◽  
Apoptosis Pathway ◽  
Bcl2 Family ◽  
Molecular Features ◽  
Intrinsic Apoptosis Pathway

AbstractMultiple molecular features, such as activation of specific oncogenes (e. g. MYC, BCL2) or a variety of gene expression signatures, have been associated with disease course in diffuse large B-cell lymphoma (DLBCL). Understanding the relationships between these features and their possible exploitation toward disease classification and therapy remains a major priority in the field. Here, we report that MYC activity in DLBCL is closely correlated with – and most likely a driver of – gene signatures related to Oxidative Phosphorylation (OxPhos). On this basis, we hypothesized that enzymes involved in Oxidative Phosphorylation, and in particular electron-transport chain (ETC) complexes, might constitute tractable therapeutic targets in MYC-associated lymphoma. Indeed, our data show that MYC sensitizes B-cells to IACS-010759, a selective inhibitor of ETC complex I. Mechanistically, IACS-010759 activates an ATF4-driven Integrated Stress Response (ISR), engaging the intrinsic apoptosis pathway through the transcription factor CHOP. In line with these findings, IACS-010759 shows synergy with the BCL2 inhibitor venetoclax against double-hit lymphoma (DHL), a high-grade form of DLBCL with concurrent activation of MYC and BCL2. Similarly, in BCL2-negative lymphoma cell lines, inhibition of the BCL2-related protein Mcl-1 potentiates killing by IACS-010759. Altogether, ETC complex I inhibition engages the ISR to lower the apoptotic threshold in MYC-driven lymphomas and, in combination with select BCL2-family inhibitors, provides a novel therapeutic principle against this aggressive DLBCL subset.Statement of significanceThis work points to OxPhos as a key MYC-activated process and a tractable therapeutic target toward personalized treatment of high-grade DLBCL, providing strong context-dependent cooperation with BH3-mimetic compounds.

scholarly journals Тhe effects of auditory amplification on subjective assessments of hearing impairment and anxiety in people with presbycusis

2019 ◽  
Vol 147 (7-8) ◽  
pp. 461-467
Author(s):  
Ivana Maletic-Sekulic ◽  
Stasa Petkovic ◽  
Ninoslava Dragutinovic ◽  
Ivana Veselinovic ◽  
Ljiljana Jelicic
Keyword(s):  
Hearing Loss ◽  
Hearing Impairment ◽  
Statistical Significance ◽  
Later Life ◽  
The Elderly ◽  
Favorable Effect ◽  
Hearing Disability ◽  
Study Results ◽  
Auditory Amplification ◽  
The Impact

Introduction/Objective. Presbycusis, elderly hearing loss, is a progressive, bilateral sensoryneural hearing loss characterized by reduced sensitivity of hearing and understanding speech in a noisy environment, thereby impairing communication and inducing anxiety. The objective was to examine the impact of hearing amplification on subjective hearing disability assessment and anxiety in people with presbycusis. Method. Sample consisted of 120 respondents aged 47?85 with presbycusis, 60 subjects with and 60 subjects with no auditory amplification. The standardized Hearing Handicap Inventory for the Elderly and the Spielberger State Trait Anxiety Inventory were used in the study. Results. In subjects with hearing amplification, test/retest has no statistical significance in the STAI and HHIE scales and subscales, except the HHIE-S (p = 0.004) with a lower score on the retest. Respondents in whom hearing amplification was performed during the year was statistically significant in HHIE (p = 0.016), HHIE-S (p = 0.004) and STAI-S (p = 0.029) which speaks of favorable effect of hearing amplification. In the group with no hearing amplification, statistical significance was observed in relation to the HHIE scores (p = 0.002), HHIE-E (p = 0.000), STAI (p = 0.000), STAI-S (p = 0.001) and STAI-T (p = 0.001) and it was noticed that anxiety, loss of emotional contacts, and more pronounced degree of hearing impairment were the result of unassisted hearing rehabilitation. Conclusion. Audiological practice should include tests for assessment of hearing disability and anxiety in order to preserve health in later life.

scholarly journals Amphiregulin Regulates Phagocytosis-Induced Cell Death in Monocytes via EGFR and the Bcl-2 Protein Family

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Christopher Platen ◽  
Stephan Dreschers ◽  
Jessica Wappler ◽  
Andreas Ludwig ◽  
Stefan Düsterhöft ◽  
...  
Keyword(s):  
Cell Death ◽  
Bacterial Infections ◽  
Caspase 3 ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Dependent Manner ◽  
Intrinsic Apoptosis ◽  
Caspase 9 ◽  
Apoptosis Pathway ◽  
Intrinsic Apoptosis Pathway

Neonates are extremely susceptible to bacterial infections, and evidences suggest that phagocytosis-induced cell death (PICD) is less frequently triggered in neonatal monocytes than in monocytes from adult donors. An insufficient termination of the inflammatory response, leading to a prolonged survival of neonatal monocytes with ongoing proinflammatory cytokine release, could be associated with the progression of various inflammatory diseases in neonates. Our previous data indicate that amphiregulin (AREG) is increasingly expressed on the cell surface of neonatal monocytes, resulting in remarkably higher soluble AREG levels after proteolytic shedding. In this study, we found that E. coli-infected neonatal monocytes show an increased phosphorylation of ERK, increased expression of Bcl-2 and Bcl-XL, and reduced levels of cleaved caspase-3 and caspase-9 compared to adult monocytes. In both cell types, additional stimulation with soluble AREG further increased ERK activation and expression of Bcl-2 and Bcl-XL and reduced levels of cleaved caspase-3 and caspase-9 in an EGFR-dependent manner. These data suggest that reduced PICD of neonatal monocytes could be due to reduced intrinsic apoptosis and that AREG can promote protection against PICD. This reduction of the intrinsic apoptosis pathway in neonatal monocytes could be relevant for severely prolonged inflammatory responses of neonates.

Sign in / Sign up

Export Citation Format

Share Document