scholarly journals Impaired peroxisomal import in Drosophila hepatocyte-like cells induces cardiac dysfunction through the pro-inflammatory cytokine Upd3

2019 ◽  
Author(s):  
Kerui Huang ◽  
Ting Miao ◽  
Kai Chang ◽  
Ping Kang ◽  
Qiuhan Jiang ◽  
...  
Keyword(s):  
Cardiac Dysfunction ◽  
Inflammatory Cytokine ◽  
Cytokine Signaling ◽  
Over Expression ◽  
Autonomous Regulation ◽  
Age Related ◽  
Evolutionarily Conserved ◽  
Age Dependent ◽  
Import Receptor

AbstractAge is a major risk factor for cardiovascular diseases. Currently, the non-autonomous regulation of age-related cardiac dysfunction is poorly understood. In the present study, we discover that age-dependent induction of cytokine unpaired 3 (Upd3) in Drosophila oenocytes (hepatocyte-like cells), due to a dampened peroxisomal import function, is the primary non-autonomous mechanism for elevated arrhythmicity in old hearts. We show that Upd3 is significantly up-regulated (52-fold) in aged oenocytes. Oenocyte-specific knockdown of Upd3 is sufficient to block aging-induced cardiac arrhythmia. We further show that the age-dependent induction of Upd3 is triggered by impaired peroxisomal import and elevated JNK signaling in aged oenocytes. Intriguingly, oenocyte-specific over-expression of Pex5, the key peroxisomal import receptor, restores peroxisomal import, blocks age-related Upd3 induction, and alleviates aging- and paraquat-induced cardiac arrhythmicity. Thus, our studies identify an important role of the evolutionarily conserved pro-inflammatory cytokine signaling and hepatocyte-specific peroxisomal import in mediating non-autonomous regulation of cardiac aging.

Abstract 87: Loss of Mir-155 Attenuates Sepsis Induced Cardiac Dysfunction

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Hui Wang ◽  
Yihua Bei ◽  
Jing Shi ◽  
Wei Sun ◽  
Peipei Huang ◽  
...  
Keyword(s):  
Cardiac Dysfunction ◽  
Foam Cell ◽  
Cardiac Metabolism ◽  
Significant Inhibition ◽  
Gene Expressions ◽  
Over Expression ◽  
Pathological Cardiac Hypertrophy ◽  
Lps Treatment ◽  
Fractional Shortening

Objective: Sepsis induced cardiac dysfunction is featured by inflammation and metabolic repression. miR-155 is a typical multifunctional miRNA and loss of miR-155 has been shown to protect the heart from pathological cardiac hypertrophy while increased miR-155 could promote the formation of foam cell in atherogenesis. However, the role of miR-155 in sepsis induced cardiac dysfunction is unclear. Methods: E.coli lipopolysaccharide (LPS) (5mg/kg) was administered to C57BL/6 mice to create a sepsis-induced cardiac dysfunction model. Cardiac function was assessed by echocardiography 5-6 h post-LPS administration. Heart tissues were collected within 7-9 h after LPS treatment for the analysis of gene expressions. Tail vein injection of miR-155 antagomir (80mg/kg/d) or miR-155 agomirs (30mg/kg/d) for 3 consecutive days were used to decrease or increase miR-155 expressions in heart. Results: LPS induced a reduction of 15% in fractional shortening (%FS) and 25% in ejection fraction (%EF). Expression of miR-155 was increased by 2 fold in sepsis-induced cardiac dysfunction mouse model. Over-expression of miR-155 agomirs led to a decrease of 5% in FS and 10% in EF as compared to scramble controls. Aggravation of LPS induced cardiac dysfunction by miR-155 agomir was not associated with alteration in inflammation or cardiac metabolism. However, miR-155 agomir increased LPS- induced myocardium apoptosis and also elevated the ratio of Bax/Bcl-2 at the protein level. Intravenous injection of cholesterol-modified antisense oligonucleorides antagomirs of miR-155 markedly rescued the LPS induced heart failure and apoptosis. Western bloting indicated that miR-155 overexpression in vivo led to a significant inhibition of Pea15a while miR-155 knock-down caused a significant upregulation of Pea15a, indicating that Pea15a was a potential target gene of miR-155. Interestingly, plasma miR-155 levels were also found to be significantly increased in critically ill patients with sepsis compared to healthy controls. Conclusion: This study demonstrates that miR-155 regulates sepsis induced cardiac dysfunction and Pea15a is a potential targer gene of miR-155. Loss of miR-155 represents a novel therapeutic method for sepsis induced cardiac dysfunction

scholarly journals Stem Cell-Derived Exosomes Prevent Aging-Induced Cardiac Dysfunction through a Novel Exosome/lncRNA MALAT1/NF-κB/TNF-α Signaling Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Bao Zhu ◽  
Lulu Zhang ◽  
Chun Liang ◽  
Bin Liu ◽  
Xiangbin Pan ◽  
...  
Keyword(s):  
Stem Cell ◽  
Signaling Pathway ◽  
Cardiac Dysfunction ◽  
Human Umbilical Cord ◽  
Beneficial Effects ◽  
Age Related ◽  
Lncrna Malat1 ◽  
Tnf Α ◽  
Heart Functions

Aging is a risk factor for cardiovascular disease, and there is no effective therapeutic approach to alleviate this condition. NF-κB and TNF-α have been implicated in the activation of the aging process, but the signaling molecules responsible for the inactivation of NF-κB and TNF-α remain unknown. Exosomes have been reported to improve heart functions by releasing miRNA. Recent studies suggest that lncRNAs are more tissue-specific and developmental stage-specific compared to miRNA. However, the role of lncRNA in exosome-mediated cardiac repair has not been explored. In the present study, we focused on metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), which is an lncRNA associated with cell senescence. We discovered that human umbilical cord mesenchymal stem cell- (UMSC-) derived exosomes prevent aging-induced cardiac dysfunction. Silencer RNA against lncRNA MALAT1 blocked the beneficial effects of exosomes. In summary, we discovered that UMSC-derived exosomes prevent aging-induced cardiac dysfunction by releasing novel lncRNA MALAT1, which in turn inhibits the NF-κB/TNF-α signaling pathway. These findings will lead to the development of therapies that delay aging and progression of age-related diseases.

scholarly journals Age-Related Alterations in Immune Contexture Are Associated with Aggressiveness in Rhabdomyosarcoma

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1380 ◽  
Author(s):  
Patrizia Gasparini ◽  
Orazio Fortunato ◽  
Loris De Cecco ◽  
Michela Casanova ◽  
Maria Federica Iannó ◽  
...  
Keyword(s):  
Myogenic Differentiation ◽  
Tumor Biology ◽  
Muscle Metabolism ◽  
Γδ T Cells ◽  
Resting Cells ◽  
Over Expression ◽  
Age Related ◽  
Immune Contexture

Adolescents and young adults (AYA) with rhabdomyosarcoma (RMS) form a subgroup of patients whose optimal clinical management and access to care remain a challenge and whose survival lacks behind that of children diagnosed with histologically similar tumors. Understanding the tumor biology that differentiates children from AYA-RMS could provide critical information and drive new initiatives to improve the final outcome. MicroRNA (miRNA) and gene expression profiling (GEP) was evaluated in a RMS cohort of 49 tumor and 15 non-neoplastic tissues. miRNAs analysis identified miR-223 over-expression and miR-431 down-regulation in AYA, validated by Real-Time PCR and miRNA in situ hybridization (ISH). GEP analysis detected 793 age-correlated genes in tumors, of which 194 were anti-correlated. NOTCH2, FGFR1/2 were significantly down-modulated in AYA-RMS. miR-223 was associated with up-regulation of epithelial mesenchymal translation (EMT) and inflammatory pathways, whereas miR-431 was correlated to myogenic differentiation and muscle metabolism. GEP showed an increase in genes associated with CD4 memory resting cells and a decrease in genes associated with γδ T-cells in AYA-RMS. Immunohistochemistry (IHC) analysis demonstrated an increase of infiltrated CD4, CD8, and neutrophils in AYA-RMS tumors. Our results show that aggressiveness of AYA-RMS could be explained by differences in microenvironmental signal modulation mediated by tumor cells, suggesting a fundamental role of immune contexture in AYA-RMS development.

Age-dependent alterations in Ca2+ homeostasis: role of TRPV5 and TRPV6

2006 ◽  
Vol 291 (6) ◽  
pp. F1177-F1183 ◽  
Author(s):  
Monique van Abel ◽  
Sylvie Huybers ◽  
Joost G. J. Hoenderop ◽  
Annemiete W. C. M. van der Kemp ◽  
Johannes P. T. M. van Leeuwen ◽  
...  
Keyword(s):  
Vitamin D ◽  
Mrna Levels ◽  
Serum Osteocalcin ◽  
Intestinal Epithelial ◽  
Receptor Mrna ◽  
Age Related ◽  
Age Dependent ◽  
Elder People ◽  
Age Related Changes

Aging is associated with alterations in Ca2+ homeostasis, which predisposes elder people to hyperparathyroidism and osteoporosis. Intestinal Ca2+ absorption decreases with aging and, in particular, active transport of Ca2+ by the duodenum. In addition, there are age-related changes in renal Ca2+ handling. To examine age-related changes in expression of the renal and intestinal epithelial Ca2+ channels, control (TRPV5+/+) and TRPV5 knockout (TRPV5−/−) mice aged 10, 30, and 52 wk were studied. Aging of TRPV5+/+ mice resulted in a tendency toward increased renal Ca2+ excretion and significantly decreased intestinal Ca2+ absorption, which was accompanied by reduced expression of TRPV5 and TRPV6, respectively, despite increased serum 1,25(OH)2D3 levels. Similarly, in TRPV5−/− mice the existing renal Ca2+ loss was more pronounced in elder animals, whereas the compensatory intestinal Ca2+ absorption and TRPV6 expression declined with aging. In both mice strains, aging resulted in a resistance to 1,25(OH)2D3 and diminished renal vitamin D receptor mRNA levels, whereas serum Ca2+ levels remained constant. Furthermore, 52-wk-old TRPV5−/− mice showed severe hyperparathyroidism, whereas PTH levels in elder TRPV5+/+ mice remained normal. In 52-wk-old TRPV5−/− mice, serum osteocalcin levels were increased in accordance with the elevated PTH levels, suggesting an increased bone turnover in these mice. In conclusion, downregulation of TRPV5 and TRPV6 is likely involved in the impaired Ca2+ (re)absorption during aging. Moreover, TRPV5−/− mice likely develop age-related hyperparathyroidism and osteoporotic characteristics before TRPV5+/+ mice, demonstrating the importance of the epithelial Ca2+ channels in Ca2+ homeostasis.

scholarly journals Immunosenescence in Choroidal Neovascularization (CNV)—Transcriptional Profiling of Naïve and CNV-Associated Retinal Myeloid Cells during Aging

2021 ◽  
Vol 22 (24) ◽  
pp. 13318
Author(s):  
Anja Schlecht ◽  
Adrian Thien ◽  
Julian Wolf ◽  
Gabriele Prinz ◽  
Hansjürgen Agostini ◽  
...  
Keyword(s):  
Choroidal Neovascularization ◽  
Transcriptional Profiling ◽  
Myeloid Cells ◽  
Age Related Macular Degeneration ◽  
Physiological Aging ◽  
Future Studies ◽  
Signature Genes ◽  
Age Related ◽  
Age Dependent

Immunosenescence is considered a possible factor in the development of age-related macular degeneration and choroidal neovascularization (CNV). However, age-related changes of myeloid cells (MCs), such as microglia and macrophages, in the healthy retina or during CNV formation are ill-defined. In this study, Cx3cr1-positive MCs were isolated by fluorescence-activated cell sorting from six-week (young) and two-year-old (old) Cx3cr1GFP/+ mice, both during physiological aging and laser-induced CNV development. High-throughput RNA-sequencing was performed to define the age-dependent transcriptional differences in MCs during physiological aging and CNV development, complemented by immunohistochemical characterization and the quantification of MCs, as well as CNV size measurements. These analyses revealed that myeloid cells change their transcriptional profile during both aging and CNV development. In the steady state, senescent MCs demonstrated an upregulation of factors contributing to cell proliferation and chemotaxis, such as Cxcl13 and Cxcl14, as well as the downregulation of microglial signature genes. During CNV formation, aged myeloid cells revealed a significant upregulation of angiogenic factors such as Arg1 and Lrg1 concomitant with significantly enlarged CNV and an increased accumulation of MCs in aged mice in comparison to young mice. Future studies need to clarify whether this observation is an epiphenomenon or a causal relationship to determine the role of immunosenescence in CNV formation.

scholarly journals Molecular Basis of Neuronal Autophagy in Ageing: Insights from Caenorhabditis elegans

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 694
Author(s):  
Georgios Konstantinidis ◽  
Nektarios Tavernarakis
Keyword(s):  
Caenorhabditis Elegans ◽  
Degradation Process ◽  
Pathogen Invasion ◽  
Age Related ◽  
Distinct Cell ◽  
Evolutionarily Conserved ◽  
Subsequent Degradation ◽  
Membrane Organelle ◽  
Neuronal Autophagy

Autophagy is an evolutionarily conserved degradation process maintaining cell homeostasis. Induction of autophagy is triggered as a response to a broad range of cellular stress conditions, such as nutrient deprivation, protein aggregation, organelle damage and pathogen invasion. Macroautophagy involves the sequestration of cytoplasmic contents in a double-membrane organelle referred to as the autophagosome with subsequent degradation of its contents upon delivery to lysosomes. Autophagy plays critical roles in development, maintenance and survival of distinct cell populations including neurons. Consequently, age-dependent decline in autophagy predisposes animals for age-related diseases including neurodegeneration and compromises healthspan and longevity. In this review, we summarize recent advances in our understanding of the role of neuronal autophagy in ageing, focusing on studies in the nematode Caenorhabditis elegans.

scholarly journals The Aging Stress Response and Its Implication for AMD Pathogenesis

2020 ◽  
Vol 21 (22) ◽  
pp. 8840
Author(s):  
Janusz Blasiak ◽  
Elzbieta Pawlowska ◽  
Anna Sobczuk ◽  
Joanna Szczepanska ◽  
Kai Kaarniranta
Keyword(s):  
Stress Response ◽  
Vision Loss ◽  
The Elderly ◽  
Cellular Level ◽  
Age Related Macular Degeneration ◽  
Age Related ◽  
Evolutionarily Conserved ◽  
Nutrient Signaling ◽  
Amp Activated Protein Kinase

Aging induces several stress response pathways to counterbalance detrimental changes associated with this process. These pathways include nutrient signaling, proteostasis, mitochondrial quality control and DNA damage response. At the cellular level, these pathways are controlled by evolutionarily conserved signaling molecules, such as 5’AMP-activated protein kinase (AMPK), mechanistic target of rapamycin (mTOR), insulin/insulin-like growth factor 1 (IGF-1) and sirtuins, including SIRT1. Peroxisome proliferation-activated receptor coactivator 1 alpha (PGC-1α), encoded by the PPARGC1A gene, playing an important role in antioxidant defense and mitochondrial biogenesis, may interact with these molecules influencing lifespan and general fitness. Perturbation in the aging stress response may lead to aging-related disorders, including age-related macular degeneration (AMD), the main reason for vision loss in the elderly. This is supported by studies showing an important role of disturbances in mitochondrial metabolism, DDR and autophagy in AMD pathogenesis. In addition, disturbed expression of PGC-1α was shown to associate with AMD. Therefore, the aging stress response may be critical for AMD pathogenesis, and further studies are needed to precisely determine mechanisms underlying its role in AMD. These studies can include research on retinal cells produced from pluripotent stem cells obtained from AMD donors with the mutations, either native or engineered, in the critical genes for the aging stress response, including AMPK, IGF1, MTOR, SIRT1 and PPARGC1A.

scholarly journals Determining the Role of ApoE4 in Age-Related Cerebrovascular Decline

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 118-119
Author(s):  
Kate Foley ◽  
Peter Borchian ◽  
Dylan Garceau ◽  
Kevin Kotredes ◽  
Paul Territo ◽  
...  
Keyword(s):  
Risk Factors ◽  
Genetic Risk ◽  
Transcriptional Profiling ◽  
Genetic Risk Factors ◽  
Expression Of Genes ◽  
Age Related ◽  
Age Dependent ◽  
Cerebrovascular Health ◽  
E4 Allele

Abstract Cerebrovascular decline occurs during aging and may be critical during prodromal phases of Alzheimer’s disease (AD). The E4 allele of apolipoprotein E (APOE4) is the greatest genetic risk factor for AD and decreased longevity and studies suggest APOE4 increases risk for age-dependent cerebrovascular damage. To study the relationship between APOE4 and age-related cerebrovascular decline, male and female C57BL/6J (B6) mice carrying combinations of APOE alleles including APOE4 (risk) and APOE3 (neutral), as well as B6 controls were assessed at a variety of ages from 4 to 24 mos for cognitive ability, biometrics and cerebrovascular health including i) PET/MRI using 64Cu-PTSM (perfusion) and 18F-FDG (metabolism), ii) transcriptional profiling and iii) immunofluorescence. Despite no cognitive decline, male APOE4 mice showed hypo-perfusion and hypo-metabolism by 12 mos, while female APOE4 mice showed an uncoupled hyper-perfusion and hypo-metabolism phenotype. Transcriptional profiling showed differential expression of genes involved in regulation of cerebral perfusion, glucose transportation and metabolism in APOE4 mice. An age-dependent blood brain barrier compromise was also apparent in the brains of female APOE4 mice. Physical activity reduces risk for human AD and our data shows exercise improves cerebrovascular health in mice. However, the effects to cerebrovascular health in individuals carrying genetic risk factors such as APOE4 are not known. To determine whether exercise can overcome APOE4-dependent cerebrovascular damage, APOE mice are being exercised from 2-4 and to 2-12 mos. Transcriptional profiling and immunofluorescence will determine whether the benefits of exercise to the cerebrovasculature are modulated by genetic risk factors such as APOE4.

scholarly journals IRBIT Directs Differentiation of Intestinal Stem Cell Progeny to Maintain Tissue Homeostasis

2019 ◽  
Author(s):  
Alexei Arnaoutov ◽  
Hangnoh Lee ◽  
Karen Plevock Haase ◽  
Vasilisa Aksenova ◽  
Michal Jarnik ◽  
...  
Keyword(s):  
Cell Types ◽  
Intestinal Stem Cells ◽  
Intestinal Tissue ◽  
Tissue Integrity ◽  
Regulatory Circuit ◽  
Age Related ◽  
Evolutionarily Conserved ◽  
Gut Homeostasis ◽  
Epithelium Cells

SummaryThe maintenance of the intestinal epithelium is ensured by the controlled proliferation of intestinal stem cells (ISCs) and differentiation of their progeny into various cell types, including enterocytes (ECs) that both mediate nutrient absorption and provide a barrier against pathogens. The signals that regulate transition of proliferative ISCs into differentiated ECs are not fully understood. IRBIT is an evolutionarily conserved protein that regulates ribonucleotide reductase (RNR), an enzyme critical for the generation of DNA precursors. Here, we show that IRBIT expression in ISC progeny within the Drosophila midgut epithelium cells is essential for their differentiation via suppression of RNR activity. Disruption of this IRBIT-RNR regulatory circuit causes a rapid, premature loss of intestinal tissue integrity as flies age. This age-related dysplasia can be reversed by suppression of RNR activity in ISC progeny. Collectively, our findings demonstrate an unexpected and novel role of the IRBIT-RNR pathway in gut homeostasis.

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