Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 22
Filtrar
1.
Ann Bot ; 2024 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-38845347

RESUMO

Plant senescence is an integrated program of plant development that aims to remobilize nutrients and energy from senescing tissues to developing organs under developmental and stress-induced conditions. Upstream in the regulatory network, a small family of single-stranded DNA/RNA-binding proteins known as WHIRLYs occupy a central node, acting at multiple regulatory levels and via trans-localization between the nucleus and organelles. In this review, we summarize the current progress on the role of WHIRLY members in plant development and stress-induced senescence. WHIRLY proteins can be traced back in evolution to green algae. WHIRLY proteins trade off the balance of plant developmental senescence and stress-induced senescence through maintaining organelle genome stability via R-loop homeostasis, repressing the transcription at a configuration condition, recruiting RNA to impact organelle RNA editing and splicing, as evidenced in several species, WHIRLY proteins also act as retrograde signal transducers between organelles and the nucleus through protein modification and stromule or vesicle trafficking. In addition, WHIRLY proteins interact with hormones, ROS and environmental signals to orchestrate cell fate in an age-dependent manner. Finally, prospects for further research and promotion to improve crop production under environmental constraints are highlighted.

2.
Plant Cell Physiol ; 63(12): 2008-2026, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36161338

RESUMO

Changes in climate conditions can negatively affect the productivity of crop plants. They can induce chloroplast degradation (senescence), which leads to decreased source capacity, as well as decreased whole-plant carbon/nitrogen assimilation and allocation. The importance, contribution and mechanisms of action regulating source-tissue capacity under stress conditions in tomato (Solanum lycopersicum) are not well understood. We hypothesized that delaying chloroplast degradation by altering the activity of the tomato chloroplast vesiculation (CV) under stress would lead to more efficient use of carbon and nitrogen and to higher yields. Tomato CV is upregulated under stress conditions. Specific induction of CV in leaves at the fruit development stage resulted in stress-induced senescence and negatively affected fruit yield, without any positive effects on fruit quality. Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated protein 9 (CRISPR/CAS9) knockout CV plants, generated using a near-isogenic tomato line with enhanced sink capacity, exhibited stress tolerance at both the vegetative and the reproductive stages, leading to enhanced fruit quantity, quality and harvest index. Detailed metabolic and transcriptomic network analysis of sink tissue revealed that the l-glutamine and l-arginine biosynthesis pathways are associated with stress-response conditions and also identified putative novel genes involved in tomato fruit quality under stress. Our results are the first to demonstrate the feasibility of delayed stress-induced senescence as a stress-tolerance trait in a fleshy fruit crop, to highlight the involvement of the CV pathway in the regulation of source strength under stress and to identify genes and metabolic pathways involved in increased tomato sink capacity under stress conditions.


Assuntos
Solanum lycopersicum , Solanum lycopersicum/genética , Frutas/metabolismo , Cloroplastos/metabolismo , Carbono/metabolismo , Nitrogênio/metabolismo
3.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 54(6): 1085-1090, 2023 Nov 20.
Artigo em Zh | MEDLINE | ID: mdl-38162078

RESUMO

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. Renal tubulointerstitial injury is an important pathophysiological basis that contributes to the progression of DN to end-stage renal disease. Stress-induced senescence of renal tubular epithelial cells (RTECs) forms a key link that causes tubulointerstitial injury. In recent years, it has been reported that organelles, such as endoplasmic reticulum, mitochondria, and lysosomes, in RTECs are damaged to varying degrees in DN, and that their functional imbalance may lead to stress-induced senescence of RTECs, thereby causing sustained cellular and tissue-organ damage, which in turn promotes the progression of the disease. However, the core mechanism underlying changes in the senescence microenvironment caused by stress-induced senescence of RTECs in DN is still not understood. In addition, the mechanism by which organelles lose homeostasis also needs to be further investigated. Herein, we described the specific pathophysiological mechanisms of renal tubular injury, stress-induced senescence of RTECs, and their association with organelles in the context of DN in order to provide reference for the next-step research, as well as the development of new therapeutic strategies.


Assuntos
Diabetes Mellitus , Nefropatias Diabéticas , Falência Renal Crônica , Humanos , Nefropatias Diabéticas/etiologia , Rim , Túbulos Renais , Células Epiteliais
4.
Cancer Metastasis Rev ; 39(2): 397-414, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32279119

RESUMO

Cellular senescence is a feature of most somatic cells. It is characterized by an irreversible cell cycle arrest and by the ability to secrete a plethora of mediators of inflammation and growth factors, which can alter the senescent cell's microenvironment. Senescent cells accumulate in tissues over time and contribute to both aging and the development of age-associated diseases. Senescent cells have antagonistic pleiotropic roles in cancer. Given the inability of senescent cells to proliferate, cellular senescence is a powerful tumor suppressor mechanism in young individuals. However, accumulation of senescent stromal cells during aging can fuel cancer cell growth in virtue of their capacity to release factors that stimulate cell proliferation. Caveolin-1 is a structural protein component of caveolae, invaginations of the plasma membrane involved in a variety of cellular processes, including signal transduction. Mounting evidence over the last 10-15 years has demonstrated a central role of caveolin-1 in the development of a senescent phenotype and the regulation of both the anti-tumorigenic and pro-tumorigenic properties of cellular senescence. In this review, we discuss the cellular mechanisms and functions of caveolin-1 in the context of cellular senescence and their relevance to the biology of cancer.


Assuntos
Caveolina 1/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Animais , Senescência Celular/fisiologia , Humanos , Transdução de Sinais
5.
Am J Physiol Heart Circ Physiol ; 321(4): H770-H783, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34506226

RESUMO

Vascular aging is highly associated with cardiovascular morbidity and mortality. Although the senescence of vascular smooth muscle cells (VSMCs) has been well established as a major contributor to vascular aging, intracellular and exosomal microRNA (miRNA) signaling pathways in senescent VSMCs have not been fully elucidated. This study aimed to identify the differential expression of intracellular and exosomal miRNA in human VSMCs (hVSMCs) during replicative senescence. To achieve this aim, intracellular and exosomal miRNAs were isolated from hVSMCs and subsequently subjected to whole genome small RNA next-generation sequencing, bioinformatics analyses, and qPCR validation. Three significant findings were obtained. First, senescent hVSMC-derived exosomes tended to cluster together during replicative senescence and the molecular weight of the exosomal protein tumor susceptibility gene 101 (TSG-101) increased relative to the intracellular TSG-101, suggesting potential posttranslational modifications of exosomal TSG-101. Second, there was a significant decrease in both intracellular and exosomal hsa-miR-155-5p expression [n = 3, false discovery rate (FDR) < 0.05], potentially being a cell type-specific biomarker of hVSMCs during replicative senescence. Importantly, hsa-miR-155-5p was found to associate with cell-cycle arrest and elevated oxidative stress. Lastly, miRNAs from the intracellular pool, that is, hsa-miR-664a-3p, hsa-miR-664a-5p, hsa-miR-664b-3p, hsa-miR-4485-3p, hsa-miR-10527-5p, and hsa-miR-12136, and that from the exosomal pool, that is, hsa-miR-7704, were upregulated in hVSMCs during replicative senescence (n = 3, FDR < 0.05). Interestingly, these novel upregulated miRNAs were not functionally well annotated in hVSMCs to date. In conclusion, hVSMC-specific miRNA expression profiles during replicative senescence potentially provide valuable insights into the signaling pathways leading to vascular aging.NEW & NOTEWORTHY This is the first study on intracellular and exosomal miRNA profiling on human vascular smooth muscle cells during replicative senescence. Specific dysregulated sets of miRNAs were identified from human vascular smooth muscle cells. Hsa-miR-155-5p was significantly downregulated in both intracellular and exosomal hVSMCs, suggesting its crucial role in cellular senescence. Hsa-miR-155-5p might be the mediator in linking cellular senescence to vascular aging and atherosclerosis.


Assuntos
Proliferação de Células , Senescência Celular , Exossomos/metabolismo , Perfilação da Expressão Gênica , MicroRNAs/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Transcriptoma , Células Cultivadas , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Complexos Endossomais de Distribuição Requeridos para Transporte/genética , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Exossomos/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , MicroRNAs/genética , Processamento de Proteína Pós-Traducional , Análise de Sequência de RNA , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Sequenciamento Completo do Genoma
6.
FASEB J ; 34(8): 10778-10800, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32619061

RESUMO

Chronic graft-vs-host disease (cGVHD) is a multifactorial inflammatory disease that affects patients undergoing hematopoietic stem cell transplantation. Multiple organs, including the lacrimal glands (LGs), are negatively affected by cGVHD and lose function due to the resultant fibrosis. An abnormal immune response is thought to be a major factor in the development of chronic ocular GVHD, which is currently treated primarily with immunosuppressive therapies. However, all the treatments yield unsatisfactory outcomes, and additional treatment strategies are needed. To meet this unmet medical need, we aimed to elucidate an additional pathway of chronic ocular GVHD. Our findings suggest a potential association between chronic ocular GVHD pathogenesis and stress-induced cellular senescence through the senescence-associated secretory phenotype (SASP). Senescent cells produce cytokines and chemokines, such as IL-6 and CXCL9. Indeed, senescent cell accumulation was presumably associated with cGVHD development in LGs, as evidenced by the improvement in LGs after the selective elimination of senescent cells (senolysis) with ABT-263. Results in the sclerodermatous cGVHD mouse model suggest that inhibiting the major components of the SASP, including IL-6 and CXCL9, with senolytics is a potential novel strategy for treating cGVHD-affected LGs. Taken together, our results indicate a potential association between the SASP and cGVHD development in LGs and suggest that targeted senolytic treatment may be a new therapeutic option for this disease.


Assuntos
Senescência Celular/fisiologia , Olho/patologia , Doença Enxerto-Hospedeiro/patologia , Animais , Quimiocina CXCL9/metabolismo , Doença Crônica , Citocinas/metabolismo , Modelos Animais de Doenças , Olho/metabolismo , Feminino , Fibrose/metabolismo , Fibrose/patologia , Doença Enxerto-Hospedeiro/metabolismo , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Interleucina-6/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C
7.
Int J Mol Sci ; 22(11)2021 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-34204098

RESUMO

Ocular graft-versus-host disease (GVHD) is a major complication after allogeneic hematopoietic stem cell transplantation. Ocular GVHD affects recipients' visual function and quality of life. Recent advanced research in this area has gradually attracted attention from a wide range of physicians and ophthalmologists. This review highlights the mechanism of immune processes and the molecular mechanism, including several inflammation cascades, pathogenic fibrosis, and stress-induced senescence related to ocular GVHD, in basic spectrum topics in this area. How the disease develops and what kinds of cells participate in ocular GVHD are discussed. Although the classical immune process is a main pathological pathway in this disease, senescence-associated changes in immune cells and stem cells may also drive this disease. The DNA damage response, p16/p21, and the expression of markers associated with the senescence-associated secretory phenotype (SASP) are seen in ocular tissue in GVHD. Macrophages, T cells, and mesenchymal cells from donors or recipients that increasingly infiltrate the ocular surface serve as the source of increased secretion of IL-6, which is a major SASP driver. Agents capable of reversing the changes, including senolytic reagents or those that can suppress the SASP seen in GVHD, provide new potential targets for the treatment of GVHD. Creating innovative therapies for ocular GVHD is necessary to treat this intractable ocular disease.


Assuntos
Envelhecimento/patologia , Síndromes do Olho Seco/etiologia , Doença Enxerto-Hospedeiro/complicações , Inflamação/complicações , Estresse Fisiológico , Animais , Doença Crônica , Fibrose , Doença Enxerto-Hospedeiro/imunologia , Humanos , Inflamação/imunologia
8.
Int J Mol Sci ; 22(7)2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33810566

RESUMO

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.


Assuntos
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/ultraestrutura
9.
Int J Mol Sci ; 22(21)2021 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-34769282

RESUMO

In our previous study, we found that high doses of several substances with antioxidant capacities (Tempol, resveratrol, diphenyleneiodonium) can cause genotoxic stress and induce premature senescence in the human mesenchymal stem cells (MSCs). Here, using whole-transcriptome analysis, we revealed the signs of endoplasmic reticulum stress and unfolded protein response (UPR) in MSCs stressed with Tempol and resveratrol. In addition, we found the upregulation of genes, coding the UPR downstream target APC/C, and E3 ubiquitin ligase that regulate the stability of cell cycle proteins. We performed the molecular analysis, which further confirmed the untimely degradation of APC/C targets (cyclin A, geminin, and Emi1) in MSCs treated with antioxidants. Human fibroblasts responded to antioxidant applications similarly. We conclude that endoplasmic reticulum stress and impaired DNA synthesis regulation can be considered as potential triggers of cell damage and premature senescence stimulated by high-dose antioxidant treatments.


Assuntos
Antioxidantes/farmacologia , Senescência Celular/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Linhagem Celular , Humanos
10.
Biochem Biophys Res Commun ; 496(4): 1162-1168, 2018 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-29397942

RESUMO

Accumulating evidence suggests that the senescence-messaging secretome (SMS) factors released by senescent cells play a key role in cellular senescence and physiological aging. Phenomenon of the senescence induction in human endometrium-derived mesenchymal stem cells (MESCs) in response to SMS factors has not yet been described. In present study, we examine a hypothesis whether the conditioned medium from senescent cells (CM-old) may promote premature senescence of young MESCs. In this case, we assume that SMS factors, containing in CM-old are capable to trigger senescence mechanism in a paracrine manner. A long-term cultivation MESCs in the presence of CM-old caused deceleration of cell proliferation along with emerging senescence phenotype, including increase in both the cell size and SA-ß-Gal activity. The phosphorylation of p53 and MAPKAPK-2, a direct target of p38MAPK, as well as the expression of p21Cip1 and p16Ink4a were increased in CM-old treated cells with senescence developing whereas the Rb phosphorylation was diminished. The senescence progression was accompanied by both enhanced ROS generation and persistent activation of DNA damage response, comprising protein kinase ATM, histone H2A.X, and adapter protein 53BP1. Thus, we suggest that a senescence inducing signal is transmitted through p16/MAPKAPK-2/Rb and DDR-mediated p53/p21/Rb signaling pathways. This study is the first to demonstrate that the SMS factors secreted in conditioned medium of senescent MESCs trigger a paracrine mechanism of premature senescence in young cells.


Assuntos
Comunicação Celular/fisiologia , Senescência Celular/fisiologia , Endométrio/citologia , Endométrio/fisiologia , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/fisiologia , Proteoma/metabolismo , Linhagem Celular , Feminino , Humanos , Transdução de Sinais/fisiologia
11.
J Exp Bot ; 69(4): 867-878, 2018 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-28992306

RESUMO

Abiotic stress-induced senescence in crops is a process particularly affecting the photosynthetic apparatus, decreasing photosynthetic activity and inducing chloroplast degradation. A pathway for stress-induced chloroplast degradation that involves the CHLOROPLAST VESICULATION (CV) gene was characterized in rice (Oryza sativa) plants. OsCV expression was up-regulated with the age of the plants and when plants were exposed to water-deficit conditions. The down-regulation of OsCV expression contributed to the maintenance of the chloroplast integrity under stress. OsCV-silenced plants displayed enhanced source fitness (i.e. carbon and nitrogen assimilation) and photorespiration, leading to water-deficit stress tolerance. Co-immunoprecipitation, intracellular co-localization, and bimolecular fluorescence demonstrated the in vivo interaction between OsCV and chloroplastic glutamine synthetase (OsGS2), affecting source-sink relationships of the plants under stress. Our results would indicate that the OsCV-mediated chloroplast degradation pathway is involved in the regulation of nitrogen assimilation during stress-induced plant senescence.


Assuntos
Cloroplastos/metabolismo , Secas , Nitrogênio/metabolismo , Oryza/fisiologia , Proteínas de Plantas/genética , Água/metabolismo , Oryza/genética , Proteínas de Plantas/metabolismo , Estresse Fisiológico
12.
J Exp Bot ; 69(4): 845-853, 2018 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-28992323

RESUMO

Senescence is an age-dependent process, ultimately leading to plant death, that in annual crop plants overlaps with the reproductive stage of development. Research on the molecular and biochemical mechanisms of leaf senescence has revealed a multi-layered regulatory network operating to control age-dependent processes. Abiotic stress-induced senescence challenges source-sink relationships and results in significant reduction in crop yields. Although processes associated with plant senescence are well studied, the mechanisms regulating stress-induced senescence are not well known. Here, we discuss the effects of abiotic stress on crop productivity, mechanisms associated with stress-induced senescence, and the possible use of these mechanisms for the generation of plant stress tolerance. We emphasize the involvement of source strength and stability of the photosynthetic apparatus in this process, and suggest a possible role of a perennial plant life strategy for the amelioration of stress-induced senescence.


Assuntos
Produtos Agrícolas/fisiologia , Folhas de Planta/fisiologia , Fenômenos Fisiológicos Vegetais , Estresse Fisiológico , Produção Agrícola , Produtos Agrícolas/crescimento & desenvolvimento , Folhas de Planta/crescimento & desenvolvimento
13.
Prostate ; 77(4): 374-384, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27859428

RESUMO

BACKGROUND: There are two principal senescence barriers that must be overcome to successfully immortalize primary human epithelial cells in culture, stress-induced senescence, and replicative senescence. The p16INK4a /retinoblastoma protein (p16/Rb) pathway mediates stress-induced senescence, and is generally upregulated by primary epithelial cells in response to the artificial conditions from tissue culture. Replicative senescence is associated with telomere loss. Following each round of cell division, telomeres progressively shorten. Once telomeres shorten to a critical length, the DNA damage response pathway is activated, and the tumor suppressor p53 pathway triggers replicative senescence. Exogenous expression of telomerase in normal human epithelial cells extends the replicative capacity of cells, and in some cases, immortalizes cells. However reliable immortalization of epithelial cells usually requires telomerase activity coupled with inactivation of the p16/Rb pathway. METHODS: A lentiviral vector, pLOX-TERT-iresTK (Addgene #12245), containing a CMV promoter upstream of a bicistronic coding cassette that includes loxP sites flanking the catalytic subunit of human telomerase gene (TERT) and herpes simplex virus type-1 thymidine kinase gene (HSV1-tk) was used to transduce normal prostate basal epithelial cells (PrECs) initiated in cell culture from prostate cancer patients undergoing radical prostatectomies. RESULTS: Transduction of early (i.e., <7) passage PrECs with TERT led to successful immortalization. However, attempts to immortalize late (i.e., >7) passage PrECs were unsuccessful. Late passage PrECs, which acquired elevated p16, were unable to overcome the senescence barrier. Immortalized PrECs (TERT-PrECs) retained a normal male karyotype and low p16 expression. Additionally, TERT-PrECs were non-tumorigenic when inoculated into intact male immunodeficient NSG mice. CONCLUSIONS: The present studies document that early passage human PrECs have sufficiently low p16 to permit immortalization by TERT expression alone. TERT-PrECs developed using this transduction approach provides an appropriate and experimentally facile model for clarifying the molecular mechanism(s) involved in both immortalization of human PrECs, as well as identifying genetic/epigenetic "drivers" for conversion of these immortalized non-tumorigenic cells into fully lethal prostate cancers. Notably, loxP sites flank the exogenous TERT gene in the TERT-PrECs. Cre recombinase can be used to excise TERT, and resolve whether TERT expression is required for these cells to be fully transformed into lethal cancer. Prostate 77: 374-384, 2017. © 2016 Wiley Periodicals, Inc.


Assuntos
Inibidor p16 de Quinase Dependente de Ciclina/biossíntese , Células Epiteliais/metabolismo , Próstata/citologia , Próstata/metabolismo , Telomerase/biossíntese , Animais , Linhagem Celular Transformada , Células Cultivadas , Inibidor p16 de Quinase Dependente de Ciclina/genética , Expressão Gênica , Humanos , Masculino , Camundongos , Telomerase/genética
14.
Biology (Basel) ; 12(10)2023 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-37887058

RESUMO

One of the little-studied ways that climate warming or temperature increases in aquaculture could affect aquatic animals is through accelerated aging. This study is dedicated to understanding the principles of molecular and cellular aging in the target tissues of juvenile whitefishes (Yenisei hump-snout whitefish and its hybrid) under the influence of acute heat stress (up to 26 °C), and the effects of thermal preconditioning as pre-adaptation. Non-adapted stressed hump-snout whitefish showed a higher induction threshold for functionally active mitochondria in the blood and a decrease in telomerase activity in the liver after heat shock exposure as a long-term compensatory response to prevent telomere shortening. However, we observed heat-induced telomere shortening in non-adapted hybrids, which can be explained by a decrease in mitochondrial membrane stability and a gradual increase in energy demand, leading to a decrease in protective telomerase activity. The pre-adapted groups of hump-snout whitefish and hybrids showed a long-term or delayed response of telomerase activity to heat shock, which served as a therapeutic mechanism against telomere shortening. We concluded that the telomerase and telomere responses to thermal stress demonstrate plasticity of tolerance limits and greater stability in hump-snout whitefish compared with hybrids.

15.
Aging Cell ; 22(9): e13893, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37547972

RESUMO

Cellular senescence constitutes a generally irreversible proliferation barrier, accompanied by macromolecular damage and metabolic rewiring. Several senescence types have been identified based on the initiating stimulus, such as replicative (RS), stress-induced (SIS) and oncogene-induced senescence (OIS). These senescence subtypes are heterogeneous and often develop subset-specific phenotypes. Reduced protein synthesis is considered a senescence hallmark, but whether this trait pertains to various senescence subtypes and if distinct molecular mechanisms are involved remain largely unknown. Here, we analyze large published or experimentally produced RNA-seq and Ribo-seq datasets to determine whether major translation-regulating entities such as ribosome stalling, the presence of uORFs/dORFs and IRES elements may differentially contribute to translation deficiency in senescence subsets. We show that translation-regulating mechanisms may not be directly relevant to RS, however uORFs are significantly enriched in SIS. Interestingly, ribosome stalling, uORF/dORF patterns and IRES elements comprise predominant mechanisms upon OIS, strongly correlating with Notch pathway activation. Our study provides for the first time evidence that major translation dysregulation mechanisms/patterns occur during cellular senescence, but at different rates depending on the stimulus type. The degree at which those mechanisms accumulate directly correlates with translation deficiency levels. Our thorough analysis contributes to elucidating crucial and so far unknown differences in the translation machinery between senescence subsets.


Assuntos
Senescência Celular , Ribossomos , Senescência Celular/genética , Ribossomos/genética , Ribossomos/metabolismo , Biossíntese de Proteínas
16.
Antioxidants (Basel) ; 11(5)2022 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-35624839

RESUMO

Non-alcoholic fatty liver disease is characterized by disturbed lipid metabolism and increased oxidative stress. These conditions lead to the activation of different cellular response mechanisms, including senescence. Cellular senescence constitutes an important response to injury in the liver. Recent findings show that chronic oxidative stress can induce senescence, and this might be a driving mechanism for NAFLD progression, aggravating the disturbance of lipid metabolism, organelle dysfunction, pro-inflammatory response and hepatocellular damage. In this context, the modulation of cellular senescence can be beneficial to ameliorate oxidative stress-related damage during NAFLD progression. This review focuses on the role of oxidative stress and senescence in the mechanisms leading to NAFLD and discusses the possibilities to modulate senescence as a therapeutic strategy in the treatment of NAFLD.

17.
Geriatr Gerontol Int ; 21(2): 125-130, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33372374

RESUMO

Historically, the findings from cellular lifespan studies have greatly affected aging research. The discovery of replicative senescence by Hayflick developed into research on telomeres and telomerase, while stress-induced senescence became known as a telomere-independent event. Senescence-inducing signals comprise several tumor suppressors or cell cycle inhibitors, e.g., p53, cyclin-dependent kinase inhibitor p16 Ink4a and others. Stress-induced senescence serves as a physiological barrier to oncogenesis in vivo, while it activates senescence-associated secretary phenotype, inducing chronic inflammation. Thus, beside telomere length, p16, p53 and inflammatory cytokines have been utilized as biomarkers for cellular senescence. Telomere lengths in human leukocytes correlate well with events of aging-related lifestyle diseases, indicating the importance of cellular senescence in organismal aging. As such, the development of senescence research will have significant future clinical applications, e.g., senolysis. Geriatr Gerontol Int 2021; 21: 125-130.


Assuntos
Telomerase , Proteína Supressora de Tumor p53 , Senescência Celular , Inibidor p16 de Quinase Dependente de Ciclina/genética , Humanos , Telomerase/genética , Telomerase/metabolismo , Telômero/metabolismo , Proteína Supressora de Tumor p53/genética
18.
Biology (Basel) ; 10(10)2021 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-34681163

RESUMO

This work simulates the consequences of HIREC using stone sculpins as model organisms. Sex-dependent effects of long-term noise exposure at mean sound pressure levels of 160-179 dB re 1 µPa (SPLpk-pk) were measured. We applied a multilevel approach to testing the stress response: a comparative analysis of the macula sacculi and an assessment of hematological and molecular stress responses. Noise exposure resulted in hair cell loss, changes in some cytometric parameters in blood, and an increase in the number of functionally active mitochondria in the red blood cells of males and its decrease in females, demonstrating a mitochondrial allostatic load and depletion of functional reserve. Finally, a statistically significant decrease in the telomerase activity of the auditory epithelium and a shortening of telomere length in the brain as molecular markers of stress were observed after noise exposure only in females. No significant decrease in telomerase activity and shortening of telomere length in nerve target tissues were observed in stressed males. However, we recorded an increase in the telomerase activity in male gonads. This sex-dependent difference in load may be associated with accelerated cellular aging in females and lower stress-related long-term risk in males. In this article, we discuss possible reasons for these noise-induced stress effects.

19.
Front Plant Sci ; 12: 635619, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33790925

RESUMO

This review synthesizes knowledge on dark-induced barley, attached, leaf senescence (DILS) as a model and discusses the possibility of using this crop system for studying senescence and autophagy mechanisms. It addresses the recent progress made in our understanding of DILS. The following aspects are discussed: the importance of chloroplasts as early targets of DILS, the role of Rubisco as the largest repository of recoverable nitrogen in leaves senescing in darkness, morphological changes of these leaves other than those described for chloroplasts and metabolic modifications associated with them, DILS versus developmental leaf senescence transcriptomic differences, and finally the observation that in DILS autophagy participates in the circulation of cell components and acts as a quality control mechanism during senescence. Despite the progression of macroautophagy, the symptoms of degradation can be reversed. In the review, the question also arises how plant cells regulate stress-induced senescence via autophagy and how the function of autophagy switches between cell survival and cell death.

20.
Int J Spine Surg ; 14(3): 341-346, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32699756

RESUMO

BACKGROUND: Diabetes mellitus is one of the leading causes of morbidity resulting in multi-organ dysfunction. Animal studies have shown that hyperglycemia results in stress-induced senescence through the p16-pRb pathway, thereby accelerating early disc degeneration. There is a paucity of literature on the effect of hyperglycemia in human intervertebral disc cells. We aimed to analyze the effect of diabetes mellitus in human intervertebral disc cells. METHODS: This is a prospective study done in patients with degenerative disc disease. Patients were categorized into a control group (no diabetes: 26 patients) and a study group (type 2 diabetes for > 3 years: 24 patients). All patients underwent either discectomy or transforaminal lumbar interbody fusion and the removed disc was transported to pathology department. Tissue was prepared and histopathological grading was done followed by immunohistochemistry studies using antibodies for MMP-1, p21, p16, and pRb. RESULTS: Samples from diabetic patients had severe (grade 2) degenerative changes compared with the control group (grade 1). Changes were more intense in the nucleus pulposus with increased cellularity and clustering of chondrocytes, and disorganization and loss of nuclear matrix. Immunohistochemical staining for MMP1, p16, and pRb was more intense (Q score = 4) whereas the staining for p21 was less intense (Q score = 1) in the diabetic group compared with the control group. CONCLUSION: Our study demonstrates that type 2 diabetes mellitus accelerates stress-induced senescence in human intervertebral discs resulting in early disc degeneration. Also, the severity of disc degeneration is severe compared with the normal subjects. CLINICAL RELEVANCE: Hyperglycemia can affect the intervertebral discs similar to other organs and hence adequate control of blood glucose in diabetics can prevent the disc degeneration, which is the initiator of degeneration cascade in spine.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA