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Whether and how certain transposable elements with viral origins, such as endogenous retroviruses (ERVs) dormant in our genomes, can become awakened and contribute to the aging process is largely unknown. In human senescent cells, we found that HERVK (HML-2), the most recently integrated human ERVs, are unlocked to transcribe viral genes and produce retrovirus-like particles (RVLPs). These HERVK RVLPs constitute a transmissible message to elicit senescence phenotypes in young cells, which can be blocked by neutralizing antibodies. The activation of ERVs was also observed in organs of aged primates and mice as well as in human tissues and serum from the elderly. Their repression alleviates cellular senescence and tissue degeneration and, to some extent, organismal aging. These findings indicate that the resurrection of ERVs is a hallmark and driving force of cellular senescence and tissue aging.
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Envelhecimento , Retrovirus Endógenos , Idoso , Animais , Humanos , Camundongos , Envelhecimento/genética , Envelhecimento/patologia , Senescência Celular , Retrovirus Endógenos/genética , PrimatasRESUMO
Cr(VI) is a toxic, teratogenic, and carcinogenic heavy metal element in soil that poses major ecological and human health risks. In this study, microcosm tests combined with X-ray absorption near-edge spectra (XANES) and 16Sr DNA amplification techniques were used to explore the effect of Ginkgo biloba leaves on the removal efficiency of Cr(VI) in soil and its underlying mechanism. Ginkgo biloba leaves had a favorable remediation effect on soil varying in Cr(VI) contamination levels, and the optimal effect was observed when 5% Ginkgo biloba leaves were added. The occurrence state of Cr(VI) in soil before and after the addition of Ginkgo biloba leaves was analyzed by XANES, which revealed that Cr(VI) was fully converted to the more biologically innocuous Cr(III), and the hydroxyl-containing quercetin in Ginkgo biloba leaves was one of the primary components mediating this reduction reaction. The Cr(VI) content was significantly lower in non-sterilized soil than in sterilized soil, suggesting that soil microorganisms play a key role in the remediation process. The addition of Ginkgo biloba leaves decreased the α-diversity and altered the ß-diversity of the soil bacterial community. Actinobacteria was the dominant phylum in the soil remediated by Ginkgo biloba leaves; four genera of Cr(VI)-reducing bacteria were also enriched, including Agrococcus, Klebsiella, Streptomyces, and Microbacterium. Functional gene abundances predicted by PICRUST indicated that the expression of glutathione synthesis genes was substantially up-regulated, which might be the main metabolic pathway underlying the mitigation of Cr(VI) toxicity in soil by Cr(VI)-reducing bacteria. In sum, Ginkgo biloba leaves can effectively remove soil Cr(VI) and reduce Cr(VI) to Cr(III) via quercetin in soil, which also functions as a carbon source to drive the production of glutathione via Cr(VI)-reducing bacteria and mitigate Cr(VI) toxicity. The findings of this study elucidate the chemical and microbial mechanisms of Cr(VI) removal in soil by Ginkgo biloba leaves and provide insights that could be used to enhance the remediation of Cr(VI)-contaminated soil.
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Ginkgo biloba , Poluentes do Solo , Humanos , Ginkgo biloba/química , Solo/química , Quercetina , Cromo/análise , Glutationa , Poluentes do Solo/análiseRESUMO
Cadmium (Cd) stress is a ubiquitous abiotic stress affecting plant growth worldwide and negatively impacting crop yield and food safety. Potato is the most important non-grain crop globally, but there is limited research available on the response of this crop to Cd stress. This study explored the coping mechanism for Cd stress in potato through analyses of miRNA and mRNA. Tissue culture seedlings (20-day-old) of potato variety 'Atlantic' were cultured for up to 48 h in liquid medium containing 5 mmol/L CdCl2, and phenotypic, physiological, and transcriptomic changes were observed at specific times. With the extension of Cd stress time, the potato leaves gradually wilted and curled, and root salicylic acid (SA), glutathione (GSH), and lignin contents and peroxidase (POD) activity increased, while indole-3-acetic acid (IAA) and zeatin (ZT) contents decreased. Using miRNA-seq, 161 existing miRNAs, 383 known miRNAs, and 7361 novel miRNAs were identified, and, 18 miRNAs were differentially expressed in response to Cd stress. Based on mRNA-seq, 7340 differentially expressed mRNAs (DEGs) were found. Through mRNA-miRNA integrated analysis, miRNA-target gene pairs consisting of 23 DEGs and 33 miRNAs were identified. Furthermore, "glutathione metabolism" "plant hormone signal transduction" and "phenylpropanoid biosynthesis" were established as crucial pathways in the Cd stress response of potato. Novel miRNAs novel-m3483-5p and novel-m2893-5p participate in these pathways through targeted regulation of cinnamic alcohol dehydrogenase (CAD; PG0005359) and alanine aminotransferase (POP; PG0024281), respectively. This study provides information that will help elucidate the complex mechanism of the Cd stress response in potato. Moreover, candidate miRNAs and mRNAs could yield new strategies for the development of Cd-tolerant potato breeding.
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BACKGROUND: Acquirement of resistance is always associated with a highly aggressive phenotype of tumor cells. Recent studies have revealed that Annexin A2 (Anxa2) is a key protein that links drug resistance and cancer metastasis. A high level of Anxa2 in cancer tissues is correlated to a highly aggressive phenotype. Increased Anxa2 expression appears to be specific in many drug-resistant cancer cells. The functional activity of Anxa2 is regulated by tyrosine phosphorylation at the Tyr23 site. Nevertheless, the accurate molecular mechanisms underlying the regulation of Anxa2 tyrosine phosphorylation and whether phosphorylation is necessary for the enhanced invasive phenotype of drug-resistant cells remain unknown. METHODS: Small interfering RNAs, small molecule inhibitors, overexpression, loss of function or gain of function, rescue experiments, Western blot, wound healing assays, transwell assays, and in vivo metastasis mice models were used to investigate the functional effects of Rack1 and Src on the tyrosine phosphorylation of Anxa2 and the invasion and metastatic potential of drug-resistant breast cancer cells. The interaction among Rack1, Src, and Anxa2 in drug-resistant cells was verified by co-immunoprecipitation assay. RESULTS: We demonstrated that Anxa2 Tyr23 phosphorylation is necessary for multidrug-resistant breast cancer invasion and metastasis. Rack1 is required for the invasive and metastatic potential of drug-resistant breast cancer cells through modulating Anxa2 phosphorylation. We provided evidence that Rack1 acts as a signal hub and mediates the interaction between Src and Anxa2, thereby facilitating Anxa2 phosphorylation by Src kinase. CONCLUSIONS: Our findings suggest a convergence point role of Rack1/Src/Anxa2 complex in the crosstalk between drug resistance and cancer aggressiveness. The interaction between Anxa2 and Rack1/Src is responsible for the association between drug resistance and invasive/metastatic potential in breast cancer cells. Thus, our findings provide novel insights on the mechanism underlying the functional linkage between drug resistance and cancer aggressiveness.
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Anexina A2/metabolismo , Neoplasias da Mama/metabolismo , Resistencia a Medicamentos Antineoplásicos , Proteínas de Neoplasias/metabolismo , Receptores de Quinase C Ativada/metabolismo , Quinases da Família src/metabolismo , Animais , Antineoplásicos/farmacologia , Apoptose/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Camundongos , Invasividade Neoplásica , Metástase Neoplásica , Fosforilação , Ligação Proteica , RNA Interferente Pequeno/metabolismoRESUMO
BACKGROUND: The study was designed to explore the value of including positive lymph node count in the TNM staging system of non-small cell lung cancer. PATIENTS AND METHODS: The X-tile model was applied to determine the cutoff values of positive lymph node count. Survival curves were generated using the Kaplan-Meier method and differences in survival among subgroups were examined using the log-rank test. The influence of different variables on overall survival and lung cancer-specific survival was further evaluated using univariate and multivariate Cox proportional hazard models. All statistical analyses were performed using SPSS version 22.0 (SPSS, Chicago, IL, USA). All p values were 2-sided and p < 0.05 was considered statistically significant. RESULTS: The overall survival and lung cancer-specific survival between stage IIIA and IIIB classified by the sixth edition TNM staging system show no statistically significant difference (p = 0.479 for overall survival; p = 0.081 for lung cancer specific survival). The X-tile model was used to screen three different cutoff values including nN = 0, nN1-3 and nN4-. The nN value is a significant independent prognostic factor that affects overall survival and lung cancer-specific survival of non-small cell lung cancer patients (all, p < 0.001). We obtained the hypothesized TNM sub-stages based on location and the number of PLN. There were significant differences between the hypothesized stage IIIA and IIIB regarding overall survival and lung cancer-specific survival (all, p < 0.001). CONCLUSIONS: It needs to be considered that N stage in combination with positive lymph node count may be used to predict the prognosis of non-small cell lung cancer for stage III cases with increased accuracy than category location-based stage.
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Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Linfonodos/patologia , Adulto , Idoso , Feminino , Humanos , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Programa de SEER , Taxa de SobrevidaRESUMO
Context Ginseng is a widely used herbal medicine in China but its mechanism of action remains unclear. Objective The objectives of this work were to study the protective effect of ginsenoside Rg1 on subacute murine renal damage induced by d-galactose and its mechanism. Materials and methods C57BL/6J mice were injected with 120 mg/kg/d (sc) d-galactose for 1 week, followed by a combined treatment of Rg1 20 mg/kg/d (ip) and 120 mg/kg/d d-galactose (sc) for 5 weeks. Mice were injected with the 0.9% saline 0.2 mL/d (sc) and 120 mg/kg/d d-galactose (sc) for 6 weeks in the control group and the d-galactose group, respectively. After 6 weeks, urea, creatinine, uric acid, cystatin (Cys-C), senescence-associated ß-galactosidase (SA-ß-gal) staining positive kidney cells, superoxide dismutase (SOD), glutathione peroxidase (GSH-PX), malondialdehyde (MDA), glycation end products (AGEs) and 8-hydroxy-2 deoxyguanosine (8-OH-dG) were measured. Results Treatment with Rg1 ameliorated kidney function and aging state (urea from 17.19 ± 1.09 to 15.77 ± 1.22 mmol·L (-) (1), creatinine from 29.40 ± 5.72 to 22.60 ± 3.97 µmol·L (-) (1), uric acid from 86.80 ± 5.97 to 72.80 ± 10.61 µmol·L (-) (1), Cys-C from 0.23 ± 0.03 to 0.18 ± 0.05 mg·L (-) (1), ROD of SA-ß-gal from 56.32 ± 10.48 to 26.78 ± 7.34, SOD from 150.22 ± 19.07 to 190.56 ± 15.83 U·(mg·prot) (-1), MDA from 9.28 ± 1.59 to 3.17 ± 0.82 nmol·(mg·prot) (-1), GSH-PX from 15.68 ± 2.11 to 20.32 ± 2.96 U·(mg·prot) (-1) as well as regulated glomerulus morphology (glomerulus diameter from 775.77 ± 18.41 to 695.04 ± 14.61 µm, renal capsule width from 39.56 ± 3.51 to 31.42 ± 2.70 µm, glomerulus basement membrane from 206.03 ± 16.22 to 157.27 ± 15.70 nm, podocyte slit from 55.21 ± 8.55 to 37.63 ± 6.65 nm). Conclusions Ginsenoside Rg1 can antagonise d-galactose subacute renal damage in mice and this may occur due to alleviating oxidative stress injury.
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Antioxidantes/farmacologia , Galactose , Ginsenosídeos/farmacologia , Nefropatias/prevenção & controle , Rim/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , 8-Hidroxi-2'-Desoxiguanosina , Animais , Biomarcadores/sangue , Citoproteção , Dano ao DNA/efeitos dos fármacos , Desoxiguanosina/análogos & derivados , Desoxiguanosina/metabolismo , Modelos Animais de Doenças , Glutationa Peroxidase/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Rim/metabolismo , Rim/ultraestrutura , Nefropatias/sangue , Nefropatias/induzido quimicamente , Nefropatias/metabolismo , Nefropatias/patologia , Masculino , Malondialdeído/metabolismo , Camundongos Endogâmicos C57BL , Superóxido Dismutase/metabolismoRESUMO
The development of multidrug resistance greatly impedes effective cancer therapy. Recent advances in cancer research have demonstrated that acquisition of multidrug resistance by cancer cells is usually accompanied by enhanced cell invasiveness. Several lines of evidence indicated that cross activation of other signaling pathways during development of drug resistance may increase invasive potential of multidrug-resistant (MDR) cancer cells. However, the accurate mechanism of this process is largely undefined. In this study, to better understand the associated molecular pathways responsible for cancer progression induced by drug resistance, a MDR human breast cancer cell line SK-BR-3/EPR with P-glycoprotein overexpression was established using stepwise long-term exposure to increasing concentration of epirubicin. The SK-BR-3/EPR cell line exhibited decreased cell proliferative activity, but enhanced cell invasive capacity. We showed that the expression of metastasis-related matrix metalloproteinase (MMP)-2/9 was elevated in SK-BR-3/EPR cells. Moreover, SK-BR-3/EPR cells showed elevated activation of STAT3. Activation of STAT3 signaling is responsible for enhanced invasiveness of SK-BR-3/EPR cells through upregulation of MMP-2/9. STAT3 is a well-known oncogene and is frequently implicated in tumorigenesis and chemotherapeutic resistance. Our findings augment insight into the mechanism underlying the functional association between MDR and cancer invasiveness.
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Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Fator de Transcrição STAT3/metabolismo , Linhagem Celular Tumoral , Resistência a Múltiplos Medicamentos , Epirubicina/farmacologia , Feminino , Humanos , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , Fator de Transcrição STAT3/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genéticaRESUMO
To explore the protective effect of Angelica sinensis polysaccharides(ASP) on subacute renal damages induced by D-galactose in mice and its mechanism. Male C57BL/6J mice were randomly divided into 3 groups, with 10 mice in each group. The D-galactose model group was subcutaneously injected with D-galactose (120 mg x kg(-1)), qd x 42; the ASP + D-galactose model group was intraperitoneally injected with ASP since the 8th day of the replication of the D-galactose model, qd x 35; and the normal control group was subcutaneously injected with saline at the same dose and time. On the 2nd day of after the injection, the peripheral blood was collected to measure the content of BUN, Crea, UA, Cys-C; paraffin sections were made to observe the renal histomorphology by HE staining; senescence-associated ß-g-alactosidase (SA-ß-Gal) stain was used to observe the relative optical density (ROD) in renal tissues; transmission electron microscopy was assayed to observe the renal ultrastructure; the renal tissue homogenate was prepared to measure the content of SOD, GSH-PX, MDA; the content of AGEs and 8-OH-dG were measured by ELISA. According to the result, compared with the D-galactose model group, the ASP + D-galactose model group showed obviously decreases in the content of BUN, Crea, UA, Cysc, AGES, 8-OH-dG, the number of hardening renal corpuscle, renal capsular space and renal tubular lumen, ROD of SA-ß-Gal staining positive kidney cells, mesangial cells, basement membrane thickness, podocyte secondary processes fusion and MDA and increases in the number of normal renal corpuscle, ribosome and rough endoplasmic reticulum in podocytes, the activity of SOD and GSH-PX. In Conclusion, A. sinensis polysaccharides can antagonize kidney subacute damages induced by D-galactose in mice. Its protective mechanism may be correlated with the inhibition of the oxidative stress injury.
Assuntos
Angelica sinensis/química , Medicamentos de Ervas Chinesas/administração & dosagem , Nefropatias/tratamento farmacológico , Polissacarídeos/administração & dosagem , Substâncias Protetoras/administração & dosagem , 8-Hidroxi-2'-Desoxiguanosina , Animais , Desoxiguanosina/análogos & derivados , Desoxiguanosina/metabolismo , Galactose/efeitos adversos , Humanos , Rim/anatomia & histologia , Rim/efeitos dos fármacos , Rim/lesões , Nefropatias/induzido quimicamente , Nefropatias/metabolismo , Nefropatias/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacosRESUMO
Institutional controls, as an important measure for risk management of contaminated sites, is widely used in site management by the United States, Canada and European countries. At present, some regions in China have also begun to explore the implementation of institutional controls, but its path, safeguard mechanism, and tracking evaluation are still unclear. Based on China's unique contaminated site remediation control system and land management system, this paper proposes a framework for the whole life cycle institutional controls of China's contaminated sites: (1) evaluate the need for institutional controls; (2) establish the objectives of institutional controls; (3) identify the restrictive requirements of institutional controls; (4) establish the implementation form of institutional controls; and (5) regularly review the effectiveness of institutional controls. To demonstrate the applicability of the institutional control framework, a case demonstration study was conducted at a petrochemical contaminated site in China. By analyzing the information on residual pollutants after the implementation of risk management measures at the site, the exposure pathways and hazards in case of re-release, and the engineering facilities, we proposed eight restrictive requirements, including the prohibition of disturbing and damaging the clean and planted soil layers of the site and the protection of long-term monitoring wells. At the same time, we constructed a multi-departmental pathway to implement institutional controls in conjunction with ecological environment, natural resources and housing departments to ensure effective implementation of institutional controls. Eventually, we summarized a set of replicable and generalizable institutional controls application models, which provide valuable theoretical and practical support for China and other local governments in the implementation of institutional controls at contaminated sites.
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Adrenal glands, vital for steroid secretion and the regulation of metabolism, stress responses and immune activation, experience age-related decline, impacting systemic health. However, the regulatory mechanisms underlying adrenal aging remain largely uninvestigated. Here we established a single-nucleus transcriptomic atlas of both young and aged primate suprarenal glands, identifying lipid metabolism and steroidogenic pathways as core processes impacted by aging. We found dysregulation in centripetal adrenocortical differentiation in aged adrenal tissues and cells in the zona reticularis region, responsible for producing dehydroepiandrosterone sulfate (DHEA-S), were highly susceptible to aging, reflected by senescence, exhaustion and disturbed hormone production. Remarkably, LDLR was downregulated in all cell types of the outer cortex, and its targeted inactivation in human adrenal cells compromised cholesterol uptake and secretion of dehydroepiandrosterone sulfate, as observed in aged primate adrenal glands. Our study provides crucial insights into endocrine physiology, holding therapeutic promise for addressing aging-related adrenal insufficiency and delaying systemic aging.
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Glândulas Suprarrenais , Envelhecimento , Animais , Humanos , Idoso , Sulfato de Desidroepiandrosterona/metabolismo , Glândulas Suprarrenais/metabolismo , Envelhecimento/genética , Zona Reticular , Primatas/metabolismoRESUMO
Epigenetic clocks are accurate predictors of human chronological age based on the analysis of DNA methylation (DNAm) at specific CpG sites. However, a systematic comparison between DNA methylation data and other omics datasets has not yet been performed. Moreover, available DNAm age predictors are based on datasets with limited ethnic representation. To address these knowledge gaps, we generated and analyzed DNA methylation datasets from two independent Chinese cohorts, revealing age-related DNAm changes. Additionally, a DNA methylation aging clock (iCAS-DNAmAge) and a group of DNAm-based multi-modal clocks for Chinese individuals were developed, with most of them demonstrating strong predictive capabilities for chronological age. The clocks were further employed to predict factors influencing aging rates. The DNAm aging clock, derived from multi-modal aging features (compositeAge-DNAmAge), exhibited a close association with multi-omics changes, lifestyles, and disease status, underscoring its robust potential for precise biological age assessment. Our findings offer novel insights into the regulatory mechanism of age-related DNAm changes and extend the application of the DNAm clock for measuring biological age and aging pace, providing the basis for evaluating aging intervention strategies.
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Envelhecimento , Metilação de DNA , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Envelhecimento/genética , Relógios Biológicos/genética , China , Estudos de Coortes , Ilhas de CpG , População do Leste Asiático/genética , Epigênese GenéticaRESUMO
Seed abortion is a common phenomenon in woody plants, especially in rare and endangered species. Serious seed abortion occurs in the dove tree and largely restricts its natural reproduction. A number of differentially expressed genes (DEGs) between normal and aborted seeds of the dove tree have been previously identified through transcriptome profiling. Among these, most DEGs encoding laccase showed significant upregulation in the aborted seeds. In this study, the laccase gene with the highest expression level in aborted seeds, DiLAC17, was cloned from the dove tree genome and further verified. Overexpression of the DiLAC17 gene in Arabidopsis resulted in retarded growth, deformed siliques, and severe seed abortion. Most Arabidopsis genes involved in seed development, such as AtLEC2, AtANT1, and AtRGE1, were suppressed in the transgenic lines. Laccase activity and lignin content were significantly improved in transgenic lines under ectopic overexpression of the DiLAC17 gene. Excessive lignin accumulation in the early developmental stage was assumed to be a key cause of restricting silique growth and seed expansion, which ultimately led to seed abortion. These results indicate a laccase-mediated pathway for seed abortion, which might be a strategy adopted by this rare and endangered species to reduce the reproductive load.
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Arabidopsis , Nyssaceae , Gravidez , Feminino , Humanos , Arabidopsis/metabolismo , Lacase/genética , Lacase/metabolismo , Lignina/metabolismo , Sementes/metabolismo , Perfilação da Expressão Gênica , Nyssaceae/genética , Regulação da Expressão Gênica de PlantasRESUMO
Aging poses a major risk factor for cardiovascular diseases, the leading cause of death in the aged population. However, the cell type-specific changes underlying cardiac aging are far from being clear. Here, we performed single-nucleus RNA-sequencing analysis of left ventricles from young and aged cynomolgus monkeys to define cell composition changes and transcriptomic alterations across different cell types associated with age. We found that aged cardiomyocytes underwent a dramatic loss in cell numbers and profound fluctuations in transcriptional profiles. Via transcription regulatory network analysis, we identified FOXP1, a core transcription factor in organ development, as a key downregulated factor in aged cardiomyocytes, concomitant with the dysregulation of FOXP1 target genes associated with heart function and cardiac diseases. Consistently, the deficiency of FOXP1 led to hypertrophic and senescent phenotypes in human embryonic stem cell-derived cardiomyocytes. Altogether, our findings depict the cellular and molecular landscape of ventricular aging at the single-cell resolution, and identify drivers for primate cardiac aging and potential targets for intervention against cardiac aging and associated diseases.
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Envelhecimento , Fatores de Transcrição Forkhead , Miócitos Cardíacos , Proteínas Repressoras , Transcriptoma , Idoso , Animais , Humanos , Envelhecimento/genética , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Miócitos Cardíacos/metabolismo , Primatas/genética , Primatas/metabolismo , Proteínas Repressoras/metabolismo , Macaca fascicularis/genética , Macaca fascicularis/metabolismoRESUMO
Aging is a major risk factor contributing to pathophysiological changes in the heart, yet its intrinsic mechanisms have been largely unexplored in primates. In this study, we investigated the hypertrophic and senescence phenotypes in the hearts of aged cynomolgus monkeys as well as the transcriptomic and proteomic landscapes of young and aged primate hearts. SIRT2 was identified as a key protein decreased in aged monkey hearts, and engineered SIRT2 deficiency in human pluripotent stem cell-derived cardiomyocytes recapitulated key senescence features of primate heart aging. Further investigations revealed that loss of SIRT2 in human cardiomyocytes led to the hyperacetylation of STAT3, which transcriptionally activated CDKN2B and, in turn, triggered cardiomyocyte degeneration. Intra-myocardial injection of lentiviruses expressing SIRT2 ameliorated age-related cardiac dysfunction in mice. Taken together, our study provides valuable resources for decoding primate cardiac aging and identifies the SIRT2-STAT3-CDKN2B regulatory axis as a potential therapeutic target against human cardiac aging and aging-related cardiovascular diseases.
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Proteômica , Sirtuína 2 , Humanos , Camundongos , Animais , Idoso , Envelhecimento/genética , Miócitos Cardíacos/metabolismo , Primatas/metabolismo , Proteínas Inibidoras de Quinase Dependente de Ciclina/metabolismo , Fator de Transcrição STAT3/genéticaRESUMO
Regeneration across tissues and organs exhibits significant variation throughout the body and undergoes a progressive decline with age. To decode the relationships between aging and regenerative capacity, we conducted a comprehensive single-cell transcriptome analysis of regeneration in eight tissues from young and aged mice. We employed diverse analytical models to study tissue regeneration and unveiled the intricate cellular and molecular mechanisms underlying the attenuated regenerative processes observed in aged tissues. Specifically, we identified compromised stem cell mobility and inadequate angiogenesis as prominent contributors to this age-associated decline in regenerative capacity. Moreover, we discovered a unique subset of Arg1+ macrophages that were activated in young tissues but suppressed in aged regenerating tissues, suggesting their important role in age-related immune response disparities during regeneration. This study provides a comprehensive single-cell resource for identifying potential targets for interventions aimed at enhancing regenerative outcomes in the aging population.
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Envelhecimento , Células-Tronco , Camundongos , Animais , Envelhecimento/fisiologia , Células-Tronco/fisiologiaRESUMO
BACKGROUND: Translating aging rejuvenation strategies into clinical practice has the potential to address the unmet needs of the global aging population. However, to successfully do so requires precise quantification of aging and its reversal in a way that encompasses the complexity and variation of aging. METHODS: Here, in a cohort of 113 healthy women, tiled in age from young to old, we identified a repertoire of known and previously unknown markers associated with age based on multimodal measurements, including transcripts, proteins, metabolites, microbes, and clinical laboratory values, based on which an integrative aging clock and a suite of customized aging clocks were developed. FINDINGS: A unified analysis of aging-associated traits defined four aging modalities with distinct biological functions (chronic inflammation, lipid metabolism, hormone regulation, and tissue fitness), and depicted waves of changes in distinct biological pathways peak around the third and fifth decades of life. We also demonstrated that the developed aging clocks could measure biological age and assess partial aging deceleration by hormone replacement therapy, a prevalent treatment designed to correct hormonal imbalances. CONCLUSIONS: We established aging metrics that capture systemic physiological dysregulation, a valuable framework for monitoring the aging process and informing clinical development of aging rejuvenation strategies. FUNDING: This work was supported by the National Natural Science Foundation of China (32121001), the National Key Research and Development Program of China (2022YFA1103700 and 2020YFA0804000), the National Natural Science Foundation of China (81502304), and the Quzhou Technology Projects (2022K46).
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Envelhecimento , População do Leste Asiático , Humanos , Feminino , Idoso , Envelhecimento/genética , Fenótipo , Rejuvenescimento , China/epidemiologiaRESUMO
The primate frontal lobe (FL) is sensitive to aging-related neurocognitive decline. However, the aging-associated molecular mechanisms remain unclear. Here, using physiologically aged non-human primates (NHPs), we depicted a comprehensive landscape of FL aging with multidimensional profiling encompassing bulk and single-nucleus transcriptomes, quantitative proteome, and DNA methylome. Conjoint analysis across these molecular and neuropathological layers underscores nuclear lamina and heterochromatin erosion, resurrection of endogenous retroviruses (ERVs), activated pro-inflammatory cyclic GMP-AMP synthase (cGAS) signaling, and cellular senescence in post-mitotic neurons of aged NHP and human FL. Using human embryonic stem-cell-derived neurons recapitulating cellular aging in vitro, we verified the loss of B-type lamins inducing resurrection of ERVs as an initiating event of the aging-bound cascade in post-mitotic neurons. Of significance, these aging-related cellular and molecular changes can be alleviated by abacavir, a nucleoside reverse transcriptase inhibitor, either through direct treatment of senescent human neurons in vitro or oral administration to aged mice.
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Retrovirus Endógenos , Animais , Camundongos , Lâmina Nuclear , Envelhecimento/fisiologia , Senescência Celular/genética , Neurônios , PrimatasRESUMO
Due to the convenience, fresh-cut vegetables or fruits as the emerging commercial products have attracted much attention in recent years. However, the preservation of food with high quality remains a big challenge. In this study, one novel kind of edible composite film (PAX) consisted of pectin, sodium alginate (SA), and xanthan gum (XG) was well developed. The optimum concentrations for pectin and SA in PAX film based on the shearing viscosity were 6 g/L and 5 g/L, respectively. Upon this condition, the experimental results from the response surface methodology showed that the tensile strength for the optimized PAX (PAXO) film can reach the maximum value of 29.65 MPa at the concentration of 4 g/L XG, 18 g/L glycerol, and 20 g/L CaCl2. The corresponding elongation at break was 19.02% and the water vapor transmission rate was evaluated to be 18.12 × 10-11 g/(m2·s·pa). Furthermore, the nanocomposites in terms of coating or films were used to keep fresh-cut potatoes, where they exhibited different efficiencies in food preservation with the order: PAXO coating + CaCl2 ≈ PAXO coating > PAXO film > sterile water. All the results indicated that the as-prepared PAXO film or PAXO solution could be good candidates in packaging preservation.
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Filmes Comestíveis , Conservação de Alimentos , Nanocompostos/química , Pectinas/química , Alginatos/química , Embalagem de Alimentos , Frutas/efeitos dos fármacos , Glicerol/química , Polissacarídeos Bacterianos/química , Vapor , Água/químicaRESUMO
Raspberry pomace extracts (RPE) with different concentrations (0.5 g/L, 1.5 g/L and 3 g/L) were incorporated into pectin/sodium alginate/xanthan gum composite film (PAX) to prepare colorimetric raspberry films (PAXR5, PAXR15 and PAXR30). Fourier Transform Infrared and Scanning Electron Microscopy analysis showed RPE had good compatibility with PAX. Compared to PAX, the raspberry films had lower water vapor permeability and water swelling ratio, higher tensile strength, opacity and antioxidant capacity. The films presented a smoother surface and denser structure than PAX. Furthermore, PAXR15 had an excellent discoloration at pH 1-13, especially at pH 5-10, the color changes of PAXR15 from pink-red-brown-blue-dark green distinguished by the naked eyes. Therefore, it has the potential to become a pH-sensitive film used in monitoring protein-rich food freshness.
Assuntos
Alginatos/química , Pectinas/química , Polissacarídeos Bacterianos/química , Rubus/química , Embalagem de Alimentos , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Microscopia Eletrônica de Varredura , Espectroscopia de Infravermelho com Transformada de Fourier , Resistência à TraçãoRESUMO
The continuing increase in the global saline-alkali land area has made saline-alkali stress the principal abiotic stress limiting plant growth. Potato is the most important non-grain crop, and its production is also severely limited by saline-alkali stress. However, few studies have addressed the mechanism of saline-alkali tolerance of potato with a focus on its response to neutral salt NaCl stress, or its response to alkali stress. Recently, miRNA-mRNA analyses have helped advance our understanding of how plants respond to stress. Here, we have characterized the morphological, physiological, and transcriptome changes of tissue culture seedlings of potato variety "Qingshu No. 9" treated with NaHCO3 (for 0, 2, 6, and 24 h). We found that the leaves of tissue culture seedlings wilted and withered under alkali stress, and the contents of ABA, BRs, trehalose, and lignin in roots increased significantly. The contents of GAs decreased significantly. Subsequently, miRNA-seq analysis results identified 168 differentially expressed miRNAs (DEMIs) under alkali stress, including 21 exist miRNAs and 37 known miRNAs from 47 families and 110 novel miRNAs. The mRNA-seq results identified 5731 differentially expressed mRNAs (DEMs) under alkali stress. By miRNA-mRNA integrated analysis, were obtained 33 miRNA-target gene pairs composed of 20 DEMIs and 33 DEMs. Next, we identified the "phenylpropanoid biosynthesis", "plant hormone signal transduction", and "starch and sucrose metabolism" pathways as necessary for potato to respond to alkali stress. miR4243-x and novel-m064-5p were involved in the response of potato to alkali stress by their negative regulatory effects on shikimate O-hydroxycinnamoyltransferase (HCT) and sucrose-phosphate synthase (SPS) genes, respectively. The expression results of miRNA and mRNA were verified by quantitative real-time PCR (qRT-PCR). Our results clarify the mechanism of potato response to alkali stress at the miRNA level, providing new insights into the molecular mechanisms of potato's response to alkali stress. We report many candidate miRNAs and mRNAs for molecular-assisted screening and salt-alkali resistance breeding.