Resveratrol inhibits pancreatic cancer proliferation and metastasis by depleting senescent tumor-associated fibroblasts

BACKGROUND Pancreatic cancer,a formidable gastrointestinal neoplasm,is characterized by its insidious onset,rapid progression,and resistance to treatment,which often lead to a grim prognosis.While the complex pathogenesis of pancreatic cancer is well recognized,recent attention has focused on the oncogenic roles of senescent tumor-associated fibroblasts.However,their precise role in pancreatic cancer remains unknown.Resveratrol is a natural polyphenol known for its multifaceted biological actions,including antioxidative and neuroprotective properties,as well as its potential to inhibit tumor proliferation and migration.Our current investigation builds on prior research and reveals the remarkable ability of resveratrol to inhibit pancreatic cancer proliferation and metastasis.AIM To explore the potential of resveratrol in inhibiting pancreatic cancer by targeting senescent tumor-associated fibroblasts.METHODS Immunofluorescence staining of pancreatic cancer tissues revealed prominent coexpression ofα-SMA and p16.HP-1 expression was determined using immunohistochemistry.Cells were treated with the senescence-inducing factors known as 3CKs.Long-term growth assays confirmed that 3CKs significantly decreased the CAF growth rate.Western blotting was conducted to assess the expression levels of p16 and p21.Immunofluorescence was performed to assess LaminB1 expression.Quantitative real-time polymerase chain reaction was used to measure the levels of several senescence-associated secretory phenotype factors,including IL-4,IL-6,IL-8,IL-13,MMP-2,MMP-9,CXCL1,and CXCL12.A scratch assay was used to assess the migratory capacity of the cells,whereas Transwell assays were used to evaluate their invasive potential.RESULTS Specifically,we identified the presence of senescent tumor-associated fibroblasts within pancreatic cancer tissues,linking their abundance to cancer progression.Intriguingly,Resveratrol effectively eradicated these fibroblasts and hindered their senescence,which consequently impeded pancreatic cancer progression.CONCLUSION This groundbreaking discovery reinforces Resveratrol's stature as a potential antitumor agent and positions senescent tumor-associated fibroblasts as pivotal contenders in future therapeutic strategies against pancreatic cancer.

Mesenchymal stem cell-derived extracellular vesicles in skin wound healing: the risk of senescent drift induction in secretome-based therapeutics

Regulatory changes in senescent cells could potentially affect the composition of extracellular vehicles(EVs),specifically altering their size and cargo.As a result,the released senescent EVs contain an unpredictable cocktail of growth factors and cytokines.These biomolecules have dual effects,potentially guiding the induction of senescence in affected cells and promoting an inflammation-related“domino effect”within the cellular environment,ultimately leading to tissue inflammaging.

A food-grade and senescent cell-targeted fisetin delivery system based on whey protein isolate-galactooligosaccharides Maillard conjugate

Cellular senescence is the results of aging and age-related diseases,and the development of anti-aging methods may improve health and extend longevity.The natural flavonol fisetin has been shown to antagonize senescence in vitro and increases longevity in vivo,but has poor water solubility and limited bioavailability.In this study,a food-grade and senescent cell-targeted delivery system for fisetin was developed based on whey protein isolate-galactooligosaccharides(WPI-GOS)Maillard conjugate,which could recognize senescence associatedβ-galactosidase in senescent cells.The fisetin nanoparticles possessed a high encapsulation efficiency,excellent dispersibility in water,good storage stability and well biocompatibility.Moreover,they could effectively accumulate and retain in senescent cells with excellent senescent cell-targeting efficacy,and inhibit the oxidative stress-induced cellular senescence in vitro.Thus,this novel nanoparticle system based on WPI-GOS Maillard conjugate showed promise to deliver hydrophobic bioactive ingredients like fisetin to senescent cells to improve their bioavailability and anti-senescence effect.

Senescent mesenchymal stem/stromal cells in pre-metastatic bone marrow of untreated advanced breast cancer patients

Breast cancer is the predominant form of carcinoma among women worldwide,with 70%of advanced patients developing bone metastases,with a high mortality rate.In this sense,the bone marrow(BM)mesenchymal stem/stromal cells(MSCs)are critical for BM/bone homeostasis,and failures in their functionality,transform the BM into a premetastatic niche(PMN).We previously found that BM-MSCs from advanced breast cancer patients(BCPs,infiltrative ductal carcinoma,stage III-B)have an abnormal profile.This work aims to study some of the metabolic and molecular mechanisms underlying MSCs shift from a normal to an abnormal profile in this group of patients.A comparative analysis was undertaken,which included self-renewal capacity,morphology,proliferation capacity,cell cycle,reactive oxygen species(ROS)levels,and senescence-associatedβ‑galactosidase(SA‑β‑gal)staining of BMderived MSCs isolated from 14 BCPs and 9 healthy volunteers(HVs).Additionally,the expression and activity of the telomerase subunit TERT,as well as telomere length,were measured.Expression levels of pluripotency,osteogenic,and osteoclastogenic genes(OCT-4,SOX-2,M-CAM,RUNX-2,BMP-2,CCL-2,M-CSF,and IL-6)were also determined.The results showed that MSCs from BCPs had reduced,self-renewal and proliferation capacity.These cells also exhibited inhibited cell cycle progression and phenotypic changes,such as an enlarged and flattened appearance.Additionally,there was an increase in ROS and senescence levels and a decrease in the functional capacity of TERT to preserve telomere length.We also found an increase in pro-inflammatory/pro-osteoclastogenic gene expression and a decrease in pluripotency gene expression.We conclude that these changes could be responsible for the abnormal functional profile that MSCs show in this group of patients.

Therapy-induced senescent tumor cells in cancer relapse

Cellular senescence is characterized by a generally irreversible cell cycle arrest and the secretion of bioactive factors known as the senescence-associated secretory phenotype(SASP).In an oncogenic context,senescence is considered a tumor suppressive mechanism as it prevents cell proliferation and inhibits the progression from pre-malignant to malignant disease.However,recent studies have demonstrated that senescent tumor cells,which could spontaneously exist within cancer tissues or arise in response to various cancer interventions(the so-called therapy-induced senescence,TIS),can acquire pro-tumorigenic properties and are capable of driving local and metastatic relapse.This highlights the complex and multifaceted nature of cellular senescence in cancer biology.Here,we summarize the current knowledge of the pathological function of therapy-induced senescent tumor cells and discuss possible mechanisms by which tumor cell senescence contributes to cancer relapse.We also discuss implications for future studies toward targeting these less appreciated cells.

Dopaminergic mediation in the brain aging and neurodegenerative diseases:a role of senescent cells

Aging is well known to be the main risk factor for the neurodegenerative pathologies,in particular,Parkinson’s disease（PD）and Alzheimer’s disease（AD）.In aging and in the diseases,similar changes in various hallmarks of neurodegeneration（lipofuscin accumulation,autophagia weakening,and disturbances in functions of mitochondriaand lysosomes） were shown （Tan et al., 2014）. Furthermore, dopami- nergic system （DAS） involvement in mechanisms of aging, PD, and AD were revealed （Martorana and Koch, 2014）.

Senescent mesenchymal stem/stromal cells and restoring their cellular functions

Mesenchymal stem/stromal cells(MSCs)have various properties that make them promising candidates for stem cell-based therapies in clinical settings.These include self-renewal,multilineage differentiation,and immunoregulation.However,recent studies have confirmed that aging is a vital factor that limits their function and therapeutic properties as standardized clinical products.Understanding the features of senescence and exploration of cell rejuvenation methods are necessary to develop effective strategies that can overcome the shortage and instability of MSCs.This review will summarize the current knowledge on characteristics and functional changes of aged MSCs.Additionally,it will highlight cell rejuvenation strategies such as molecular regulation,noncoding RNA modifications,and microenvironment controls that may enhance the therapeutic potential of MSCs in clinical settings.

Effects of short-term heat stress on PSII and subsequent recovery for senescent leaves of Vitis vinifera L. cv. Red Globe

Heat stress occurs frequently in energy-saving sunlight greenhouses(ESSG) at the late growth stage. Three-year delayed cultivation(DC) of the Red Globe cultivar of Vitis vinifera L. was used to clarify the physiological mechanisms of short-term heat stress on PSII and subsequent recovery from heat stress. By November, the photosynthetic function had declined and the fall in transpiration rate(E) with heating time increased the possibility of heat damage. In July, the most obvious increase was in the relative variable fluorescence at J point at 40°C, and in November it changed to K point. The 5 min of heat treatment resulted in a significant increase of the relative variable fluorescence at 0.3 ms(W), and after 10 min of heat treatment, the number of reactive centres per excited cross section(RC/CS), probability that a trapped exciton moves an electron into the electron transport chain beyond Q–(at t=0)(Ψ) and quantum yield of electron transport at t=0(φ) decreased significantly(P<0.05), suggesting that the reaction centre, donor and acceptor side of photosystem II(PSII) were all significantly inhibited(P<0.05) and that the thermal stability of the photosynthetic mechanism was reduced. The inhibition of energy fluxes for senescent leaves in November was earlier and more pronounced than that for healthy leaves, which did not recover from heat stress of more than 15 min after 2 h recovery at room temperature.

Increased expression of inflammation cytokines in senescent vascular smooth muscle cells by balloon catheter denudation is associated with NF-[kappa]B pathway

Objective： To determine whether balloon catheter denudation can induce vascular smooth muscle cells （VSMCs） to senescence, and whether this senescence can result in inflammation activity. Methods： Twelve male Chinese white rabbits were denuded of the carotid arteries or VSMCs. Acidic β-galactosidase activity of carotid arteries or VSMCs was detected. Transfection and chloramphenicol acetyltransferase （CAT） assay for iNOS gene and nitrite （NO2^-） assay were undertaken. Reverse transcription-polymerase chain reaction （RT-PCR） was used to evaluate inflammation cytokines mRNA expression. Measurement of NF-kB activity was detected by electrophoretic mobility shift assay （EMSA）. MMP-9, ICAM-1, P-p65, and IkBα expressions were analyzed by Western blotting. Results： After denudation VSMCs from denuded arteries showed an accumulation of significantly more senescence-associated β-galactosidase （SA-β-Gal） positive ceils and greater iNOS activity. Transcriptional activity of iNOS was highly expressed. The mRNA expressions of IL-1β, ICAM-1,MMP-9, TNF-α and the iNOS enzyme were significantly increased in injuring-induced senescence SMCs. However, the TNF-α or IL-1β-induced the protein production （ICAM-1 and MMP-9） was prevented by PDTC and MG132, which are inhibitors of NF-kB activation. Also, activation of NF-kB and cytokine-induced degradation of IKBα in the denuded VSMC were significantly affected. Conclusion： Intraluminal injury to the artery may lead to the emergence of senescent VSMC. Inflammation activity in SMCs is closely related to the senescence and the activation of NF-kB is involved.

Effect of 2LMISEN^®on Long-Term Hippocampal Neurons Culture as a Screening Senescent Cells Model: p16^INK4Aand Caspase 3 Quantification

The aim of the present study was to investigate the effect of one capsule of the micro-immunotherapy medicine (MIM) 2LMISEN&reg;compared to vehicle, in a neuronal aging model. Senescence and apoptosis of hippocampal neurons were evaluated by measuring p16INK4a and caspase 3 levels, respectively. The data presented is a single observation. Mice hippocampal neuron cultures were treated with MIM (11 mM) or vehicle (11 mM) from 22 days in vitro (DIV) until 27 DIV. After incubation, hippocampal neuron cultures were fixed at 15 (control condition), 22, 25 and 27 DIV and then incubated with primary antibodies p16INK4a, MAP2 and Caspase 3. Quantification of p16INK4a and Caspase 3-positive neurons was done using Developer software. We found that vehicle had no effect on p16INK4a expression, whereas MIM was able to decrease p16INK4a levels at 22, 25 and 27 DIV in a statistically significant manner. The MIM had no significative effect on Caspase 3 expression. Our preliminary results showed that the MIM capsule significantly reduced neuronal senescence and not apoptosis.

Erythrocyte Senescent Markers by Flow Cytometry

Background: Mature red blood cells lack protein synthesis and are unable to restore inactivated enzymes, damaged cytoskeleton and membrane proteins. An oxidation breakdown of band 3 is probably part of the mechanism leading to the generation of a senescent cell antigen. This specific signal serves for the clearance of RBCs by inducing the binding of autologous IgG and C3, leading to phagocytosis. In addition, phosphatidilserin molecules appear in the outer membrane and the CD47 expression diminishes. Methods: Erythrocytes of different ages from whole blood were studied by flow cytometry analysing light scatter proprieties, binding of autologous IgG, C3 complement deposits, externalization of phosphatidylserine and CD47 expression. Dot-plot analysis based on forward scatter versus side scatter parameters showed two RBCs populations of different sizes and density. RBCs were further incubated with Alexa 488 IgG, APC-anti-C3, PE-annexin-V and PE-CD47. The comparison of the values obtained for the different variables studied in SeRBC and YRBC populations was carried out by the Student t-test for matched samples or by the Wilcoxon test (after verification of the normality assumption). Results: The percentage of IgG and C3 positive cells was significantly higher in senescent red blood cells population. The fraction of annexin-V positive RBCs was also larger in SeRBCs while the CD47 expression was lower in this population. Conclusions: These results indicate that flow cytometry allow differenciation of erythrocytes populations of different ages, turning this tool into an useful alternative option to study erythrocyte aging process. These findings will contribute to a better understanding of the process and mechanisms involved in erythrocyte senescence process.

Magnesium-containing bioceramics stimulate exosomal miR-196a-5p secretion to promote senescent osteogenesis through targeting Hoxa7/MAPK signaling axis

Stem cell senescence is characterized by progressive functional dysfunction and secretory phenotypic changes including decreased proliferation,dysfunction of osteogenic and angiogenic differentiation,increased secretion of the senescence-associated secretory phenotype(SASP),which bring difficulties for bone repair.Rescuing or delaying senescence of aged bone marrow mesenchymal stem cells(O-BMSCs)was considered as effective strategy for bone regeneration in aging microenvironment.Magnesium(Mg)ion released from bioceramics was reported to facilitate bone regeneration via enhancing osteogenesis and alleviating senescence.In this study,Akermanite biocreamics(Akt)containing Mg ion as a model was demonstrated to promote osteogenesis and angiogenesis effects of O-BMSCs by activating the MAPK signaling pathway in vitro.Moreover,the enhanced osteogenesis effects might be attributed to enhanced Mg-containing Akt-mediated exosomal miR-196a-5p cargo targeting Hoxa7 and activation of MAPK signaling pathway.Furthermore,the in vivo study confirmed that 3D-printed porous Mg-containing Akt scaffolds effectively increased bone regeneration in cranial defects of aged rats.The current results indicated that the exosomal-miR-196a-5p/Hoxa7/MAPK signaling axis might be the potential mechanism underlying Akt-mediated osteogenesis.The exosome-meditaed therapy stimulated by the released Mg ion contained in Akt biocreamics or other biomaterials might serve as a candidate strategy for bone repair in aged individuals.

Repurpose dasatinib and quercetin:Targeting senescent cells ameliorates postmenopausal osteoporosis and rejuvenates bone regeneration

Clinical therapies developed for estrogen-deficiency-driven postmenopausal osteoporosis(PMO)and related diseases,such as bone degeneration,show multiple adverse effects nowadays.Targeting senescent cells(SnCs)and the consequent senescence-associated secretory phenotype(SASP)with a combination of dasatinib and quercetin(DQ)is a recently developed novel therapy for multiple age-related diseases.Herein,we found that estrogen deficiency induced-bone loss was attributed to a pro-inflammatory microenvironment with SASP secretions and accelerated SnC accumulation,especially senescent mesenchymal stem cells(MSCs)characterized by exhaustion and dysfunction in middle aged rats.Systematically targeting SnCs with DQ strikingly ameliorated PMO and restored MSC function.Local administration of DQ and bone morphogenetic protein 2(BMP2)in combination promoted osteogenic differentiation of MSCs and rejuvenated osteoporotic bone regeneration.Our results repurposed DQ as an attractive therapy for treating PMO and related diseases.

A near-infrared fluorescent probe for fast and precise imaging of senescent cells and ovarian cancer cells via trackingβ-galactosidase

Aging-related diseases are gradually becoming a major problem with the rapid development of aged population in human society.Although many fluorescent probes have been employed to diagnosis senescence via imaging senescence-associatedβ-galactosidase(SA-β-Gal),which is proved to be closely associated with senescent cells,the similar catalytic effectiveness of enzymatic reaction of ovarian cancer-associatedβ-Gal(OA-β-Gal)will interfere with imaging accuracy.Herein,a near-infrared(NIR)hemicyanine based fluorescent probe HCyXA-βGal was designed for light-up imaging of live cells containingβ-Gal.With the organelle-targeting morpholinyl and positive charge moieties,HCyxA-βGal was successfully applicated to image the difference of enzymatic location in senescent cells and ovarian cancer cells.Furthermore,inspired by the fast response performance,fast and precise imaging of the two cell lines was realized via covering another dimension of fluorescence signal:time-dependent intensity.

P-MSC-derived extracellular vesicles facilitate diabetic wound healing via miR-145-5p/CDKN1A-mediated functional improvements of high glucose-induced senescent fibroblasts

Background:Persistent hyperglycaemia in diabetes causes functional abnormalities of human dermal fibroblasts(HDFs),partially leading to delayed skin wound healing.Extracellular vesicles(EVs)containing multiple pro-healing microRNAs(miRNAs)have been shown to exert therapeutic effects on diabetic wound healing.The present study aimed to observe the effects of EVs derived from placental mesenchymal stem cells(P-MSC-EVs)on diabetic wound healing and high glucose(HG)-induced senescent fibroblasts and to explore the underlying mechanisms.Methods:P-MSC-EVs were isolated by differential ultracentrifugation and locally injected into the full-thickness skin wounds of diabetic mice,to observe the beneficial effects on wound healing in vivo by measuring wound closure rates and histological analysis.Next,a series of assays were conducted to evaluate the effects of low(2.28 x 1010 particles/ml)and high(4.56 x 1010 particles/ml)concentrations of P-MSC-EVs on the senescence,proliferation,migration,and apoptosis of HG-induced senescent HDFs in vitro.Then,miRNA microarrays and real-time quantitative PCR(RT-qPCR)were carried out to detect the differentially expressed miRNAs in HDFs after EVs treatment.Specific RNA inhibitors,miRNA mimics,and small interfering RNA(siRNA)were used to evaluate the role of a candidate miRNA and its target genes in P-MSC-EV-induced improvements in the function of HG-induced senescent HDFs.Results:Local injection of P-MSC-EVs into diabetic wounds accelerated wound closure and reduced scar widths,with better-organized collagen deposition and decreased p16INK4a expression.In vitro,P-MSC-EVs enhanced the antisenescence,proliferation,migration,and antiapoptotic abilities of HG-induced senescent fibroblasts in a dose-dependent manner.MiR-145-5p was found to be highly enriched in P-MSC-EVs.MiR-145-5p inhibitors effectively attenuated the P-MSC-EV-induced functional improvements of senescent fibroblasts.MiR-145-5p mimics simulated the effects of P-MSC-EVs on functional improvements of fibroblasts by suppressing the expression of cyclin-dependent kinase inhibitor 1A and activating the extracellular signal regulated kinase(Erk)/protein kinase B(Akt)signaling pathway.Furthermore,local application of miR-145-5p agomir mimicked the effects of P-MSC-EVs on wound healing.Conclusions:These results suggest that P-MSC-EVs accelerate diabetic wound healing by improv-ing the function of senescent fibroblasts through the transfer of miR-145-5p,which targets cyclin-dependent kinase inhibitor 1A to activate the Erk/Akt signaling pathway.P-MSC-EVs are promising therapeutic candidates for diabetic wound treatment.

How aging affects bone health via the intestinal micro-environment

Increasing life expectancy and an aging population lead to age-related bone diseases like osteoporosis and low bone mass more prevalent.These conditions represent a common,costly and chronic burden,not only for elderly but also to society at large.Consequently,elucidating the pathophysiology and developing effective therapies for these diseases is of paramount importance.Recent advances in research have identified the gut as a novel and promising target for addressing bone disorders,giving rise to the concept of the“gut-bone axis”.An in-depth review of the latest insights into the effects of age-related physiological changes in the gastrointestinal tract on bone health is presented in this article.It examines how the“gut-bone”axis interacts with bone aging across various domains,including metabolism,nutrition,intestinal permeability,immunity,and oxidative stress.

Melatonin delays leaf senescence in pak choi(Brassica rapa subsp.chinensis)by regulating biosynthesis of the second messenger cGMP

Melatonin(MT)is a low molecular weight compound with multiple biological functions in plants.It is known to delay leaf senescence in various species.However,no data are available on the MT signaling pathway in postharvest vegetables.This study demonstrates that MT increases cGMP concentration and the expression of the cGMP synthesis gene BcGC1 in pak choi.The c GMP inhibitor LY83583 destroys effect of MT delaying the leaf senescence.LY83583 also prevents MT treatment from reducing the expression of chlorophyll metabolism-related genes(BcNYC1,BcNOL,BcPPH1/2,BcSGR1/2,and BcPAO)and senescence genes(BcSAG12 and BcSAG21).It also inhibits MT from reducing the activity of the key chlorophyll catabolism enzymes Mg-dechelatase,pheophytinase,and pheide a oxygenase.Thus,the ability of MT to maintain high levels of chlorophyll metabolites is also destroyed.The Arabidopsis c GMP synthetic gene mutant atgc1 was used to confirm that delayed leaf senescence caused by MT is mediated,at least in part,by the second messenger c GMP.

Comprehensive analyses of the proteome and ubiquitome revealed mechanism of high temperature accelerating petal abscission in tree peony

Tree peony(Paeonia suffruticosa Andrews)is a well-known ornamental plant with high economic value,but the short fluorescence is a key obstacle to its ornamental value and industry development.High temperature accelerates flower senescence and abscission,but the associated mechanisms are poorly understood.In this study,the tandem mass tag(TMT)proteome and label-free quantitative ubiquitome from tree peony cut flowers treated with 20℃for 0 h(RT0),20℃or 28℃for 60 h(RT60 or HT60)were examined based on morphological observation,respectively.Totally,6970 proteins and 1545 lysine ubiquitinated(Kub)sites in 844 proteins were identified.Hydrophilic residues(such as glutamate and aspartate)neighboring the Kub sites were in preference,and 36.01%of the Kub sites were located on the protein surface.The differentially expressed proteins(DEPs)and Kub-DEPs in HT60 vs RT60 were mainly enriched in ribosomal protein,protein biosynthesis,secondary metabolites biosynthesis,flavonoid metabolism,carbohydrate catabolism,and auxin biosynthesis and signaling revealed by GO and KEGG analysis,accompanying the increase of endogenous abscisic acid(ABA)accumulation and decrease of endogenous indoleacetic acid(IAA)level.Additionally,the expression patterns of six enzymes(SAMS,ACO,YUC,CHS,ANS and PFK)putatively with Kub modifications were analyzed by proteome and real-time quantitative RT-PCR.The cell-free degradation assays showed PsSAMS and PsACO proteins could be degraded via the 26 S proteasome system in tree peony flowers.Finally,a working model was proposed for the acceleration of flower senescence and abscission by high temperature.In summary,all results contributed to understanding the mechanism of flower senescence induced by high temperature and prolonging fluorescence in tree peony.

Ethylene accelerates maize leaf senescence in response to nitrogen deficiency by regulating chlorophyll metabolism and autophagy

Leaf senescence is an orderly and highly coordinated process,and finely regulated by ethylene and nitrogen(N),ultimately affecting grain yield and nitrogen-use efficiency(NUE).However,the underlying regulatory mechanisms on the crosstalk between ethylene-and N-regulated leaf senescence remain a mystery in maize.In this study,ethylene biosynthesis gene ZmACS7 overexpressing(OE-ZmACS7)plants were used to study the role of ethylene regulating leaf senescence in response to N deficiency,and they exhibited the premature leaf senescence accompanied by increased ethylene release,decreased chlorophyll content and F_v/F_m ratio,and accelerated chloroplast degradation.Then,we investigated the dynamics changes of transcriptome reprogramming underlying ethylene-accelerated leaf senescence in response to N deficiency.The differentially expressed genes(DEGs)involved in chlorophyll biosynthesis were significantly down-regulated,while DEGs involved in chlorophyll degradation and autophagy processes were significantly up-regulated,especially in OE-ZmACS7 plants in response to N deficiency.A gene regulatory network(GRN)was predicted during ethylene-accelerated leaf senescence in response to N deficiency.Three transcription factors(TFs)ZmHSF4,Zmb HLH106,and ZmEREB147 were identified as the key regulatory genes,which targeted chlorophyll biosynthesis gene ZmLES22,chlorophyll degradation gene ZmNYC1,and autophagy-related gene ZmATG5,respectively.Furthermore,ethylene signaling key genes might be located upstream of these TFs,generating the signaling cascade networks during ethylene-accelerated leaf senescence in response to N deficiency.Collectively,these findings improve our molecular knowledge of ethylene-accelerated maize leaf senescence in response to N deficiency,which is promising to improve NUE by manipulating the progress of leaf senescence in maize.

Silencing of peroxiredoxin 2 suppresses proliferation and Wnt/β-catenin pathway,and induces senescence in hepatocellular carcinoma

Hepatocellular carcinoma(HCC),a common malignancy worldwide,still lacks effective clinical treatment.The study aimed to investigate the oncogenes that affect the progression of HCC and their possible mechanisms.In our study,we initially confirmed a higher level of PRDX2 in the bile of HCC patients compared to those with choledocholithiasis by 2-DE,LC-MS,and ELISA.Subsequently,we demonstrated the high expression of peroxiredoxin 2(PRDX2)in HCC based on the TCGA database and clinical sample analysis.Furthermore,PRDX2 overexpression enhanced the viability of HCC cells.And PRDX2 silencing induced senescence of HCC cells.In vivo,knockdown of PRDX2 significantly reduced the weight of xenograft tumors.PRDX2 also was found to activate the Wnt/β-catenin pathway by inducingβ-catenin nuclear translocation.Consequently,we proved that silencing PRDX2 could inhibit proliferation and Wnt/β-catenin pathway while promoting senescence in HCC cells.