Oxygen is an essential molecule for animal respiration,growth,and survival.Unlike in terrestrial environments,contamination and climate change have led to the frequent occurrence of hypoxia in aquatic environments,thu...Oxygen is an essential molecule for animal respiration,growth,and survival.Unlike in terrestrial environments,contamination and climate change have led to the frequent occurrence of hypoxia in aquatic environments,thus impacting aquatic animal survival.However,the adaptative mechanisms underlying fish responses to environmental hypoxia remain largely unknown.Here,we used large yellow croaker(Larimichthys crocea)and large yellow croaker fry(LYCF)cells to investigate the roles of the Hif-1α/Hsf1/Hsp70 signaling pathway in the regulation of cellular redox homeostasis,and apoptosis.We confirmed that hypoxia induced the expression of Hif-1α,Hsf1,and Hsp70 in vivo and in vitro.Genetic Hsp70 knockdown/overexpression indicated that Hsp70 was required for maintaining redox homeostasis and resisting oxidative stress in LYCF cells under hypoxic stress.Hsp70 inhibited caspase-dependent intrinsic apoptosis by maintaining normal mitochondrial membrane potential,enhancing Bcl-2 mRNA and protein expression,inhibiting Bax and caspase3 mRNA expression,and suppressing caspase-3 and caspase-9 activation.Hsp70 suppressed caspaseindependent intrinsic apoptosis by inhibiting nuclear translocation of apoptosis-inducing factor(AIF)and disturbed extrinsic apoptosis by inactivating caspase-8.Genetic knockdown/overexpression of Hif-1αand dual-luciferase reporter assay indicated that Hif-1αactivated the Hsf1 DNA promoter and enhanced Hsf1 mRNA transcription.Hsf1 enhanced Hsp70 mRNA transcription in a similar manner.In summary,the Hif-1α/Hsf1/Hsp70 signaling pathway plays an important role in regulating redox homeostasis and anti-apoptosis in L.crocea under hypoxic stress.展开更多
Artemisinin and its derivatives have emerged as promising therapeutic agents for cancer therapy by endogenous iron-mediated generation of free radicals.However,the enhanced antioxidant defense systems in cancer cells ...Artemisinin and its derivatives have emerged as promising therapeutic agents for cancer therapy by endogenous iron-mediated generation of free radicals.However,the enhanced antioxidant defense systems in cancer cells provide them with resistance to oxidative damage,greatly antagonizing the therapeutic efficacy that relies on inducing oxidative stress.Herein,a metal-organic framework(MOF)-based nanoplatform(CMD)is constructed to disrupt the cellular redox homeostasis and selectively potentiate the cytotoxicity of dihydroartemisinin for cancer therapy.In cancer cells,the copper(II)sites in the MOF nanocarrier of CMD can efficiently weaken the cellular antioxidant capacity by depleting the overexpressed glutathione,simultaneously leading to the decomposition of the framework structure and the release of the encapsulated dihydroartemisinin.As a result,the damaged antioxidant defense system of cancer cells reduces its effect on oxidative stress alleviation and strengthens the therapeutic efficacy of dihydroartemisinin.On contrast,the low concentration of cellular glutathione in normal cells protects them from dihydroartemisinin-induced cytotoxicity by decelerating the drug release.In vivo results demonstrate that CMD could completely suppress the tumor growth in mice and show no evidence of toxicity,providing an effective strategy for the practical usage of dihydroartemisinin in cancer therapy.展开更多
In plants,glycerol-3-phosphate dehydrogenase(GPDH)catalyzes the interconversion of glycerol-3-phosphate(G3P)and dihydroxyacetone phosphate(DHAP)coupled to the reduction/oxidation of the nicotinamide adenine dinucleoti...In plants,glycerol-3-phosphate dehydrogenase(GPDH)catalyzes the interconversion of glycerol-3-phosphate(G3P)and dihydroxyacetone phosphate(DHAP)coupled to the reduction/oxidation of the nicotinamide adenine dinucleotide(NADH)pool,and plays a central role in glycerolipid metabolism and stress response.Previous studies have focused mainly on the NAD+-dependent GPDH isoforms,neglecting the role of flavin adenine dinucleotide(FAD)-dependent GPDHs.We isolated and characterized three mitochondrialtargeted FAD-GPDHs in soybean,of which one isoform(GmGPDH12)showed a significant transcriptional response to NaCl and mannitol treatments,suggesting the existence of a major FAD-GPDH isoform acting in soybean responses to salt and osmotic stress.An enzyme kinetic assay showed that the purified GmGPDH12 protein possessed the capacity to oxidize G3P to DHAP in the presence of FAD.Overexpression and RNA interference of GmGPDH12 in soybean hairy roots resulted in elevated tolerance and sensitivity to salt and osmotic stress,respectively.G3P contents were significantly lower in GmGPDH12-overexpressing hair roots and higher in knockdown hair roots,indicating that GmGPDH12 was essential for G3P catabolism.A significant perturbation in redox status of NADH,ascorbic acid(ASA)and glutathione(GSH)pools was observed in GmGPDH12-knockdown plants under stress conditions.The impaired redox balance was manifested by higher reactive oxygen species generation and consequent cell damage or death;however,overexpressing plants showed the opposite results for these traits.GmGPDH12 overexpression contributed to maintaining constant respiration rates under salt or osmotic stress by regulating mRNA levels of key mitochondrial respiratory enzymes.This study provides new evidence for the roles of mitochondria-localized GmGPDH12 in conferring resistance to salt or osmotic stress by maintaining cellular redox homeostasis,protecting cells and respiration from oxidative injury.展开更多
Temperature tolerance restricts the distribution of a species. However, the molecular and cellular mechanisms that set the thermal tolerance limits of an organism are poorly understood. Here, we report on the function...Temperature tolerance restricts the distribution of a species. However, the molecular and cellular mechanisms that set the thermal tolerance limits of an organism are poorly understood. Here, we report on the function of dual-specificity phosphatase 1(DUSP1) in thermal tolerance regulation. Notably, we found that dusp1-/- zebrafish grew normally but survived within a narrowed temperature range. The higher susceptibility of these mutant fish to both cold and heat challenges was attributed to accelerated cell death caused by aggravated mitochondrial dysfunction and over-production of reactive oxygen species in the gills. The DUSP1-MAPK-DRP1 axis was identified as a key pathway regulating these processes in both fish and human cells. These observations suggest that DUSP1 may play a role in maintaining mitochondrial integrity and redox homeostasis. We therefore propose that maintenance of cellular redox homeostasis may be a key mechanism for coping with cellular thermal stress and that the interplay between signaling pathways regulating redox homeostasis in the most thermosensitive tissue(i.e., gills) may play an important role in setting the thermal tolerance limit of zebrafish.展开更多
The large yellow croaker(Larimichthys crocea),which is an economically important mariculture fish in China,is often exposed to environmental hypoxia.Reactive oxygen species(ROS)homeostasis is essential for the mainten...The large yellow croaker(Larimichthys crocea),which is an economically important mariculture fish in China,is often exposed to environmental hypoxia.Reactive oxygen species(ROS)homeostasis is essential for the maintenance of normal physiological conditions in an organism.Direct evidence that environmental hypoxia leads to ROS overproduction is scarce in marine fish.Furthermore,the sources of ROS overproduction in marine fish under hypoxic stress are poorly known.In this study,we investigated the effects of hypoxia on redox homeostasis in L.crocea and the impact of impaired redox homeostasis on fish.We first confirmed that hypoxia drove ROS production mainly via the mitochondrial electron transport chain and NADPH oxidase complex pathways in L.crocea and its cell line(large yellow croaker fry(LYCF)cells).We subsequently detected a marked increase in the antioxidant systems of the fish.However,imbalance between the pro-oxidation and antioxidation systems ultimately led to excessive ROS and oxidative stress.Cell viability showed a remarkable decrease while oxidative indicators,such as malondialdehyde,proteincarbonylation,and8-hydroxy-2 deoxyguanosine,showed a significant increase after hypoxia,accompanied by tissue damage.Nacetylcysteine(NAC)reduced ROS levels,alleviated oxidative damage,and improved cell viability in vitro.Appropriate uptake of ROS scavengers(e.g.,NAC and elamipretide Szeto-Schiller-31)and inhibitors(e.g.,apocynin,diphenylene iodonium,and 5-hydroxydecanoate)may be effective at overcoming hypoxic toxicity.Our findings highlight previously unstudied strategies of hypoxic toxicity resistance in marine fish.展开更多
To elucidate the response of oxidative metabolism,triggered by elevated ammonium(NH_(4)^(+))concentrations,on root growth of wheat seedlings,Yumai 49(NH_(4)^(+)-tolerant)and Lumai 15(NH_(4)^(+)-sensitive)cultivars wer...To elucidate the response of oxidative metabolism,triggered by elevated ammonium(NH_(4)^(+))concentrations,on root growth of wheat seedlings,Yumai 49(NH_(4)^(+)-tolerant)and Lumai 15(NH_(4)^(+)-sensitive)cultivars were supplied with either 5.0 mmol L^(–1)NH_(4)^(+)-N(EAC)or 5.0 mmol L–1 NO_(3)–-N(CON)under hydroponic conditions.Root growth in both cultivars was significantly reduced under EAC,and the negative effect was greater in Lumai 15.EAC enhanced the activities of monodehydroascorbate reductase and dehydroascorbate reductase in the roots of both cultivars,while it decreased ascorbic acid(ASA)content and GDP-mannose pyrophosphorylase(GMPase)activity at the 12 th day after treatment in Lumai 15 by 62.0 and 71.4%;and in Yumai 49 by 38.8 and 62.2%,respectively,indicating that the regeneration of ASA was increased,but the biosynthesis of ASA was reduced under EAC treatment.Moreover,EAC increased DHA/ASA,reactive oxygen species(ROS),and malondialdehyde contents,as well as antioxidant enzyme activities in the roots of both cultivars.Relatively greater increases in ROS and soluble sugar,and lower antioxidant enzyme activities in Lumai 15 indicate severe disruption of oxidative metabolism when compared to Yumai 49.Results reveal that the reduction of ASA biosynthesis via decreased GMPase activity under the EAC condition probably acts as a trigger for accumulated ROS and imbalanced redox status,resulting in root growth inhibition during wheat seedling growth stage.Yumai 49,being an NH_(4)^(+)-tolerant cultivar,had the stronger capacity to protect itself from oxidative stress,which allowed it to retain a lower DHA to ASA ratio by maintaining a better redox homeostasis than could be maintained in the NH_(4)^(+)-sensitive cultivar Lumai 15.展开更多
Sepsis can develop during the body’s response to a critical illness leading to multiple organ failure,irreversible shock,and death.Sepsis has been vexing health care providers for centuries due to its insidious onset...Sepsis can develop during the body’s response to a critical illness leading to multiple organ failure,irreversible shock,and death.Sepsis has been vexing health care providers for centuries due to its insidious onset,generalized metabolic dysfunction,and lack of specific therapy.A common factor underlying sepsis is the characteristic hypermetabolic response as the body ramps up every physiological system in its fight against the underlying critical illness.A hypermetabolic response requires supraphysiological amounts of energy,which is mostly supplied via oxidative phosphorylation generated ATP.A by-product of oxidative phosphorylation is hydrogen peroxide(H2O2),a toxic,membranepermeable oxidizing agent that is produced in far greater amounts during a hypermetabolic state.Continued production of mitochondrial H2O2 can overwhelm cellular reductive(antioxidant)capacity leading to a build-up within cells and eventual diffusion into the bloodstream.H2O2 is a metabolic poison that can inhibit enzyme systems leading to organ failure,microangiopathic dysfunction,and irreversible septic shock.The toxic effects of H2O2 mirror the clinical and laboratory abnormalities observed in sepsis,and toxic levels of blood H2O2 have been reported in patients with septic shock.This review provides evidence to support a causal role for H2O2 in the pathogenesis of sepsis,and an evidence-based therapeutic intervention to reduce H2O2 levels in the body and restore redox homeostasis,which is necessary for normal organ function and vascular responsiveness.展开更多
The scarcity of native periosteum poses a significant clinical barrier in the repair of critical-sized bone defects.The challenge of enhancing regenerative potential in bone healing is further compounded by oxidative ...The scarcity of native periosteum poses a significant clinical barrier in the repair of critical-sized bone defects.The challenge of enhancing regenerative potential in bone healing is further compounded by oxidative stress at the fracture site.However,the introduction of artificial periosteum has demonstrated its ability to promote bone regeneration through the provision of appropriate mechanical support and controlled release of proosteogenic factors.In this study,a poly(L-lactic acid)(PLLA)/hyaluronic acid(HA)-based nanofibrous membrane was fabricated using the coaxial electrospinning technique.The incorporation of irisin into the core-shell structure of PLLA/HA nanofibers(PLLA/HA@Irisin)achieved its sustained release.In vitro experiments demonstrated that the PLLA/HA@Irisin membranes exhibited favorable biocompatibility.The osteogenic differentiation of bone marrow mesenchymal stem cells(BMMSCs)was improved by PLLA/HA@Irisin,as evidenced by a significant increase in alkaline phosphatase activity and matrix mineralization.Mechanistically,PLLA/HA@Irisin significantly enhanced the mitochondrial function of BMMSCs via the activation of the sirtuin 3 antioxidant pathway.To assess the therapeutic effectiveness,PLLA/HA@Irisin membranes were implanted in situ into critical-sized calvarial defects in rats.The results at 4 and 8 weeks post-surgery indicated that the implantation of PLLA/HA@Irisin exhibited superior efficacy in promoting vascularized bone formation,as demonstrated by the enhancement of bone matrix synthesis and the development of new blood vessels.The results of our study indicate that the electrospun PLLA/HA@Irisin nanofibers possess characteristics of a biomimetic periosteum,showing potential for effectively treating critical-sized bone defects by improving the mitochondrial function and maintaining redox homeostasis of BMMSCs.展开更多
Reactive oxygen species (ROS) are harmful to all living organisms and therefore they must be removed to ensure normal growth and development. ROS are also signaling molecules, but so far little is known about the me...Reactive oxygen species (ROS) are harmful to all living organisms and therefore they must be removed to ensure normal growth and development. ROS are also signaling molecules, but so far little is known about the mecha- nisms of ROS perception and developmental response in plants. We here report that hydrogen peroxide induces cortex proliferation in the Arabidopsis root and that SPINDLY (SPY), an O-linked glucosamine acetyltransferase, regulates cortex proliferation by maintaining cellular redox homeostasis. We also found that mutation in the leucine-rich receptor kinase ERECTA and its putative peptide ligand STOMAGEN block the effect of hydrogen peroxide on root cortex proliferation. However, ERECTA and STOMAGEN are expressed in the vascular tissue, whereas extra cortex cells are produced from the endodermis, suggesting the involvement of intercellular signaling~ SPY appears to act downstream of ERECTA, because the spy mutation still caused cortex proliferation in the erecta mutant background. We therefore have not only gained insight into the mechanism by which SPY regulates root development but also uncovered a novel pathway for ROS signal- ing in plants. The importance of redox-mediated cortex proliferation as a protective mechanism against oxidative stress is also discussed.展开更多
At the altitude,hypoxia and training load are key factors in the development of oxidative stress.Altitude-induced oxidative stress is developed due to the depletion of antioxidant potential.In the current study,we exa...At the altitude,hypoxia and training load are key factors in the development of oxidative stress.Altitude-induced oxidative stress is developed due to the depletion of antioxidant potential.In the current study,we examined the non-enzymatic antioxidant profile of blood plasma in 7 males and 5 females specializing in speed skating at a 21-day training camp at 1850m above sea level.Training included:cycling,roller skating,ice skating,strength training,and special training.At the start point and the endpoint,total hemoglobin mass(tHb-mass),hemoglobin concentration,and circulating blood volume were determined.Antioxidant profiles,hypoxic doses,hypoxic impulses,and training impulses were assessed at 3,6,10,14,and 18 days.Antioxidant profiles consisting of“urate”and“thiol”parts were registered with chemiluminometry.In the training dynamics,antioxidant parameters changed individually,but in total there was a decrease in the“urate”capacity by a factor of 1.6(p=0.001)and an increase in the“thiol”capacity by a factor of 1.8(p=0.013).The changes in“urate”capacity positively correlated(r_(S)=0.40)and the changes in“thiol”capacity negatively correlated(r_(S)=−0.45)with changes in tHb-mass.Both exercise and hypoxic factors affect the antioxidant parameters bidirectionally.They correlated with a decrease in thiol capacity and with an increase in urate capacity.The assessment of the non-enzymatic antioxidant profile can be a simple and useful addition to screening the reactive oxygen species homeostasis and can help choose the personalized training schedule,individualize recovery and ergogenic support.展开更多
Multidrug resistance(MDR) remains a major clinical obstacle to successful cancer treatment.Although diverse mechanisms of MDR have been well elucidated, such as dysregulation of drugs transporters, defects of apoptosi...Multidrug resistance(MDR) remains a major clinical obstacle to successful cancer treatment.Although diverse mechanisms of MDR have been well elucidated, such as dysregulation of drugs transporters, defects of apoptosis and autophagy machinery, alterations of drug metabolism and drug targets, disrupti on of redox homeostasis, the exact mechanisms of MDR in a specific cancer patient and the cross-talk among these different mechanisms and how they are regulated are poorly understood.Micro RNAs(mi RNAs) are a new class of small noncoding RNAs that could control the global activity of the cell by post-transcriptionally regulating a large variety of target genes and proteins expression.Accumulating evidence shows that mi RNAs play a key regulatory role in MDR through modulating various drug resistant mechanisms mentioned above, thereby holding much promise for developing novel and more effective individualized therapies for cancer treatment. This review summarizes the various MDR mechanisms and mainly focuses on the role of mi RNAs in regulating MDR in cancer treatment.展开更多
Over the last few years, it has become evident that reactive oxygen species (ROS) signalling plays an important role in various physiological responses, including pathogen defense and stomatal opening/closure. On th...Over the last few years, it has become evident that reactive oxygen species (ROS) signalling plays an important role in various physiological responses, including pathogen defense and stomatal opening/closure. On the other hand, ROS overproduction is detrimental for proper plant growth and development, indicating that the regulation of an appropriate redox balance is essential for plants. ROS homeostasis in plants involves the mitogen-activated protein kinase (MAPK) pathway consisting of the MAPK kinase kinase MEKK1 and the MAPK MPK4. Phenotypic and molecular analysis revealed that the MAPK kinases MKK1 and MKK2 are part of a cascade, regulating ROS and salicylic acid (SA) accumulation. Gene expression analysis shows that of 32 transcription factors reported to be highly responsive to multiple ROS-inducing conditions, 20 are regulated by the MEKK1, predominantly via the MEKK1-MKK1/2-MPK4 pathway. However, MEKK1 also functions on other as yet unknown pathways and part of the MEKK1-dependent MPK4 responses are regulated independently of MKK1 and MKK2. Overall, this analysis emphasizes the central role of this MAPK cascade in oxidative stress signalling, but also indicates the high level of complexity revealed by this signalling network.展开更多
Disrupted redox status primarily contributes to myocardial ischemia/reperfusion injury(MIRI).NRF2,the endogenous antioxidant regulator,might provide therapeutic benefits.Dihydrotanshinone-Ⅰ(DT)is an active component ...Disrupted redox status primarily contributes to myocardial ischemia/reperfusion injury(MIRI).NRF2,the endogenous antioxidant regulator,might provide therapeutic benefits.Dihydrotanshinone-Ⅰ(DT)is an active component in Salvia miltiorrhiza with NRF2 induction potency.This study seeks to validate functional links between NRF2 and cardioprotection of DT and to investigate the molecular mechanism particularly emphasizing on NRF2 cytoplasmic/nuclear translocation.DT potently induced NRF2 nuclear accumulation,ameliorating post-reperfusion injuries via redox alterations.Abrogated cardioprotection in NRF2-deficient mice and cardiomyocytes strongly supports NRF2-dependent cardioprotection of DT.Mechanistically,DT phosphorylated NRF2 at Ser40,rendering its nuclear-import by dissociating from KEAP1 and inhibiting degradation.Importantly,we identified PKC-δ-(Thr505)phosphorylation as primary upstream event triggering NRF2-(Ser40)phosphorylation.Knockdown of PKC-δdramatically retained NRF2 in cytoplasm,convincing its pivotal role in mediating NRF2 nuclear-import.NRF2 activity was further enhanced by activated PKB/GSK-3βsignaling via nuclear-export signal blockage independent of PKC-δactivation.By demonstrating independent modulation of PKC-δand PKB/GSK-3β/Fyn signaling,we highlight the ability of DT to exploit both nuclear import and export regulation of NRF2 in treating reperfusion injury harboring redox homeostasis alterations.Coactivation of PKC and PKB phenocopied cardioprotection of DT in vitro and in vivo,further supporting the potential applicability of this rationale.展开更多
The physiological role of plant mitochondrial glutathione peroxidases is scarcely known. This study attempted to elucidate the role of a rice mitochondrial isoform(GPX1) in photosynthesis under normal growth and sal...The physiological role of plant mitochondrial glutathione peroxidases is scarcely known. This study attempted to elucidate the role of a rice mitochondrial isoform(GPX1) in photosynthesis under normal growth and salinity conditions. GPX1 knockdown rice lines(GPX1s) were tested in absence and presence of 100 mM NaCl for 6 d.Growth reduction of GPX1 s line under non-stressful conditions, compared with non-transformed(NT) plants occurred in parallel to increased H_2O_2 and decreased GSH contents. These changes occurred concurrently with photosynthesis impairment, particularly in Calvin cycle's reactions, since photochemical efficiency did not change.Thus, GPX1 silencing and downstream molecular/metabolic changes modulated photosynthesis differentially. In contrast, salinity induced reduction in both phases of photosynthesis, which were more impaired in silenced plants.These changes were associated with root morphology alterations but not shoot growth. Both studied lines displayed increased GPX activity but H_2O_2 content did not change in response to salinity. Transformed plants exhibited lower photorespiration, water use efficiency and root growth, indicating that GPX1 could be important to salt tolerance. Growth reduction of GPX1 s line might be related to photosynthesis impairment, which in turn could have involved a cross talk mechanism between mitochondria and chloroplast originated from redox changes due to GPX1 deficiency.展开更多
Cancer cells uniquely reprogram their cellular activities to support their rapid proliferation and migration and to coun-teract metabolic and genotoxic stress during cancer progression.In this reprograming,cancer cell...Cancer cells uniquely reprogram their cellular activities to support their rapid proliferation and migration and to coun-teract metabolic and genotoxic stress during cancer progression.In this reprograming,cancer cells’metabolism and other cellular activities are integrated and mutually regulated,and cancer cells modulate metabolic enzymes spatially and temporally so that these enzymes not only have altered metabolic activities but also have modulated subcellular localization and gain non-canonical functions.This review and several others in this issue of Cancer Communications discuss these enzymes’newly acquired functions and the non-canonical functions of some metabolites as features of cancer cell metabolism,which play critical roles in various cellular activities,including gene expression,anabolism,catabolism,redox homeostasis,and DNA repair.展开更多
Tumor cells have unique metabolic programming that is biologically distinct from that of corresponding normal cells.Resetting tumor metabolic programming is a promising strategy to ameliorate drug resistance and impro...Tumor cells have unique metabolic programming that is biologically distinct from that of corresponding normal cells.Resetting tumor metabolic programming is a promising strategy to ameliorate drug resistance and improve the tumor microenvironment.Here,we show that carboxyamidotriazole(CAI),an anticancer drug,can function as a metabolic modulator that decreases glucose and lipid metabolism and increases the dependency of colon cancer cells on glutamine metabolism.CAI suppressed glucose and lipid metabolism utilization,causing inhibition of mitochondrial respiratory chain complex I,thus producing reactive oxygen species(ROS).In parallel,activation of the aryl hydrocarbon receptor(Ah R)increased glutamine uptake via the transporter SLC1A5,which could activate the ROS-scavenging enzyme glutathione peroxidase.As a result,combined use of inhibitors of GLS/GDH1,CAI could effectively restrict colorectal cancer(CRC)energy metabolism.These data illuminate a new antitumor mechanism of CAI,suggesting a new strategy for CRC metabolic reprogramming treatment.展开更多
As a member of an important group of lipid soluble antioxidants, tocopherols play a paramount role in the daily diet of humans and animals. Recently, genes required for tocochromanol biosynthesis pathway have been ide...As a member of an important group of lipid soluble antioxidants, tocopherols play a paramount role in the daily diet of humans and animals. Recently, genes required for tocochromanol biosynthesis pathway have been identified and cloned with the help of genomics-based approaches and molecular manipulation in the model organisms: Arabidopsis thaliana and Synechocystis sp. PCC 6803. At the basis of these foundations, genetic manipulation of tocochromanol biosynthesis pathway can give rise to strategies that enhance the level of tocochromanol content or convert the constitution of tocochromanol. In addition, genetic manipulations of the tocochromanol biosynthesis pathway provide help for the study of the function of tocopherol in plant systems. The present article summarizes recent advances and pays special attention to the functions of tocopherol in plants. The roles of tocopherol in the network of reactiv.e oxygen species, antioxidants and phytohormones to maintain redox homeostasis and the functions of tocopherol as a signal molecule in chloroplast-to- nucleus signaling to regulate carbohydrate metabolism are also discussed.展开更多
Metabolic and epigenetic reprogramming play important roles in cancer therapeutic resistance.However,their interplays are poorly understood.We report here that elevated TIGAR(TP53-induced glycolysis and apoptosis regu...Metabolic and epigenetic reprogramming play important roles in cancer therapeutic resistance.However,their interplays are poorly understood.We report here that elevated TIGAR(TP53-induced glycolysis and apoptosis regulator),an antioxidant and glucose metabolic regulator and a target of oncogenic histone methyltransferase NSD2(nuclear receptor binding SET domain protein 2),is mainly localized in the nucleus of therapeutic resistant tumor cells where it stimulates NSD2 expression and elevates global H3K36me2 mark.Mechanistically,TIGAR directly interacts with the antioxidant master regulator NRF2 and facilitates chromatin recruitment of NRF2,H3K4me3 methylase MLL1 and elongating Pol-II to stimulate the expression of both new(NSD2)and established(NQO1/2,PRDX1 and GSTM4)targets of NRF2,independent of its enzymatic activity.Nuclear TIGAR confers cancer cell resistance to chemotherapy and hormonal therapy in vitro and in tumors through effective maintenance of redox homeostasis.In addition,nuclear accumulation of TIGAR is positively associated with NSD2 expression in clinical tumors and strongly correlated with poor survival.These findings define a nuclear TIGAR-mediated epigenetic autoregulatory loop in redox rebalance for tumor therapeutic resistance.展开更多
Lesion mutants can be valuable tools to reveal the interactions between genetic factors and environmental signals and to improve grain production.Here we identified a rice(Oryza sativa)mutant,lesion spotleaf1(lsl1),wh...Lesion mutants can be valuable tools to reveal the interactions between genetic factors and environmental signals and to improve grain production.Here we identified a rice(Oryza sativa)mutant,lesion spotleaf1(lsl1),which produces necrotic leaf lesions throughout its life cycle.LSL1 encodes a protein of unknown function and belongs to a grass-specific clade.The lesion phenotype of the lsl1 mutant was sharply induced by shading,and its detached leaves incubated in 6-benzylamino purine similarly formed lesions in the dark.In addition,the lsl1 mutant exhibited reactive oxygen species accumulation and cell death.The terminal deoxynucleotidyl transferase d UTP nick end-labeling(TUNEL)and comet assays revealed that the lsl1 mutant contained severe DNA damage,resulting in reduced grain yield and quality.RNA sequencing,gene expression,and protein activity analyses indicate that LSL1 is required for chloroplast function.Furthermore,LSL1 interacts with Psa D and PAP10 to form a regulatory module that functions in chlorophyll synthesis and chloroplast development to maintain redox balance.Our results reveal that LSL1 maintains chloroplast structure,redox homeostasis,and DNA stability,and plays important roles in the interaction between genetic factors and environmental signals and in regulating grain size and quality.展开更多
Mitochondria are highly involved in the metastasis of cancer cells.However,tumor cells impede the efficiency of mitochondrial targeted drugs by protecting mitochondria through an intrinsic and adaptive antioxidant mec...Mitochondria are highly involved in the metastasis of cancer cells.However,tumor cells impede the efficiency of mitochondrial targeted drugs by protecting mitochondria through an intrinsic and adaptive antioxidant mechanism.We aim to disturb the redox homeostasis by prolyl-isomerase PIN1 inhibitor all-trans retinoic acid(ATRA)to improve the therapeutic efficacy of mitochondrial targeted lonidamine(TL).The combination of ATRA and TL with a ratio of 2:1 was found to have the best synergistic effect in inhibiting the proliferation and metastasis of metastatic 4T1 breast cancer cells.Dual-drug loaded nanoparticles(TL-ATRA NPs)were further developed by self-assembly and were observed to disturb the redox homeostasis drastically and triggered a robust mitochondrial disruption on metastatic 4T1 breast cancer cells.The molecular mechanism was related to the downregulation of nuclear factor E2-related factor 2(NRF2),a critical transcription factor that regulated antioxidant responses,and its downstream molecules.As a result,TL-ATRA NPs significantly suppressed the growth of primary tumors and the formation of lung metastasis nodes.Collectively,our findings showed that sensitizing mitochondria to anti-cancer drugs by disturbing redox homeostasis achieved a satisfactory therapeutic effect to inhibit tumor growth and metastasis.展开更多
基金This work was supported by the National Key Research and Development Program of China(2018YFC1406300)NSFC-Zhejiang Joint Fund for the Integration of Industrialization and Informatization(U1809212)+4 种基金Scientific and Technical Project of Zhejiang Province(2021C02069-1,2016C02055-7)Scientific and Technical Project of Ningbo City(2021Z002,2015C110005)Ningbo Science and Technology Plan Projects(2018A610228)Teaching and Research Project of Ningbo University(XYL19023)Collaborative Innovation Center for Zhejiang Marine High-Efficiency and Healthy Aquaculture,K.C.Wong Magna Fund in Ningbo University。
文摘Oxygen is an essential molecule for animal respiration,growth,and survival.Unlike in terrestrial environments,contamination and climate change have led to the frequent occurrence of hypoxia in aquatic environments,thus impacting aquatic animal survival.However,the adaptative mechanisms underlying fish responses to environmental hypoxia remain largely unknown.Here,we used large yellow croaker(Larimichthys crocea)and large yellow croaker fry(LYCF)cells to investigate the roles of the Hif-1α/Hsf1/Hsp70 signaling pathway in the regulation of cellular redox homeostasis,and apoptosis.We confirmed that hypoxia induced the expression of Hif-1α,Hsf1,and Hsp70 in vivo and in vitro.Genetic Hsp70 knockdown/overexpression indicated that Hsp70 was required for maintaining redox homeostasis and resisting oxidative stress in LYCF cells under hypoxic stress.Hsp70 inhibited caspase-dependent intrinsic apoptosis by maintaining normal mitochondrial membrane potential,enhancing Bcl-2 mRNA and protein expression,inhibiting Bax and caspase3 mRNA expression,and suppressing caspase-3 and caspase-9 activation.Hsp70 suppressed caspaseindependent intrinsic apoptosis by inhibiting nuclear translocation of apoptosis-inducing factor(AIF)and disturbed extrinsic apoptosis by inactivating caspase-8.Genetic knockdown/overexpression of Hif-1αand dual-luciferase reporter assay indicated that Hif-1αactivated the Hsf1 DNA promoter and enhanced Hsf1 mRNA transcription.Hsf1 enhanced Hsp70 mRNA transcription in a similar manner.In summary,the Hif-1α/Hsf1/Hsp70 signaling pathway plays an important role in regulating redox homeostasis and anti-apoptosis in L.crocea under hypoxic stress.
基金the Program of Science and Technology Development Plan of Jilin Province of China(No.20200201099JC)the National Natural Science Foundation of China(Nos.21871249 and 22105197).
文摘Artemisinin and its derivatives have emerged as promising therapeutic agents for cancer therapy by endogenous iron-mediated generation of free radicals.However,the enhanced antioxidant defense systems in cancer cells provide them with resistance to oxidative damage,greatly antagonizing the therapeutic efficacy that relies on inducing oxidative stress.Herein,a metal-organic framework(MOF)-based nanoplatform(CMD)is constructed to disrupt the cellular redox homeostasis and selectively potentiate the cytotoxicity of dihydroartemisinin for cancer therapy.In cancer cells,the copper(II)sites in the MOF nanocarrier of CMD can efficiently weaken the cellular antioxidant capacity by depleting the overexpressed glutathione,simultaneously leading to the decomposition of the framework structure and the release of the encapsulated dihydroartemisinin.As a result,the damaged antioxidant defense system of cancer cells reduces its effect on oxidative stress alleviation and strengthens the therapeutic efficacy of dihydroartemisinin.On contrast,the low concentration of cellular glutathione in normal cells protects them from dihydroartemisinin-induced cytotoxicity by decelerating the drug release.In vivo results demonstrate that CMD could completely suppress the tumor growth in mice and show no evidence of toxicity,providing an effective strategy for the practical usage of dihydroartemisinin in cancer therapy.
基金financially supported by National Natural Science Foundation of China(31701449,31971968,31971899,31501332)National Key Research and Development Program of China(2016YFD 0100500,2016YFD0100300,2016YFD0100201-21,JFYS2016ZY03003792-01-21)+7 种基金China Postdoctoral Science Foundation(2019M661243)Postdoctoral Project of Northeast Agricultural University(NEAUBH-19002)EUCLEG(727312,2017YFE0111000)Natural Science Foundation of Heilongjiang Province(QC2017013)Special Financial Aid to Post-doctor Research Fellow in Heilongjiang(LBH-TZ1714)Heilongjiang Academy of Agricultural Sciences Funds(2019YYYF019)International Postdoctoral Exchange Fellowship Program of China Postdoctoral Council(20180004)Heilongjiang Funds for Distinguished Young Scientists(JC2016004,JC2017006)。
文摘In plants,glycerol-3-phosphate dehydrogenase(GPDH)catalyzes the interconversion of glycerol-3-phosphate(G3P)and dihydroxyacetone phosphate(DHAP)coupled to the reduction/oxidation of the nicotinamide adenine dinucleotide(NADH)pool,and plays a central role in glycerolipid metabolism and stress response.Previous studies have focused mainly on the NAD+-dependent GPDH isoforms,neglecting the role of flavin adenine dinucleotide(FAD)-dependent GPDHs.We isolated and characterized three mitochondrialtargeted FAD-GPDHs in soybean,of which one isoform(GmGPDH12)showed a significant transcriptional response to NaCl and mannitol treatments,suggesting the existence of a major FAD-GPDH isoform acting in soybean responses to salt and osmotic stress.An enzyme kinetic assay showed that the purified GmGPDH12 protein possessed the capacity to oxidize G3P to DHAP in the presence of FAD.Overexpression and RNA interference of GmGPDH12 in soybean hairy roots resulted in elevated tolerance and sensitivity to salt and osmotic stress,respectively.G3P contents were significantly lower in GmGPDH12-overexpressing hair roots and higher in knockdown hair roots,indicating that GmGPDH12 was essential for G3P catabolism.A significant perturbation in redox status of NADH,ascorbic acid(ASA)and glutathione(GSH)pools was observed in GmGPDH12-knockdown plants under stress conditions.The impaired redox balance was manifested by higher reactive oxygen species generation and consequent cell damage or death;however,overexpressing plants showed the opposite results for these traits.GmGPDH12 overexpression contributed to maintaining constant respiration rates under salt or osmotic stress by regulating mRNA levels of key mitochondrial respiratory enzymes.This study provides new evidence for the roles of mitochondria-localized GmGPDH12 in conferring resistance to salt or osmotic stress by maintaining cellular redox homeostasis,protecting cells and respiration from oxidative injury.
基金supported by the National Key Research and Development Program of China(2018YFD0900601)National Natural Science Foundation of China(32130109)。
文摘Temperature tolerance restricts the distribution of a species. However, the molecular and cellular mechanisms that set the thermal tolerance limits of an organism are poorly understood. Here, we report on the function of dual-specificity phosphatase 1(DUSP1) in thermal tolerance regulation. Notably, we found that dusp1-/- zebrafish grew normally but survived within a narrowed temperature range. The higher susceptibility of these mutant fish to both cold and heat challenges was attributed to accelerated cell death caused by aggravated mitochondrial dysfunction and over-production of reactive oxygen species in the gills. The DUSP1-MAPK-DRP1 axis was identified as a key pathway regulating these processes in both fish and human cells. These observations suggest that DUSP1 may play a role in maintaining mitochondrial integrity and redox homeostasis. We therefore propose that maintenance of cellular redox homeostasis may be a key mechanism for coping with cellular thermal stress and that the interplay between signaling pathways regulating redox homeostasis in the most thermosensitive tissue(i.e., gills) may play an important role in setting the thermal tolerance limit of zebrafish.
基金supported by the NSFC-Zhejiang Joint Fund for the Integration of Industrialization and Informatization(U1809212)Scientific and Technical Project of Zhejiang Province(2016C02055-7)+3 种基金Scientific and Technical Project of Ningbo City(2021Z002,2015C110005)Ningbo Science and Technology Plan Projects(2018A610228)Teaching and Research Project of Ningbo University(XYL19023)Collaborative Innovation Center for Zhejiang Marine High-efficiency and Healthy Aquaculture,K.C.Wong Magna Fund in Ningbo University。
文摘The large yellow croaker(Larimichthys crocea),which is an economically important mariculture fish in China,is often exposed to environmental hypoxia.Reactive oxygen species(ROS)homeostasis is essential for the maintenance of normal physiological conditions in an organism.Direct evidence that environmental hypoxia leads to ROS overproduction is scarce in marine fish.Furthermore,the sources of ROS overproduction in marine fish under hypoxic stress are poorly known.In this study,we investigated the effects of hypoxia on redox homeostasis in L.crocea and the impact of impaired redox homeostasis on fish.We first confirmed that hypoxia drove ROS production mainly via the mitochondrial electron transport chain and NADPH oxidase complex pathways in L.crocea and its cell line(large yellow croaker fry(LYCF)cells).We subsequently detected a marked increase in the antioxidant systems of the fish.However,imbalance between the pro-oxidation and antioxidation systems ultimately led to excessive ROS and oxidative stress.Cell viability showed a remarkable decrease while oxidative indicators,such as malondialdehyde,proteincarbonylation,and8-hydroxy-2 deoxyguanosine,showed a significant increase after hypoxia,accompanied by tissue damage.Nacetylcysteine(NAC)reduced ROS levels,alleviated oxidative damage,and improved cell viability in vitro.Appropriate uptake of ROS scavengers(e.g.,NAC and elamipretide Szeto-Schiller-31)and inhibitors(e.g.,apocynin,diphenylene iodonium,and 5-hydroxydecanoate)may be effective at overcoming hypoxic toxicity.Our findings highlight previously unstudied strategies of hypoxic toxicity resistance in marine fish.
基金funded by a project of the National Natural Science Foundation of China(31471443)the Jiangsu Collaborative Innovation Center for Modern Crop Production,China(JCIC-MCP)the Priority Academic Program Development of Jiangsu Higher Education Institutions,China(PAPD)。
文摘To elucidate the response of oxidative metabolism,triggered by elevated ammonium(NH_(4)^(+))concentrations,on root growth of wheat seedlings,Yumai 49(NH_(4)^(+)-tolerant)and Lumai 15(NH_(4)^(+)-sensitive)cultivars were supplied with either 5.0 mmol L^(–1)NH_(4)^(+)-N(EAC)or 5.0 mmol L–1 NO_(3)–-N(CON)under hydroponic conditions.Root growth in both cultivars was significantly reduced under EAC,and the negative effect was greater in Lumai 15.EAC enhanced the activities of monodehydroascorbate reductase and dehydroascorbate reductase in the roots of both cultivars,while it decreased ascorbic acid(ASA)content and GDP-mannose pyrophosphorylase(GMPase)activity at the 12 th day after treatment in Lumai 15 by 62.0 and 71.4%;and in Yumai 49 by 38.8 and 62.2%,respectively,indicating that the regeneration of ASA was increased,but the biosynthesis of ASA was reduced under EAC treatment.Moreover,EAC increased DHA/ASA,reactive oxygen species(ROS),and malondialdehyde contents,as well as antioxidant enzyme activities in the roots of both cultivars.Relatively greater increases in ROS and soluble sugar,and lower antioxidant enzyme activities in Lumai 15 indicate severe disruption of oxidative metabolism when compared to Yumai 49.Results reveal that the reduction of ASA biosynthesis via decreased GMPase activity under the EAC condition probably acts as a trigger for accumulated ROS and imbalanced redox status,resulting in root growth inhibition during wheat seedling growth stage.Yumai 49,being an NH_(4)^(+)-tolerant cultivar,had the stronger capacity to protect itself from oxidative stress,which allowed it to retain a lower DHA to ASA ratio by maintaining a better redox homeostasis than could be maintained in the NH_(4)^(+)-sensitive cultivar Lumai 15.
文摘Sepsis can develop during the body’s response to a critical illness leading to multiple organ failure,irreversible shock,and death.Sepsis has been vexing health care providers for centuries due to its insidious onset,generalized metabolic dysfunction,and lack of specific therapy.A common factor underlying sepsis is the characteristic hypermetabolic response as the body ramps up every physiological system in its fight against the underlying critical illness.A hypermetabolic response requires supraphysiological amounts of energy,which is mostly supplied via oxidative phosphorylation generated ATP.A by-product of oxidative phosphorylation is hydrogen peroxide(H2O2),a toxic,membranepermeable oxidizing agent that is produced in far greater amounts during a hypermetabolic state.Continued production of mitochondrial H2O2 can overwhelm cellular reductive(antioxidant)capacity leading to a build-up within cells and eventual diffusion into the bloodstream.H2O2 is a metabolic poison that can inhibit enzyme systems leading to organ failure,microangiopathic dysfunction,and irreversible septic shock.The toxic effects of H2O2 mirror the clinical and laboratory abnormalities observed in sepsis,and toxic levels of blood H2O2 have been reported in patients with septic shock.This review provides evidence to support a causal role for H2O2 in the pathogenesis of sepsis,and an evidence-based therapeutic intervention to reduce H2O2 levels in the body and restore redox homeostasis,which is necessary for normal organ function and vascular responsiveness.
基金supported by the Natural Science Foundation of Jiangsu Province(BK20220046)Key Laboratory of Orthopaedics of Suzhou(SZS2022017)the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD).
文摘The scarcity of native periosteum poses a significant clinical barrier in the repair of critical-sized bone defects.The challenge of enhancing regenerative potential in bone healing is further compounded by oxidative stress at the fracture site.However,the introduction of artificial periosteum has demonstrated its ability to promote bone regeneration through the provision of appropriate mechanical support and controlled release of proosteogenic factors.In this study,a poly(L-lactic acid)(PLLA)/hyaluronic acid(HA)-based nanofibrous membrane was fabricated using the coaxial electrospinning technique.The incorporation of irisin into the core-shell structure of PLLA/HA nanofibers(PLLA/HA@Irisin)achieved its sustained release.In vitro experiments demonstrated that the PLLA/HA@Irisin membranes exhibited favorable biocompatibility.The osteogenic differentiation of bone marrow mesenchymal stem cells(BMMSCs)was improved by PLLA/HA@Irisin,as evidenced by a significant increase in alkaline phosphatase activity and matrix mineralization.Mechanistically,PLLA/HA@Irisin significantly enhanced the mitochondrial function of BMMSCs via the activation of the sirtuin 3 antioxidant pathway.To assess the therapeutic effectiveness,PLLA/HA@Irisin membranes were implanted in situ into critical-sized calvarial defects in rats.The results at 4 and 8 weeks post-surgery indicated that the implantation of PLLA/HA@Irisin exhibited superior efficacy in promoting vascularized bone formation,as demonstrated by the enhancement of bone matrix synthesis and the development of new blood vessels.The results of our study indicate that the electrospun PLLA/HA@Irisin nanofibers possess characteristics of a biomimetic periosteum,showing potential for effectively treating critical-sized bone defects by improving the mitochondrial function and maintaining redox homeostasis of BMMSCs.
文摘Reactive oxygen species (ROS) are harmful to all living organisms and therefore they must be removed to ensure normal growth and development. ROS are also signaling molecules, but so far little is known about the mecha- nisms of ROS perception and developmental response in plants. We here report that hydrogen peroxide induces cortex proliferation in the Arabidopsis root and that SPINDLY (SPY), an O-linked glucosamine acetyltransferase, regulates cortex proliferation by maintaining cellular redox homeostasis. We also found that mutation in the leucine-rich receptor kinase ERECTA and its putative peptide ligand STOMAGEN block the effect of hydrogen peroxide on root cortex proliferation. However, ERECTA and STOMAGEN are expressed in the vascular tissue, whereas extra cortex cells are produced from the endodermis, suggesting the involvement of intercellular signaling~ SPY appears to act downstream of ERECTA, because the spy mutation still caused cortex proliferation in the erecta mutant background. We therefore have not only gained insight into the mechanism by which SPY regulates root development but also uncovered a novel pathway for ROS signal- ing in plants. The importance of redox-mediated cortex proliferation as a protective mechanism against oxidative stress is also discussed.
文摘At the altitude,hypoxia and training load are key factors in the development of oxidative stress.Altitude-induced oxidative stress is developed due to the depletion of antioxidant potential.In the current study,we examined the non-enzymatic antioxidant profile of blood plasma in 7 males and 5 females specializing in speed skating at a 21-day training camp at 1850m above sea level.Training included:cycling,roller skating,ice skating,strength training,and special training.At the start point and the endpoint,total hemoglobin mass(tHb-mass),hemoglobin concentration,and circulating blood volume were determined.Antioxidant profiles,hypoxic doses,hypoxic impulses,and training impulses were assessed at 3,6,10,14,and 18 days.Antioxidant profiles consisting of“urate”and“thiol”parts were registered with chemiluminometry.In the training dynamics,antioxidant parameters changed individually,but in total there was a decrease in the“urate”capacity by a factor of 1.6(p=0.001)and an increase in the“thiol”capacity by a factor of 1.8(p=0.013).The changes in“urate”capacity positively correlated(r_(S)=0.40)and the changes in“thiol”capacity negatively correlated(r_(S)=−0.45)with changes in tHb-mass.Both exercise and hypoxic factors affect the antioxidant parameters bidirectionally.They correlated with a decrease in thiol capacity and with an increase in urate capacity.The assessment of the non-enzymatic antioxidant profile can be a simple and useful addition to screening the reactive oxygen species homeostasis and can help choose the personalized training schedule,individualize recovery and ergogenic support.
基金supported by U. S. National Institute of Health Grants R01 HL124122, AR067766American Heart Association Grant 12SDG12070174supported by the National Natural Science Foundation of China (Grant No. 81401155)
文摘Multidrug resistance(MDR) remains a major clinical obstacle to successful cancer treatment.Although diverse mechanisms of MDR have been well elucidated, such as dysregulation of drugs transporters, defects of apoptosis and autophagy machinery, alterations of drug metabolism and drug targets, disrupti on of redox homeostasis, the exact mechanisms of MDR in a specific cancer patient and the cross-talk among these different mechanisms and how they are regulated are poorly understood.Micro RNAs(mi RNAs) are a new class of small noncoding RNAs that could control the global activity of the cell by post-transcriptionally regulating a large variety of target genes and proteins expression.Accumulating evidence shows that mi RNAs play a key regulatory role in MDR through modulating various drug resistant mechanisms mentioned above, thereby holding much promise for developing novel and more effective individualized therapies for cancer treatment. This review summarizes the various MDR mechanisms and mainly focuses on the role of mi RNAs in regulating MDR in cancer treatment.
文摘Over the last few years, it has become evident that reactive oxygen species (ROS) signalling plays an important role in various physiological responses, including pathogen defense and stomatal opening/closure. On the other hand, ROS overproduction is detrimental for proper plant growth and development, indicating that the regulation of an appropriate redox balance is essential for plants. ROS homeostasis in plants involves the mitogen-activated protein kinase (MAPK) pathway consisting of the MAPK kinase kinase MEKK1 and the MAPK MPK4. Phenotypic and molecular analysis revealed that the MAPK kinases MKK1 and MKK2 are part of a cascade, regulating ROS and salicylic acid (SA) accumulation. Gene expression analysis shows that of 32 transcription factors reported to be highly responsive to multiple ROS-inducing conditions, 20 are regulated by the MEKK1, predominantly via the MEKK1-MKK1/2-MPK4 pathway. However, MEKK1 also functions on other as yet unknown pathways and part of the MEKK1-dependent MPK4 responses are regulated independently of MKK1 and MKK2. Overall, this analysis emphasizes the central role of this MAPK cascade in oxidative stress signalling, but also indicates the high level of complexity revealed by this signalling network.
基金supported by the National Key R&D Program of China(No.2019YFC1711000)National Natural Science Foundation of China(81421005 and 81722048)+2 种基金111 Project(B16046,China)“Double First-Class”University Project(CPU2018GF04,China)the Qing Lan Project of Jiangsu Province(China)
文摘Disrupted redox status primarily contributes to myocardial ischemia/reperfusion injury(MIRI).NRF2,the endogenous antioxidant regulator,might provide therapeutic benefits.Dihydrotanshinone-Ⅰ(DT)is an active component in Salvia miltiorrhiza with NRF2 induction potency.This study seeks to validate functional links between NRF2 and cardioprotection of DT and to investigate the molecular mechanism particularly emphasizing on NRF2 cytoplasmic/nuclear translocation.DT potently induced NRF2 nuclear accumulation,ameliorating post-reperfusion injuries via redox alterations.Abrogated cardioprotection in NRF2-deficient mice and cardiomyocytes strongly supports NRF2-dependent cardioprotection of DT.Mechanistically,DT phosphorylated NRF2 at Ser40,rendering its nuclear-import by dissociating from KEAP1 and inhibiting degradation.Importantly,we identified PKC-δ-(Thr505)phosphorylation as primary upstream event triggering NRF2-(Ser40)phosphorylation.Knockdown of PKC-δdramatically retained NRF2 in cytoplasm,convincing its pivotal role in mediating NRF2 nuclear-import.NRF2 activity was further enhanced by activated PKB/GSK-3βsignaling via nuclear-export signal blockage independent of PKC-δactivation.By demonstrating independent modulation of PKC-δand PKB/GSK-3β/Fyn signaling,we highlight the ability of DT to exploit both nuclear import and export regulation of NRF2 in treating reperfusion injury harboring redox homeostasis alterations.Coactivation of PKC and PKB phenocopied cardioprotection of DT in vitro and in vivo,further supporting the potential applicability of this rationale.
基金the Improvement of Higher Education Personnel(Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior-CAPES)National Council for Scientific and Technological Development(Conselho Nacional de Desenvolvimento Cientifico e Tecnológico-CNPq)-Proc.486231-2012-7 for financial support
文摘The physiological role of plant mitochondrial glutathione peroxidases is scarcely known. This study attempted to elucidate the role of a rice mitochondrial isoform(GPX1) in photosynthesis under normal growth and salinity conditions. GPX1 knockdown rice lines(GPX1s) were tested in absence and presence of 100 mM NaCl for 6 d.Growth reduction of GPX1 s line under non-stressful conditions, compared with non-transformed(NT) plants occurred in parallel to increased H_2O_2 and decreased GSH contents. These changes occurred concurrently with photosynthesis impairment, particularly in Calvin cycle's reactions, since photochemical efficiency did not change.Thus, GPX1 silencing and downstream molecular/metabolic changes modulated photosynthesis differentially. In contrast, salinity induced reduction in both phases of photosynthesis, which were more impaired in silenced plants.These changes were associated with root morphology alterations but not shoot growth. Both studied lines displayed increased GPX activity but H_2O_2 content did not change in response to salinity. Transformed plants exhibited lower photorespiration, water use efficiency and root growth, indicating that GPX1 could be important to salt tolerance. Growth reduction of GPX1 s line might be related to photosynthesis impairment, which in turn could have involved a cross talk mechanism between mitochondria and chloroplast originated from redox changes due to GPX1 deficiency.
基金supported by the National Institute of Neurological Disorders and Stroke grant R01 NS089754(to Z.L.)by the National Cancer Institute(NCI)grant 1R01 CA204996(to Z.L.)+1 种基金by the National Institutes of Health/NCI through MD Anderson’s Cancer Center Support grant P30CA016672Brain Cancer Specialized Program of Research Excellence grant 2P50 CA127001。
文摘Cancer cells uniquely reprogram their cellular activities to support their rapid proliferation and migration and to coun-teract metabolic and genotoxic stress during cancer progression.In this reprograming,cancer cells’metabolism and other cellular activities are integrated and mutually regulated,and cancer cells modulate metabolic enzymes spatially and temporally so that these enzymes not only have altered metabolic activities but also have modulated subcellular localization and gain non-canonical functions.This review and several others in this issue of Cancer Communications discuss these enzymes’newly acquired functions and the non-canonical functions of some metabolites as features of cancer cell metabolism,which play critical roles in various cellular activities,including gene expression,anabolism,catabolism,redox homeostasis,and DNA repair.
基金supported by the National Natural Science Foundation of China(grants 81872897 and 81672966)the CAMS Major Collaborative Innovation Project 2016-I2 M-1-011(China)。
文摘Tumor cells have unique metabolic programming that is biologically distinct from that of corresponding normal cells.Resetting tumor metabolic programming is a promising strategy to ameliorate drug resistance and improve the tumor microenvironment.Here,we show that carboxyamidotriazole(CAI),an anticancer drug,can function as a metabolic modulator that decreases glucose and lipid metabolism and increases the dependency of colon cancer cells on glutamine metabolism.CAI suppressed glucose and lipid metabolism utilization,causing inhibition of mitochondrial respiratory chain complex I,thus producing reactive oxygen species(ROS).In parallel,activation of the aryl hydrocarbon receptor(Ah R)increased glutamine uptake via the transporter SLC1A5,which could activate the ROS-scavenging enzyme glutathione peroxidase.As a result,combined use of inhibitors of GLS/GDH1,CAI could effectively restrict colorectal cancer(CRC)energy metabolism.These data illuminate a new antitumor mechanism of CAI,suggesting a new strategy for CRC metabolic reprogramming treatment.
基金the State Key Basic Research and Development Program of China (973 Program, 2007CB108805)
文摘As a member of an important group of lipid soluble antioxidants, tocopherols play a paramount role in the daily diet of humans and animals. Recently, genes required for tocochromanol biosynthesis pathway have been identified and cloned with the help of genomics-based approaches and molecular manipulation in the model organisms: Arabidopsis thaliana and Synechocystis sp. PCC 6803. At the basis of these foundations, genetic manipulation of tocochromanol biosynthesis pathway can give rise to strategies that enhance the level of tocochromanol content or convert the constitution of tocochromanol. In addition, genetic manipulations of the tocochromanol biosynthesis pathway provide help for the study of the function of tocopherol in plant systems. The present article summarizes recent advances and pays special attention to the functions of tocopherol in plants. The roles of tocopherol in the network of reactiv.e oxygen species, antioxidants and phytohormones to maintain redox homeostasis and the functions of tocopherol as a signal molecule in chloroplast-to- nucleus signaling to regulate carbohydrate metabolism are also discussed.
基金This work was supported by the National Natural Science Foundation of China(81872891)the Guangdong Natural Science Funds for Distinguished Young Scholar(No.2019B151502016,China)+4 种基金Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program(2017BT01Y093,China)National Engineering and Technology Research Center for New drug Druggability Evaluation(Seed Program of Guangdong Province,2017B090903004,China)the Fundamental Research Funds for the Central Universities(No.19ykzd23,China)The Manitoba Breast Tumor Bank,a member of the Canadian Tissue Repository Network,was funded in part by the Cancer Care Manitoba Foundation(CCMF,Canada)previously the Canadian Institutes of Health Research(CIHR,PRG80155,Canada).
文摘Metabolic and epigenetic reprogramming play important roles in cancer therapeutic resistance.However,their interplays are poorly understood.We report here that elevated TIGAR(TP53-induced glycolysis and apoptosis regulator),an antioxidant and glucose metabolic regulator and a target of oncogenic histone methyltransferase NSD2(nuclear receptor binding SET domain protein 2),is mainly localized in the nucleus of therapeutic resistant tumor cells where it stimulates NSD2 expression and elevates global H3K36me2 mark.Mechanistically,TIGAR directly interacts with the antioxidant master regulator NRF2 and facilitates chromatin recruitment of NRF2,H3K4me3 methylase MLL1 and elongating Pol-II to stimulate the expression of both new(NSD2)and established(NQO1/2,PRDX1 and GSTM4)targets of NRF2,independent of its enzymatic activity.Nuclear TIGAR confers cancer cell resistance to chemotherapy and hormonal therapy in vitro and in tumors through effective maintenance of redox homeostasis.In addition,nuclear accumulation of TIGAR is positively associated with NSD2 expression in clinical tumors and strongly correlated with poor survival.These findings define a nuclear TIGAR-mediated epigenetic autoregulatory loop in redox rebalance for tumor therapeutic resistance.
基金the National Natural Science Foundation of China(32188102,32071993,31971872,31861143006,U2004204)the Zhejiang Provincial“Ten Thousand Talent Program”Project(2018R52025,2019R52031)+3 种基金the Hainan Yazhou Bay Seed Laboratory(a project of B21HJ0220)the Key Research and Development Program of Zhejiang Province(2021C02056)the Nanfan Special Project,CAAS(ZDXM06)the Central Public-Interest Scientific Institution Basal Research Fund(CPSIBRF-CNRRI-202111,CPSIBRF-CNRRI202110)。
文摘Lesion mutants can be valuable tools to reveal the interactions between genetic factors and environmental signals and to improve grain production.Here we identified a rice(Oryza sativa)mutant,lesion spotleaf1(lsl1),which produces necrotic leaf lesions throughout its life cycle.LSL1 encodes a protein of unknown function and belongs to a grass-specific clade.The lesion phenotype of the lsl1 mutant was sharply induced by shading,and its detached leaves incubated in 6-benzylamino purine similarly formed lesions in the dark.In addition,the lsl1 mutant exhibited reactive oxygen species accumulation and cell death.The terminal deoxynucleotidyl transferase d UTP nick end-labeling(TUNEL)and comet assays revealed that the lsl1 mutant contained severe DNA damage,resulting in reduced grain yield and quality.RNA sequencing,gene expression,and protein activity analyses indicate that LSL1 is required for chloroplast function.Furthermore,LSL1 interacts with Psa D and PAP10 to form a regulatory module that functions in chlorophyll synthesis and chloroplast development to maintain redox balance.Our results reveal that LSL1 maintains chloroplast structure,redox homeostasis,and DNA stability,and plays important roles in the interaction between genetic factors and environmental signals and in regulating grain size and quality.
基金This work was supported by the National Natural Science Foundation for Distinguished Young Scholars(No.81625023).
文摘Mitochondria are highly involved in the metastasis of cancer cells.However,tumor cells impede the efficiency of mitochondrial targeted drugs by protecting mitochondria through an intrinsic and adaptive antioxidant mechanism.We aim to disturb the redox homeostasis by prolyl-isomerase PIN1 inhibitor all-trans retinoic acid(ATRA)to improve the therapeutic efficacy of mitochondrial targeted lonidamine(TL).The combination of ATRA and TL with a ratio of 2:1 was found to have the best synergistic effect in inhibiting the proliferation and metastasis of metastatic 4T1 breast cancer cells.Dual-drug loaded nanoparticles(TL-ATRA NPs)were further developed by self-assembly and were observed to disturb the redox homeostasis drastically and triggered a robust mitochondrial disruption on metastatic 4T1 breast cancer cells.The molecular mechanism was related to the downregulation of nuclear factor E2-related factor 2(NRF2),a critical transcription factor that regulated antioxidant responses,and its downstream molecules.As a result,TL-ATRA NPs significantly suppressed the growth of primary tumors and the formation of lung metastasis nodes.Collectively,our findings showed that sensitizing mitochondria to anti-cancer drugs by disturbing redox homeostasis achieved a satisfactory therapeutic effect to inhibit tumor growth and metastasis.