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This work was supported by National Research Foundation of Korea NRF grants funded by the Korean government MSIT Nos. Department of Periodontology, School of Dentistry and Dental Research Institute, Seoul National University and Seoul National University Dental Hospital, Seoul, , South Korea.

You can also search for this author in PubMed Google Scholar. Correspondence to Woo-Jin Kim or Hyun-Mo Ryoo. Open Access This article is licensed under a Creative Commons Attribution 4.

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Download PDF. Subjects Energy metabolism Stress signalling. Abstract Although the normal physiological level of oxidative stress is beneficial for maintaining bone homeostasis, imbalance between reactive oxygen species ROS production and antioxidant defense can cause various bone diseases.

Introduction Reactive oxygen species ROS are highly reactive molecules that are mainly generated from the mitochondrial electron transport chain ETC 1. Alkaline phosphatase staining and alizarin red S staining Alkaline phosphatase ALP staining and alizarin red S ARS staining were performed as described previously Reverse transcription and quantitative real-time polymerase chain reaction Total RNA extraction from cells, reverse transcription and quantitative real-time polymerase chain reaction were performed as described previously Immunoblotting Cellular proteins obtained using a PRO-PREP protein extraction solution iNtRON, South Korea were used for immunoblotting IB.

Oxygen consumption rate assay MC3T3-E1 cells were plated in XF well microplates Agilent Technologies, USA. Intracellular ROS determination Cellular ROS were visualized using CellROX TM Deep Red Reagent Invitrogen, USA and observed by confocal microscopy Zeiss, Germany.

Luciferase reporter assay The transcription-activating activity of FOXO3A was evaluated with the FHRE-Luc reporter gene purchased from Addgene.

Immunofluorescence staining and confocal microscopy Immunofluorescence analysis was performed as described previously Quantification of γH2AX foci Quantification of γ-H2AX foci was performed as previously described Differentially expressed gene DEG , Gene Ontology GO and correlation analyses DESeq2 v1.

Statistics Each experiment was performed at least two or three times, and representative results are shown in the figures. Results NAM stimulates osteoblast differentiation To investigate whether NAM promotes osteoblast differentiation, MC3T3-E1 osteoblasts were treated with NAM in osteogenic medium.

Full size image. Table 1 Enrichment analysis based on OMIM disease libraries for H 2 O 2 -decreased DEGs. Full size table. Table 2 Enrichment analysis based on OMIM disease libraries for H 2 O 2 -decreased DEGs restored by NAM.

Discussion Mitochondria are key intracellular organelles for the generation and regulation of cellular bioenergetics and produce the majority of ATP molecules via the OXPHOS system. References Alfadda, A. Article PubMed PubMed Central Google Scholar Auten, R.

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Both the JWB-resistant and -susceptible varieties grafted on the diseased trees exhibited elongated peduncle in June Figure 1E and G , but then the JWB-resistant variety resumed normal growth in July Figure 1H , while the susceptible one directly developed more severe symptoms, i.

Meanwhile, the successful infection by phytoplasmas of different samples was measured and confirmed at different stages, and as shown in Figure S1 available as Supplementary Data at Tree Physiology Online, the expression of thymidylate kinase TMK increased gradually in the diseased leaves and the susceptible variety from June to September and was highest in September diseased leaves and October susceptible variety , respectively.

The high level of phytoplasma was detected during the whole infected period in the susceptible variety Figure S1 available as Supplementary Data at Tree Physiology Online.

On the contrary, the lower content of phytoplasma was detected at early infected stage June in resistant variety, and then almost no phytoplasma was found at later stages Figure S1 available as Supplementary Data at Tree Physiology Online.

In three types of diseased leaves, the expression levels of TMK were much lower in July than other periods Figure S1 available as Supplementary Data at Tree Physiology Online.

However, the expression level of TMK in the susceptible variety was much lower in August. The results in the two kinds of condition did not conflict with each other.

The susceptible and resistant varieties were infected in the current year by grafting inoculation; therefore, the scions sprouted 1 month later than other branches without grafting, and their diseased stages were also 1 month later than those of the three types of diseased leaves.

In the susceptible variety, the expression level of TMK in July should compare with that of diseased leaves in June. Their changing trends were in accordance with each other. In order to determine whether the phytoplasma invasion could induce the ROS in jujube leaves, a fluorescence-based measurement was performed to detect the formation of ROS Meng and Ma As observed in Figure 2 , phytoplasma invasion stimulated the production of ROS in diseased leaves, and the ROS level gradually increased with the development of the disease severity Figure 2A , Figure S2 available as Supplementary Data at Tree Physiology Online.

ROS levels were significantly higher in phyllody PL and WBL than in the HL. Meanwhile, we found that ROS level in susceptible varieties was higher than in the resistant one Figure 2B , Figure S2 available as Supplementary Data at Tree Physiology Online.

This result demonstrated that the production of ROS in jujube leaves was clearly induced by phytoplasma invasion. Detection of ROS. The green speckles show the distribution of ROS.

Bars, μm. DS, susceptible varieties grafted on diseased jujube; HS, susceptible varieties grafted on healthy jujube; DR, resistant varieties grafted on diseased jujube; HR, resistant varieties grafted on healthy jujube.

The synthesis of AsA plays an important role in oxidative stress, and AsA metabolism might also be involved in phytoplasma attack in Chinese jujube. Thus, the contents of AsA were tested in four types of jujube tissues and in susceptible and resistant varieties.

Next, the AsA content in the above samples was detected by HPLC Figure 3. The results showed that the AsA content of diseased leaves such as in ANL and WBL was higher than that of HL in July and lower than that of HL in August and September Figure 3A.

On the other hand, the AsA contents of infected susceptible and resistant varieties were higher than that of noninfected controls in August and September, and then decreased markedly in October Figure 3B. All these results illustrated that compared with HL, the AsA contents in diseased leaves were increased in early disease stages and decreased significantly with the accumulation of phytoplasma.

A The AsA content and the expression of genes related to AsA metabolism in four types of jujube leaves. B The AsA content and the expression of genes related to AsA metabolism in the susceptible and resistant varieties.

Significant differences were compared between the different cultivars at each time point; the same is true below. Based on the obvious change of AsA content in jujube after phytoplasma infection, the AsA-associated genes were further analyzed.

As shown in Figure 3 , the expression levels of key AsA synthesis ZjGLDH , l -galactono-1,4-lactone dehydrogenase; EC 1. However, the expression of ZjAO ascorbate oxidase, EC l.

In addition, the expression level of ZjGLDH increased considerably in both susceptible and resistant varieties in September and decreased significantly in October, which was in accordance with the patterns of the AsA content Figure 3B. These results indicated that the synthesis, regeneration and decomposition pathways of AsA were all strengthened in jujube leaves under phytoplasma stress Figure 3.

l -Gulonolactone oxidase GULO, EC 1. Interestingly, during the interaction between jujube and phytoplasmas, the expression level of ZjGULO4 , in particular, dramatically increased in the diseased jujube leaves and the susceptible variety Figure 3 , whereas the expression levels of all the GULO genes were not detected or extremely low in healthy organs root, stem, leaf, flower and fruit Figure S3 available as Supplementary Data at Tree Physiology Online.

The abnormally high expression of ZjGULO indicated that the pathway from aldonolactone to AsA was triggered in diseased jujube tissues. For example, GSH peroxidase GSH-Px, EC 1. In diseased tissues, higher expression of γ-glutamylcysteine synthase GCL, Figure 4 , which can synthesize a precursor of GSH, was observed.

In addition, the expression of ZjGSH-Px increased significantly from August to September in the diseased leaves, indicating that GSH actively responds to phytoplasma infection and might lead to the accumulation of AsA.

However, the expression levels of GSH transferase genes ZjGSTs showed no obvious changes in the diseased leaves but were higher in the resistant variety Figure 4B. This result indicated that glutathione S-transferases GSTs might be involved in the resistance to JWB.

The expression of GSH-associated genes in four types of jujube leaves A and in the susceptible and resistant varieties under phytoplasma stress B.

GCL γ-glutamate cysteine ligase and GSH-Px glutathione peroxidase. Trx proteins are antioxidants that catalyze thiol-disulfide interchange in the target protein.

H-type Trx proteins are involved in the regulation of cellular redox and defense responses Sun et al.

Thus, the expression levels of three Trxh genes were evaluated in the four types of jujube tissues and the susceptible and resistant varieties. ZjTrxh2 and ZjTrxh4 expression was upregulated in the diseased leaves compared with that in the healthy controls Figure 5A , and ZjTrxh4 expression increased significantly in the susceptible variety compared with that in the resistant variety.

This result indicated that ZjTrxh4 actively responded to phytoplasma infection, whereas ZjTrxh2 showed slightly higher expression in the resistant variety than in the susceptible variety from June to September Figure 5B.

The distinct expression pattern of ZjTrxhs in the susceptible and resistant varieties might contribute to the difference in antioxidant capacity of these two varieties. The expression of three ZjTrxh genes in four types of jujube leaves A and in the susceptible and resistant varieties B under phytoplasma stress.

In addition to the important function of nonenzymatic antioxidants in response to ROS production during pathogenic infection, antioxidant enzymes are also critical molecules for scavenging toxic ROS, which could protect host plants from pathogenic attack. Therefore, the activities of SOD, POD and laccase in jujube leaves and the expression of their related genes were examined to evaluate the effect of JWB phytoplasma on antioxidant enzymes.

As shown in Figure 6 , the trend in SOD activity was similar in diseased jujube and the healthy controls and was not significantly different in the infected susceptible and resistant varieties. While the activity of laccase was increased in slightly diseased leaves ANL and decreased in severely diseased leaves WBL at the early stage of infection, its activity in both resistant and susceptible varieties showed no significant differences from June to October.

However, at the early stage of phytoplasma infection June—July , the POD activity in diseased trees was significantly higher than that in healthy trees. The activity of POD increased significantly in July in the susceptible trees and was activated earlier in resistant trees June than in susceptible trees.

These results indicated that POD might play more important roles than the other two enzymes in the ROS response and functions at the early stage June—July of infection. The activity of SOD, POD and laccase in four types of jujube leaves A and in the susceptible and resistant varieties B under phytoplasma stress.

The expression of antioxidant genes in jujube leaves under phytoplasma stress. A Heat map of qRT-PCR data for antioxidant genes in four types of jujube leaves. Scaled log2 expression values are shown from green to red, indicating low to high expression.

B The expression of antioxidant genes in the susceptible and resistant varieties under phytoplasma stress. As POD might be the key enzyme during phytoplasma infection, the expression levels of POD synthesis-related genes were tested.

ZjPOD4 was expressed at continuously high levels in diseased leaves from June to September Figure 7A , which might have led to the high activity of POD.

Compared with their expression in the susceptible variety, ZjPOD2 and ZjPOD4 were expressed at a higher level in the resistant variety at the early stage of infection June Figure 7B , which might have contributed to their different patterns of POD enzyme activity.

Moreover, there were no significant differences in the expression levels of the six genes encoding SOD between diseased and HL, whereas their expression levels were markedly higher in the resistant variety than in the susceptible variety Figure 7B. The expression levels of the four genes encoding POD in diseased leaves were markedly increased at the middle stage of infection July Figure 7A.

Overall, phytoplasma infection had a more significant impact on the POD activity in jujube tissues than the other two antioxidant enzymes.

Model proposed for the antioxidant defense system of jujube in response to phytoplasma infection. Plants have a complex and sophisticated antioxidant system whose function is to protect cells from the damage caused by ROS Desikan et al.

As one of the most powerful antioxidants, AsA is a key antioxidant molecule for sustained photosynthesis Torres et al. AsA biosynthesis takes place in the mitochondria; however, its prime requirement is in the chloroplast Foyer , Foyer and Noctor , Torres et al.

In this study, lower AsA contents were confirmed in diseased jujube leaves in the later infection stages. Previous results also showed that the chlorophyll contents decreased markedly and that the structure of chloroplasts was destroyed in diseased jujube leaves Xue et al.

In Arabidopsis, the chlorophyll content also decreased more rapidly in vitamin C-deficient vtc1 mutants than in wild-type plants Zhang The above results suggested that there is a link between the inhibition of photosynthesis and AsA biosynthesis in the chloroplast, which also occurs during the interaction between the host plant and phytoplasma.

For AsA metabolism, the l -galactose pathway is the dominant synthetic pathway in Chinese jujube Liu et al. In this study, it was proven that this pathway is significantly strengthened under phytoplasma stress. The d -mannose pathway, a negligible pathway in AsA biosynthesis by healthy jujube trees, was triggered by an extremely high expression of ZjGULOs in the diseased trees.

All wild-type and vtc mutant lines expressing GULO showed an increased AsA content compared with that in controls Radzio et al. This result indicated that the high expression of ZjGULOs should increase the AsA content in diseased jujube plants; thus, the lower content observed is a result of accelerating decomposition.

However, in further work, it will be worthwhile to clarify how ZjGULOs are triggered by phytoplasma. In addition, this cycle might protect against biotic stress by activating defense mechanisms through redox signaling.

A previous study suggested that the AsA redox state in the leaf apoplast was regulated by l -ascorbate oxidase AO and that it played an important role in modulating the ROS tolerance of plant tissue Fotopoulos et al.

Laccase can catalyze the formation of lignin and other phenolic oxides to form a protective barrier against invasion by pathogens. The laccase-catalyzed formation of quinone is toxic and plays a direct role in disease resistance.

In this study, the expression levels of laccase genes were markedly increased in jujube tissues after infection by phytoplasma, which indicated that laccase positively responds to phytoplasma infection. In addition, the higher expression of ZjPOD2 and ZjPOD4 in the resistant variety at the early infection stage suggested that these genes might participate in the resistance to phytoplasma.

In the present study, both nonenzymatic and enzymatic antioxidants were strongly stimulated in the host jujube, indicating that a strong and comprehensive antioxidant defense system was triggered Figure 8. Overall, phytoplasma invasion induces the overproduction of ROS in jujube, and the ROS trigger an enhanced antioxidant defense system that neutralizes the ROS and re-establishes cellular redox balance.

At the same time, the ROS can also function as signaling molecules to induce a variety of defense responses Figure 8. Therefore, ROS reduction in the host jujube is beneficial not only for the host jujube cells but also for the survival and propagation of the phytoplasma.

In July, the POD activity was significantly higher, and the expression of some genes encoding antioxidants such as ZjAO , ZjMDHAR , ZjDHAR and ZjGCL was also clearly upregulated in diseased leaves compared with the activity and expression in healthy controls, indicating that the enhanced antioxidant defense system in diseased tissues contributed to the temporary decrease in the phytoplasma concentration during the same period Figure S1 available as Supplementary Data at Tree Physiology Online.

With the extension of the infection time and the accumulation of phytoplasma, the damage to the structure and function of jujube cells became increasingly severe. In general, the diseased jujube trees survived for 3—5 years after phytoplasma infection; thus, the antioxidant defense system should function as an important weapon in the confrontation between jujube and phytoplasma.

Phytoplasma encounter strong resistance from host jujube trees, which should contribute to the host survival for several years after infection. This study improves our understanding of the crucial function of the antioxidant defense system involved in phytoplasma tolerance.

The phytoplasma diseases are very difficult to control because the pathogens exist in plant phloem tissue. Phytoplasma infection causes a series of biochemical changes in the plant and in the recovery process Musetti Screening resistant genotypes can prevent the disease effectively.

In this study, the JWB-resistant variety could recover to the normal growth from slight diseased symptoms. The similar recovery processes were also reported in other phytoplasma diseases Seemüller et al.

In their breeding program, they found that the resistance to phytoplasma could be inherited. Thus, the JWB-resistant variety can be used in jujube breeding programs to produce offspring with resistance.

In the other side, further studies should focus on the molecular mechanism of resistance to phytoplasma, which would provide some novel insights on the plant—phytoplasma interaction. The authors owe deep gratitude to Dr Lixin Wang for his critical reading and revising of the manuscript.

All data and materials are presented in the main paper and additional supporting file. designed the research; C. and J. performed the experiments, analyzed the data and wrote the paper.

Others participated in the data analysis. All authors read and approved the final the manuscript. These funding bodies had no role in the design of the study, sample collection, analysis or interpretation of data, or in writing the manuscript.

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Plant Mol Biol 53 : — Rossatto T , Amaral MN , Benitez LC , Vighi IL , Braga E , Magalhaes Júnior AM , Silva Pinto L Gene expression and activity of antioxidant enzymes in rice plants, cv. BRS AG, under saline stress. Physiol Mol Biol Plants 23 : — Sánchez-Rojo S , López-Delgado HA , Mora-Herrera ME , Almeyda-León HI , Zavaleta-Mancera HA , Espinosa-Victoria D Salicylic acid protects potato plants-from phytoplasma-associated stress and improves tuber photosynthate assimilation.

Am J Potato Res 88 : — Seemüller E , Kartte S , Kunze L Resistance in established and experimental apple rootstocks to apple proliferation disease. Acta Hortic : — Sugio A , MacLean AM , Hogenhout SA The small phytoplasma virulence effector SAP11 contains distinct domains required for nuclear targeting and CIN-TCP binding and destabilization.

New Phytol : — Sun L , Ren H , Liu R , Li B , Wu T , Sun F , Dong H An h-type thioredoxin functions in tobacco defense responses to two species of viruses and an abiotic oxidative stress.

Mol Plant Microbe Interact 23 : — Tada Y , Spoel SH , Pajerowska-Mukhtar K , Mou Z , Song J , Wang C , Dong X Plant immunity requires conformational charges of NPR1 via S-nitrosylation and thioredoxins. Science : — Timm AE , Reineke A First insights into grapevine transcriptional responses as a result of vine mealybug Planococcus ficus feeding.

Arthropod Plant Interact 8 : — Torres MA , Jones JD , Dangl JL Reactive oxygen species signaling in response to pathogens.

Trivedi DK , Gill SS , Yadav S , Tuteja N Genome-wide analysis of glutathione reductase GR genes from rice and arabidopsis. Plant Signal Behav 8 : e BMC Genomics 19 : Wei W , Davis RE , Bauchan GR , Zhao Y New symptoms identified in phytoplasma-infected plants reveal extra stages of pathogen-induced meristem fate-derailment.

Mol Plant Microbe Interact. Wheeler G , Ishikawa T , Pornsaksit V , Smirnoff N Evolution of alternative biosynthetic pathways for vitamin C following plastid acquisition in photosynthetic eukaryotes.

eLife 4 : e Xue C , Liu Z , Dai L , Bu J , Liu M , Zhao Z , Zhao J Changing host photosynthetic, carbohydrate, and energy metabolisms play important roles in phytoplasma infection. Phytopathology : — Xue C , Li H , Liu Z , Wang L , Zhao Y , Wei X , Fang H , Liu M , Zhao J Genome-wide analysis of the WRKY gene family and their positive responses to phytoplasma invasion in Chinese jujube.

BMC Genomics 20 : Zafari S , Niknam V , Musetti R , Noorbakhsh SN Effect of phytoplasma infection on metabolite content and antioxidant enzyme activity in lime Citrus aurantifolia.

Acta Physiol Plant 34 : —

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