18ß-Glycyrrhetinic acid protects against deoxynivalenol-induced liver injury via modulating ferritinophagy and mitochondrial quality control.

Deoxynivalenol (DON), a widespread mycotoxin, represents a substantial public health hazard due to its propensity to contaminate agricultural produce, leading to both acute and chronic health issues in humans and animals upon consumption. The role of ferroptosis in DON-induced hepatic damage remains largely unexplored. This study investigates the impact of 18ß-glycyrrhetinic acid (GA), a prominent constituent of glycyrrhiza, on DON hepatotoxicity and elucidates the underlying mechanisms. Our results indicate that GA effectively attenuates liver injury inflicted by DON. This was achieved by inhibiting nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy and ferroptosis, as well as by adjusting mitochondrial quality control (MQC). Specifically, GA curtails ferritinophagy by diminishing NCOA4 expression without affecting the autophagic flux. At a molecular level, GA binds to and stabilizes programmed cell death protein 4 (PDCD4), thereby inhibiting its ubiquitination and subsequent degradation. This stabilization of PDCD4 leads to the downregulation of NCOA4 via the JNK-Jun-NCOA4 axis. Knockdown of PDCD4 weakened GA's protective action against DON exposure. Furthermore, GA improved mitochondrial function and limited excessive mitophagy and mitochondrial division induced by DON. Disrupting GA's modulation of MQC nullified its anti-ferroptosis effects. Overall, GA offers protection against DON-induced ferroptosis by blocking ferritinophagy and managing MQC. ENVIRONMENTAL IMPLICATION: Food contamination from mycotoxins, is a problem for agricultural and food industries worldwide. Deoxynivalenol (DON), the most common mycotoxins in cereal commodities. A survey in 2023 showed that the positivity rate for DON contamination in food reached more than 70% globally. DON can damage the health of humans whether exposed to high doses for short periods of time or low doses for long periods of time. We have discovered 18ß-Glycyrrhetinic acid (GA), a prominent constituent of glycyrrhiza. Liver damage caused by low-dose DON can be successfully treated with GA. This study will support the means of DON control, including antidotes.

Genetic prediction of the causal relationship between schizophrenia and tumors: a Mendelian randomized study.

Background: Patients with schizophrenia are at a higher risk of developing cancer. However, the causal relationship between schizophrenia and different tumor types remains unclear. Methods: Using a two-sample, two-way Mendelian randomization method, we used publicly available genome-wide association analysis (GWAS) aggregate data to study the causal relationship between schizophrenia and different cancer risk factors. These tumors included lung adenocarcinoma, lung squamous cell carcinoma, small-cell lung cancer, gastric cancer, alcohol-related hepatocellular cancer, tumors involving the lungs, breast, thyroid gland, pancreas, prostate, ovaries and cervix, endometrium, colon and colorectum, and bladder. We used the inverse variance weighting (IVW) method to determine the causal relationship between schizophrenia and different tumor risk factors. In addition, we conducted a sensitivity test to evaluate the effectiveness of the causality. Results: After adjusting for heterogeneity, evidence of a causal relationship between schizophrenia and lung cancer risk was observed (odds ratio [OR]=1.001, 95% confidence interval [CI], 1.000-1.001; P=0.0155). In the sensitivity analysis, the causal effect of schizophrenia on the risk of lung cancer was consistent in both direction and degree. However, no evidence of causality or reverse causality between schizophrenia and other tumors was found. Conclusion: This study elucidated a causal relationship between the genetic predictors of schizophrenia and the risk of lung cancer, thereby providing a basis for the prevention, pathogenesis, and treatment of schizophrenia in patients with lung cancer.

Potential of natural flavonoids to target breast cancer angiogenesis (review).

Angiogenesis is the process by which new blood vessels form and is required for tumour growth and metastasis. It helps in supplying oxygen and nutrients to tumour cells and plays a crucial role in the local progression and distant metastasis of, and development of treatment resistance in, breast cancer. Tumour angiogenesis is currently regarded as a critical therapeutic target; however, anti-angiogenic therapy for breast cancer fails to produce satisfactory results, owing to issues such as inconsistent efficacy and significant adverse reactions. As a result, new anti-angiogenic drugs are urgently needed. Flavonoids, a class of natural compounds found in many foods, are inexpensive, widely available, and exhibit a broad range of biological activities, low toxicity, and favourable safety profiles. Several studies find that various flavonoids inhibit angiogenesis in breast cancer, indicating great therapeutic potential. In this review, we summarize the role of angiogenesis in breast cancer and the potential of natural flavonoids as anti-angiogenic agents for breast cancer treatment. We discuss the value and significance of nanotechnology for improving flavonoid absorption and utilization and anti-angiogenic effects, as well as the challenges of using natural flavonoids as drugs.

Advances of new drugs bedaquiline and delamanid in the treatment of multi-drug resistant tuberculosis in children.

Tuberculosis (TB) is a major public health problem, with nearly 10 million new cases and millions of deaths each year. Around 10% of these cases are in children, but only a fraction receive proper diagnosis and treatment. The spread of drug-resistant (DR) strain of TB has made it difficult to control, with only 60% of patients responding to treatment. Multi-drug resistant TB (MDR-TB) is often undiagnosed in children due to lack of awareness or under-diagnosis, and the target for children's DR-TB treatment has only been met in 15% of goals. New medications such as bedaquiline and delamanid have been approved for treating DR-TB. However, due to age and weight differences, adults and children require different dosages. The availability of child-friendly formulations is limited by a lack of clinical data in children. This paper reviews the development history of these drugs, their mechanism of action, efficacy, safety potential problems and current use in treating DR-TB in children.

Trends and challenges of multi-drug resistance in childhood tuberculosis.

Drug-resistant tuberculosis (DR-TB) in children is a growing global health concern, This review provides an overview of the current epidemiology of childhood TB and DR-TB, including prevalence, incidence, and mortality. We discuss the challenges in diagnosing TB and DR-TB in children and the limitations of current diagnostic tools. We summarize the challenges associated with treating multi-drug resistance TB in childhood, including limitations of current treatment options, drug adverse effects, prolonged regimens, and managing and monitoring during treatment. We highlight the urgent need for improved diagnosis and treatment of DR-TB in children. The treatment of children with multidrug-resistant tuberculosis will be expanded to include the evaluation of new drugs or new combinations of drugs. Basic research is needed to support the technological development of biomarkers to assess the phase of therapy, as well as the urgent need for improved diagnostic and treatment options.

ncRNA-mediated ceRNA regulatory network: Transcriptomic insights into breast cancer progression and treatment strategies.

With the rapid development of next-generation sequencing technology, several studies have shown that ncRNAs can act as competitive endogenous RNAs (ceRNAs) and are involved in various biological processes, such as proliferation, differentiation, apoptosis, and migration of breast cancer (BC) cells, and plays an important role in BC progression as a molecular target for its diagnosis, treatment, prognosis, and differentiation of subtypes and age groups of BC patients. Based on the description of ceRNA-related biological functions, this study screened and sorted the sequencing analysis and experimental verification conclusions of BC-related ceRNAs and found that the ncRNAs mediated ceRNA networks can promote the development of BC by promoting the expression of genes related to BC proliferation, drug resistance, and apoptosis, inducing the production of epithelial-mesenchymal transition (EMT) to promote metastasis and activating cancer-related signaling pathways.

MYB pathways that regulate UV-B-induced anthocyanin biosynthesis in blueberry (Vaccinium corymbosum).

Ultraviolet-B (UV-B) promotes anthocyanin accumulation and improves fruit quality in plants. To explore the underlying network of MYB transcription factors that regulates UV-B-induced anthocyanin biosynthesis in blueberry (Vaccinium corymbosum), we analyzed the response of MYB transcription factor genes to UV-B treatment. Transcriptome sequencing analysis revealed that VcMYBA2 and VcMYB114 expression were upregulated and were positively correlated with the expression of anthocyanin structural genes under UV-B radiation according to weighted gene co-expression network analysis (WGCNA) data. The VcUVR8-VcCOP1-VcHY5 pathway perceives UV-B signals and promotes the expression of anthocyanin structural genes by upregulating VcMYBA2 and VcMYB114 or by regulating the VcBBXs-VcMYB pathway, ultimately promoting anthocyanin accumulation. By contrast, VcMYB4a and VcUSP1 were downregulated under UV-B treatment, and VcMYB4a expression was negatively correlated with that of anthocyanin biosynthesis genes in response to UV-B. Analysis of VcMYB4a-overexpressing and wild-type blueberry calli exposed to UV-B radiation revealed that VcMYB4a represses UV-B-induced anthocyanin accumulation. Yeast one-hybrid and dual luciferase assays showed that the universal stress protein VcUSP1 directly bound to the promoter of VcMYB4a. These results suggest that the VcUSP1-VcMYB4a pathway negatively regulates UV-B-induced anthocyanin biosynthesis and provide insight into UV-B-induced anthocyanin biosynthesis.

Exosomal ncRNAs facilitate interactive 'dialogue' between tumor cells and tumor-associated macrophages.

As a biological carrier, exosomes participate in the communication between various kinds of cells, and can mediate the interactive 'dialogue' between tumor cells and tumor-associated macrophages (TAMs). TAMs are the most abundant cell population in the tumor stroma and are an important part of the tumor immune microenvironment. Various stimulating factors in the tumor microenvironment influence the polarization of TAMs into multiple phenotypes, such as M1 and M2. It plays a dual role in tumor immunity by both promoting and inhibiting tumor growth. Exosome-encapsulated non-coding RNAs (ncRNAs) participate in the interactive 'dialogue' between exosome-mediated TAMs and tumor cells. Tumor-derived exosomal ncRNAs can promote macrophage polarization, whereas exosomal ncRNAs derived from TAMs can affect tumor proliferation, metastasis, angiogenesis, and chemotherapy resistance. The present review summarizes the dual effects of exosomal ncRNAs on tumor cells and TAMs, and discusses the application of exosomal ncRNAs as a potential diagnostic or prognostic marker and drug delivery system, to provide a new perspective and potential therapeutic drugs on targeting exosomes and macrophages in the treatment of tumors.

Advances in Regulating Cellular Behavior Using Micropatterns.

Micropatterns, characterized as distinct physical microstructures or chemical adhesion matrices on substance surfaces, have emerged as a powerful tool for manipulating cellular activity. By creating specific extracellular matrix microenvironments, micropatterns can influence various cell behaviors, including orientation, proliferation, migration, and differentiation. This review provides a comprehensive overview of the latest advancements in the use of micropatterns for cell behavior regulation. It discusses the influence of micropattern morphology and coating on cell behavior and the underlying mechanisms. It also highlights future research directions in this field, aiming to inspire new investigations in materials medicine, regenerative medicine, and tissue engineering. The review underscores the potential of micropatterns as a novel approach for controlling cell behavior, which could pave the way for breakthroughs in various biomedical applications.

UV-B induces the expression of flavonoid biosynthetic pathways in blueberry (Vaccinium corymbosum) calli.

Ultraviolet-B (UV-B) radiation is an environmental signal that affects the accumulation of secondary metabolites in plants. In particular, UV-B promotes flavonoid biosynthesis, leading to improved fruit quality. To explore the underlying molecular mechanism, we exposed blueberry (Vaccinium corymbosum) calli to UV-B radiation and performed a transcriptome deep sequencing (RNA-seq) analysis to identify differentially expressed genes (DEGs). We detected 16,899 DEGs among different treatments, with the largest number seen after 24 h of UV-B exposure relative to controls. Functional annotation and enrichment analysis showed a significant enrichment for DEGs in pathways related to plant hormone signal transduction and phenylpropanoid and flavonoid biosynthesis. In agreement with the transcriptome data, flavonol, anthocyanin and proanthocyanidin accumulated upon UV-B radiation, and most DEGs mapping to the phenylpropanoid and flavonoid biosynthetic pathways using the KEGG mapper tool were upregulated under UV-B radiation. We also performed a weighted gene co-expression network analysis (WGCNA) to explore the relationship among genes involved in plant hormone signal transduction, encoding transcription factors or participating in flavonoid biosynthesis. The transcription factors VcMYBPA1, MYBPA2.1, MYB114, MYBA2, MYBF, and MYB102 are likely activators, whereas MYB20, VcMYB14, MYB44, and VcMYB4a are inhibitors of the flavonoid biosynthetic pathway, as evidenced by the direction of correlation between the expression of these MYBs and flavonoid biosynthesis-related genes. The transcription factors bHLH74 and bHLH25 might interact with MYB repressors or directly inhibited the expression of flavonoid biosynthetic genes to control flavonoid accumulation. We also observed the downregulation of several genes belonging to the auxin, gibberellin and brassinosteroid biosynthetic pathways, suggesting that MYB inhibitors or activators are directly or indirectly regulated to promote flavonoid biosynthesis under UV-B radiation.

NF-κB inhibitors gifted by nature: The anticancer promise of polyphenol compounds.

Polyphenol compounds are natural antioxidants, which are rich in anti-inflammatory and antioxidant components. They have a wide range of medicinal benefits that are believed to improve human health across various aspects; especially its anticancer effect has been gradually confirmed. The anticancer effect of polyphenols is mainly based on their strong antioxidant and immunomodulatory effects. The innate and adaptive immune responses as well as the development and maintenance of cells and tissues of the immune system are regulated by the NF-κB family of transcription factors. Dysregulation of NF-κB can lead to autoimmune diseases, chronic inflammation, and even cancer. Polyphenol compounds can exert antioxidant and immunomodulatory effects by targeting NF-κB, thus hindering the occurrence and development of tumors.Polyphenol compounds have unique advantages over conventional anticancer therapies such as chemotherapy because they have few side effects and do not cause toxicity to healthy cells. Additionally, they can attenuate the toxic effects of current anticancer therapies. Based on these characteristics, polyphenols have great potential in the prevention and treatment of cancer. This article systematically summarizes the mechanism of NF-κB in tumor genesis, progression, metastasis, angiogenesis, and drug resistance. In addition, we present the anticancer effect of polyphenol compounds by targeting NF-κB during the different stages of tumorigenesis.

Flavonoids regulate tumor-associated macrophages - From structure-activity relationship to clinical potential (Review).

In recent years, the strategy for tumor therapy has changed from focusing on the direct killing effect of different types of therapeutic agents on cancer cells to the new mainstream of multi-mode and -pathway combined interventions in the microenvironment of the developing tumor. Flavonoids, with unique tricyclic structures, have diverse and extensive immunomodulatory and anti-cancer activities in the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) are the most abundant immunosuppressive cells in the TME. The regulation of macrophages to fight cancer is a promising immunotherapeutic strategy. This study covers the most comprehensive cognition of flavonoids in regulating TAMs so far. Far more than a simple list of studies, we try to dig out evidence of crosstalk at the molecular level between flavonoids and TAMs from literature, in order to discuss the most relevant chemical structure and its possible relationship with the multimodal pharmacological activity, as well as systematically build a structure-activity relationship between flavonoids and TAMs. Additionally, we point out the advantages of the macro-control of flavonoids in the TME and discuss the potential clinical implications as well as areas for future research of flavonoids in regulating TAMs. These results will provide hopeful directions for the research of antitumor drugs, while providing new ideas for the pharmaceutical industry to develop more effective forms of flavonoids.

New insights from the single-cell level: Tumor associated macrophages heterogeneity and personalized therapy.

Tumor-associated macrophages (TAMs) are important immune cells in the tumor microenvironment, and their invasion in tumors is closely related to poor prognosis. Although TAMs are recognized as therapeutic targets, their heterogeneity makes studying tumor mechanism and developing drugs targeting TAMs difficult. The study of TAMs heterogeneity can be used to analyze the mechanism of tumor progression and drug resistance, and may provide possible treatment strategies for cancer patients. Single-cell RNA sequencing (scRNA-seq) can reveal the RNA expression profile for each TAM to distinguish heterogeneity, thereby providing a more efficient detection method and more accurate information for TAM-related studies. In this review, by summarizing the research progress in macrophage heterogeneity and other aspects of scRNA-seq over the past five years, we introduced the development of scRNA-seq technology and its application status in solid tumors, analyzed the advantages and selections of scRNA-seq in TAMs, and summarized the detailed specific research fields. To explore the mechanism of tumor progression and drug intervention from single cell level will provide new perspective for personalized treatment strategies targeting macrophages.

Natural compounds: A new perspective on targeting polarization and infiltration of tumor-associated macrophages in lung cancer.

With the development in tumor immunology, people are gradually understanding the complexity and diversity of the tumor microenvironment immune status and its important effect on tumors. Tumor-associated macrophages (TAMs), an important part of the tumor immune microenvironment, have a double effect on tumor growth and metastasis. Many studies have focused on lung cancer, especially non-small cell lung cancer and other "hot tumors" with typical inflammatory characteristics. The polarization and infiltration of TAMs is an important mechanism in the occurrence and development of malignant tumors, such as lung cancer, and in the tumor immune microenvironment. Therapeutic drugs designed for these reasons are key to targeting TAMs in the treatment of lung cancer. A large number of reports have suggested that natural compounds have a strong potential of affecting immunity by targeting the polarization and infiltration of TAMs to improve the immune microenvironment of lung cancer and exert a natural antitumor effect. This paper discusses the infiltration and polarization effects of natural compounds on lung cancer TAMs, provides a detailed classification and systematic review of natural compounds, and summarizes the bias of different kinds of natural compounds by affecting their antitumor mechanism of TAMs, with the aim of providing new perspectives and potential therapeutic drugs for targeted macrophages in the treatment of lung cancer.

The Mycobacterial DNA Methyltransferase HsdM Decreases Intrinsic Isoniazid Susceptibility.

Tuberculosis, caused by the pathogen Mycobacterium tuberculosis, is a serious infectious disease worldwide. Multidrug-resistant TB (MDR-TB) remains a global problem, and the understanding of this resistance is incomplete. Studies suggested that DNA methylation promotes bacterial adaptability to antibiotic treatment, but the role of mycobacterial HsdM in drug susceptibility has not been explored. Here, we constructed an inactivated Mycobacterium bovis (BCG) strain, ΔhsdM. ΔhsdM shows growth advantages over wild-type BCG under isoniazid treatment and hypoxia-induced stress. Using high-precision PacBio single-molecule real-time sequencing to compare the ΔhsdM and BCG methylomes, we identified 219 methylated HsdM substrates. Bioinformatics analysis showed that most HsdM-modified genes were enriched in respiration- and energy-related pathways. qPCR showed that HsdM-modified genes directly affected their own transcription, indicating an altered redox regulation. The use of the latent Wayne model revealed that ΔhsdM had growth advantages over wild-type BCG and that HsdM regulated trcR mRNA levels, which may be crucial in regulating transition from latency to reactivation. We found that HsdM regulated corresponding transcription levels via gene methylation; thus, altering the mycobacterial redox status and decreasing the bacterial susceptibility to isoniazid, which is closely correlated with the redox status. Our results provide valuable insight into DNA methylation on drug susceptibility.

Identification of G-protein signaling modulator 2 as a diagnostic and prognostic biomarker of pancreatic adenocarcinoma: an exploration of its regulatory mechanisms.

BACKGROUND: Pancreatic adenocarcinoma (PAAD) has a high rate of mortality. Unfortunately, it is difficult to diagnosis. This study aimed to develop a more in-depth understanding of the disease. METHODS: A total of 177 patients with PAAD were recruited from The Cancer Genome Atlas (TCGA) database. Microarray analysis was performed to identify differentially expressed genes (DEGs) in PAAD. The microarray data were adapted to the ingenuity pathway analysis (IPA) for annotation and visualization, followed by protein-protein interaction (PPI) network analysis. In vitro transwell migration assays were conducted to explore the molecular and functional characteristics of pancreatic adenocarcinoma cells (PANC-1) with stable low expression of G-protein signaling modulator 2 (GPSM2). Expression of GPSM2 and the associated hub genes were detected by reverse transcription-quantitative polymerase chain reaction (qPCR). RESULTS: The overexpression of GPSM2 was proved in PAAD, as compared with the healthy tissues, as well as its correlation with history of chronic pancreatitis, T stage, TNM stage and tumor grade. We described it as an independent prognostic factor and found that it could influence the infiltration of immune cells in the tumor microenvironment. Silencing of GPSM2 restrained the and migration of the cells. Microarray analysis identified 1,631 DEGs in PAAD cells. The PPI network analysis identified hub genes including CD44, ITGB1, ITGB5, ITGA2, ITGA5, AKT1, EGFR, NRAS and MAP2K1, and their relationship with GPSM2 was confirmed by qPCR. CONCLUSIONS: GPSM2 is a novel prognostic factor and therapeutic target for PAAD. GPSM2 promoted the migration of pancreatic adenocarcinoma cells .Targeting GPSM2 and its downstream genes may prolong the survival time of patients with PAAD.

Comparative transcriptomic and metabolomic analyses of carotenoid biosynthesis reveal the basis of white petal color in Brassica napus.

MAIN CONCLUSION: The molecular mechanism underlying white petal color in Brassica napus was revealed by transcriptomic and metabolomic analyses. Rapeseed (Brassica napus L.) is one of the most important oilseed crops worldwide, but the mechanisms underlying flower color in this crop are known less. Here, we performed metabolomic and transcriptomic analyses of the yellow-flowered rapeseed cultivar 'Zhongshuang 11' (ZS11) and the white-flowered inbred line 'White Petal' (WP). The total carotenoid contents were 1.778-fold and 1.969-fold higher in ZS11 vs. WP petals at stages S2 and S4, respectively. Our findings suggest that white petal color in WP flowers is primarily due to decreased lutein and zeaxanthin contents. Transcriptome analysis revealed 10,116 differentially expressed genes with a fourfold or greater change in expression (P-value less than 0.001) in WP vs. ZS11 petals, including 1,209 genes that were differentially expressed at four different stages and 20 genes in the carotenoid metabolism pathway. BnNCED4b, encoding a protein involved in carotenoid degradation, was expressed at abnormally high levels in WP petals, suggesting it might play a key role in white petal formation. The results of qRT-PCR were consistent with the transcriptome data. The results of this study provide important insights into the molecular mechanisms of the carotenoid metabolic pathway in rapeseed petals, and the candidate genes identified in this study provide a resource for the creation of new B. napus germplasms with different petal colors.

Genome-wide identification and expression profiling of the carotenoid cleavage dioxygenase (CCD) gene family in Brassica napus L.

Carotenoid cleavage dioxygenase (CCD), a key enzyme in carotenoid metabolism, cleaves carotenoids to form apo-carotenoids, which play a major role in plant growth and stress responses. CCD genes had not previously been systematically characterized in Brassica napus (rapeseed), an important oil crop worldwide. In this study, we identified 30 BnCCD genes and classified them into nine subgroups based on a phylogenetic analysis. We identified the chromosomal locations, gene structures, and cis-promoter elements of each of these genes and performed a selection pressure analysis to identify residues under selection. Furthermore, we determined the subcellular localization, physicochemical properties, and conserved protein motifs of the encoded proteins. All the CCD proteins contained a retinal pigment epithelial membrane protein (RPE65) domain. qRT-PCR analysis of expression of 20 representative BnCCD genes in 16 tissues of the B. napus cultivar Zhong Shuang 11 ('ZS11') revealed that members of the BnCCD gene family possess a broad range of expression patterns. This work lays the foundation for functional studies of the BnCCD gene family.

The plasmid-borne quinolone resistance protein QnrB, a novel DnaA-binding protein, increases the bacterial mutation rate by triggering DNA replication stress.

Bacterial antibiotic resistance, a global health threat, is caused by plasmid transfer or genetic mutations. Quinolones are important antibiotics, partially because they are fully synthetic and resistance genes are unlikely to exist in nature; nonetheless, quinolone resistance proteins have been identified. The mechanism by which plasmid-borne quinolone resistance proteins promotes the selection of quinolone-resistant mutants is unclear. Here, we show that QnrB increases the bacterial mutation rate. Transcriptomic and genome sequencing analyses showed that QnrB promoted gene abundance near the origin of replication (oriC). In addition, the QnrB expression level correlated with the replication origin to terminus (oriC/ter) ratio, indicating QnrB-induced DNA replication stress. Our results also show that QnrB is a DnaA-binding protein that may act as an activator of DNA replication initiation. Interaction of QnrB with DnaA promoted the formation of the DnaA-oriC open complex, which leads to DNA replication over-initiation. Our data indicate that plasmid-borne QnrB increases bacterial mutation rates and that genetic changes can alleviate the fitness cost imposed by transmitted plasmids. Derivative mutations may impair antibiotic efficacy and threaten the value of antibiotic treatments. Enhanced understanding of how bacteria adapt to the antibiotic environment will lead to new therapeutic strategies for antibiotic-resistant infections.

The potato transcription factor StbZIP61 regulates dynamic biosynthesis of salicylic acid in defense against Phytophthora infestans infection.

Salicylic acid (SA) signalling plays an essential role in plant innate immunity. In this study, we identified a component in the SA signaling pathway in potato (Solanum tuberosum), the transcription factor StbZIP61, and characterized its function in defence against Phytophthora infestans. Expression of StbZIP61 was induced upon P. infestans infection and following exposure to the defense signaling hormones SA, ethylene and jasmonic acid. Overexpression of StbZIP61 increased the tolerance of potato plants to P. infestans while RNA interference (RNAi) increased susceptibility. Yeast two-hybrid and pull down experiments revealed that StbZIP61 could interact with an NPR3-like protein (StNPR3L) that inhibited its DNA-binding and transcriptional activation activities. Moreover, StNPR3L interacted with StbZIP61 in an SA-dependent manner. Among candidate genes involved in SA-regulated defense responses, StbZIP61 had a significant impact on expression of StICS1, which encodes a key enzyme for SA biosynthesis. StICS1 transcription was induced upon P. infestans infection and this responsive expression to the pathogen was reduced in StbZIP61 RNAi plants. Accordingly, StICS1 expression was remarkably enhanced in StbZIP61-overexpressing plants. Together, our data demonstrate that StbZIP61 functions in concert with StNPR3L to regulate the temporal activation of SA biosynthesis, which contributes to SA-mediated immunity against P. infestans infection in potato.