A chronic stress-induced microbiome perturbation, highly enriched in Ruminococcaceae_UCG-014, promotes colorectal cancer growth and metastasis.

Purpose: Mounting evidence indicates that psychological stress adversely affects cancer progression including tumor growth and metastasis. The aim of this study was to investigate the role of chronic stress-induced microbiome perturbation in colorectal cancer (CRC) progression. Methods: Chronic restraint stress (CRS) was used to establish the chronic stress mouse model, behavioral tests were used for the CRS model evaluation. Subcutaneous xenograft model and lung metastasis model were established to investigate the growth and metastasis of CRC promoted by CRS exposure. 16S rRNA gene sequencing and liquid chromatograph-mass spectrometer (LC-MS) were applied to observe the effects of CRS exposure on the alteration of the gut microbiome and microbial metabolites. Bioinformatics analysis and correlation analyses were applied to analyse the changes in the frequency of body mass, tumor volume, inflammatory factors, neuroendocrine hormones and metabolites of the gut microbiota. Results: In this study, we identifed that CRS exposure model was appropriately constructed by achieving expected increases in disease activity index and enhanced depressive-like behaviors. CRS exposure can promote growth and metastasis of CRC. Besides, the data indicated that CRS exposure not only increased the neuro- and immune-inflammation, but also weakened the gut mucosal immunological function. The 16s rRNA gene sequencing data showed that CRS exposure increased the abundance of g_Ruminococcaceae_UCG_014. Furthermore, the LC-MS data indicated that with only 2 exceptions of carpaine and DG (15:0/20:4(5Z,8Z,11Z,14Z)/0:0), the majority of these 24 metabolites were less abundant in CRS-exposed mice. Bioinformatics analysis and correlation analyses indicated that only Ruminoscoccaceae-UCG-014 was significantly associated with inflammation (IL-6), neurotransmission (5-HT), and microbial metabolism (PS). Conclusion: CRS exposure altered diversity, composition and metabolites of the gut microbiome, with Ruminococcaceae_UCG-014 perturbation consistently correlated to inflammatory responses, suggesting a particular role of this bacterial genus in CRC growth and metastasis.

Tong-Xie-Yao-Fang strengthens intestinal feedback control of bile acid synthesis to ameliorate irritable bowel syndrome by enhancing bile salt hydrolase-expressing microbiota.

ETHNOPHARMACOLOGICAL RELEVANCE: A herbal formula Tong-Xie-Yao-Fang (TXYF) is traditionally used to treat irritable bowel syndrome (IBS), modern pharmacological evidence supports that the formula efficacy is associated with altered gut microbiota. Yet, the mechanistic role of gut microbiota in the therapy of TXYF remains unclear. We previously clarified that gut microbiota-dysregulated bile acid (BA) metabolism contribute to the pathogenesis of IBS, deriving a hypothesis that microbiota-BA metabolic axis might be a potential target of TXYF. AIM OF THE STUDY: We aim to investigate a new gut microbiota-mediated mechanism underlying anti-IBS efficacy of TXYF. MATERIALS AND METHODS: We established an IBS rat model with a combination of stressors, compared the herbal efficacy in models undergone gut bacterial manipulations, also examined BA metabolism-related microbiota, metabolites, genes and proteins by 16S rRNA gene sequencing, targeted metabolomics, qPCR and multiplex immunofluorescence staining. RESULTS: We observed that TXYF attenuated visceral hyperalgesia and diarrhea in IBS rats but not in those underwent gut bacteria depletion. Transferring gut microbiota from TXYF-treated donors also decreased visceral sensitivity and slightly relief diarrhea-like behaviors in IBS recipient rats. Fecal 16S rRNA gene sequencing revealed that TXYF modulated microbial ß-diversity and taxonomic structure of IBS rats, with a significant increase in relative abundance of bile salt hydrolase (BSH)-expressing Bacteroidaceae. qPCR and culturing data validated that TXYF had a promotive effect on the growth and BSH activity of Bacteroides species. TXYF-reshaped microbiota upregulated the expression of intestinal Fgf15, a feedback signal to control BA synthesis in the liver. As a result, the BA synthetic and excretory levels in IBS rats were decreased by TXYF, so as that colonic BA membrane receptor Tgr5 sensing and its mediated Calcitonin gene-related peptide (Cgrp)-positive neuronal response were attenuated. CONCLUSION: This study poses a new microbiota-driven therapeutic action for TXYF, highlighting the potential of developing new anti-IBS strategies from the herbal formula targeting BSH-expressing gut bacteria.

Synergy between Th1 and Th2 responses during endometriosis: A review of current understanding.

Endometriosis is widely perceived as an estrogen-dependent chronic disorder with infertility and pelvic pain. Although the etiology of endometriosis has remained elusive, many studies have proclaimed the relevance of immune system disorders with endometriosis. With the discovery that the dysregulation of multiple biological functions in endometriosis is caused by the aberrant differentiation of T helper cells, a shift towards Th2 immune response may account for the disease progression. This review attempts to present mechanisms of cytokines, chemokines, signal pathways, transcription factors and some other factors related with the derivation of Th1/Th2 immune response involved in the development of endometriosis. The current understanding of treatment approaches and potential therapeutic targets will also be outlined with brief discussion.

Gut microbiota and colorectal cancer metastasis.

Gut microbiota play critical roles in the development of colorectal cancer (CRC) metastasis, but the underlying mechanisms remain elusive. This review discusses the molecular mechanisms by which the gut microbiota contribute to a tumor-permissive microenvironment and facilitate malignant transformation and dissemination of tumor cells, thereby mediating CRC metastasis.

A High Hepatic Uptake of Conjugated Bile Acids Promotes Colorectal Cancer-Associated Liver Metastasis.

The liver is the most common site for colorectal cancer (CRC)-associated metastasis. There remain unsatisfactory medications in liver metastasis given the incomplete understanding of pathogenic mechanisms. Herein, with an orthotopic implantation model fed either regular or high-fat diets (HFD), more liver metastases were associated with an expansion of conjugated bile acids (BAs), particularly taurocholic acid (TCA) in the liver, and an increased gene expression of Na+-taurocholate cotransporting polypeptide (NTCP). Such hepatic BA change was more apparently shown in the HFD group. In the same model, TCA was proven to promote liver metastases and induce a tumor-favorable microenvironment in the liver, characterizing a high level of fibroblast activation and increased proportions of myeloid-derived immune cells. Hepatic stellate cells, a liver-residing source of fibroblasts, were dose-dependently activated by TCA, and their conditioned medium significantly enhanced the migration capability of CRC cells. Blocking hepatic BA uptake with NTCP neutralized antibody can effectively repress TCA-triggered liver metastases, with an evident suppression of tumor microenvironment niche formation. This study points to a new BA-driven mechanism of CRC-associated liver metastases, suggesting that a reduction of TCA overexposure by limiting liver uptake is a potential therapeutic option for CRC-associated liver metastasis.

Effects of gut microbiota on immune responses and immunotherapy in colorectal cancer.

Accumulating evidence suggests that gut microbial dysbiosis is implicated in colorectal cancer (CRC) initiation and progression through interaction with host immune system. Given the intimate relationship between the gut microbiota and the antitumor immune responses, the microbiota has proven to be effective targets in modulating immunotherapy responses of preclinical CRC models. However, the proposed putative mechanisms of how these bacteria affect immune responses and immunotherapy efficacy remains obscure. In this review, we summarize recent findings of clinical gut microbial dysbiosis in CRC patients, the reciprocal interactions between gut microbiota and the innate and/or the adaptive immune system, as well as the effect of gut microbiota on immunotherapy response in CRC. Increased understanding of the gut microbiota-immune system interactions will benefit the rational application of microbiota to the clinical promising biomarker or therapeutic strategy as a cancer immunotherapy adjuvant.

The Spatiotemporal Characteristics of Flow-Sediment Relationships in a Hilly Watershed of the Chinese Loess Plateau.

The flow-sediment relationship is important to understand soil erosion and sediment transport in severely eroded areas, such as Loess Plateau. Previous research focused on the variation and driving forces of runoff and sediment at the different scales in a watershed. However, the variations of the flow-sediment relationship on multispatial scales (slope, subgully, gully, and watershed scales) and multitemporal scales (annual, flood events, and flood process) were less focused. Taking the Peijiamao watershed, which includes whole slope runoff plot (0.25 ha, slope scale), branch gully (6.9 ha, subgully scale), gully (45 ha, gully scale), and watershed (3930 ha, watershed scale), four different geomorphic units located at the Chinese Loess Plateau, as the research site, a total of 31 flood events from 1986 to 2008 were investigated, and two flood process data were recorded across all the four geomorphic units. The results showed that on the annual timescale, the average sediment transport modulus and runoff depth at four scales exhibited a linear relationship, with determination coefficients of 0.81, 0.72, 0.74, and 0.77, respectively. At the flood event timescale, the relationships between sediment transport modulus and runoff depth at the gully and watershed scales could also be fitted with a linear relationship with high determination coefficients (from 0.77 to 0.99), but the determination coefficient at the slope scale was only 0.37 at the event scale. On the single rainfall event timescale, the flow-sediment relationship at the slope scale showed a figure-eight hysteretic pattern while those relationships at larger scales showed an anticlockwise loop hysteretic pattern. Under the same flow condition, the suspended sediment concentrations during the falling stage were significantly higher than those during the rising stage. Moreover, the difference was bigger as the spatial scale increased due to the wash loads in the downstream gullies, which favored the occurrence of hyper-concentration flow. The results of the study could provide useful insights into the temporal-spatial scale effects of sediment transport and their internal driving mechanisms at the watershed scale.

Experiment on the bract stripping and crushing device of a corn harvester.

In order to study the mechanism of bract peeling and crushing of a corn harvester, a bract stripping and crushing device was designed that mainly consists of a stripping device, a crushing device, and a frame. The kinematics and dynamics of the roller of bract stripping device were analyzed, and the conditions of bract stripping were obtained. Single factor tests of stripping roller speed and crushing roller speed were carried out. On the basis of single factor tests, orthogonal experiments were carried out to determine crushing roller speed, distance between crushing device axis and stripping device axis, stripping roller speed, and offset angle of stripping roller. The orthogonal experiments showed that the optimum parameters of the device were obtained: the speed of the crushing drum was 1,100 r/min, the axis distance between the stripping and crushing devices was 180 mm, the speed of the stripping roller was 400 r/min, and the offset angle of the stripping roller was 5 degrees. On the basis of orthogonal experiment, three, five, seven, nine and eleven corn feeding and high-speed photography experiments were carried out respectively. The results showed that when three ears of corn were fed at the same time, the effect of corn bract stripping and crushing was the best with the increase of corn number. The stripping roller only grasps most of the bracts of corn at 0.019 s, after stripping the bracts into the crushing device, the bracts were crushed after 0.077 s. The crushing time of bracts was approximately four times as long as that of the bracts.

San-Wu-Huang-Qin decoction attenuates tumorigenesis and mucosal barrier impairment in the AOM/DSS model by targeting gut microbiome.

BACKGROUND: A classic herbal formula San-Wu-Huang-Qin (SWHQ) decoction has been widely used in clinical practices to prevent and treat colorectal cancer (CRC) for years, but its anti-tumorigenic properties and the underlying mechanisms remain undetermined. PURPOSE: The present study used a CRC mouse model to clarify whether and how SWHQ suppresses tumorigenesis. METHODS: Different doses of SWHQ were gavaged to the AOM/DSS model mice to examine its anti-tumor efficacy in comparison with the positive control drug Aspirin. The underlying microbiota-driven anti-tumor action of SWHQ was proven with bacterial manipulations by fecal microbial transplantation (FMT) in vivo and anaerobic culturing in vitro. RESULTS: SWHQ decoction dose-dependently reduced colonic tumor numbers/loads of AOM/DSS models and suppressed their disease activity index scores. SWHQ also recovered epithelial MUC2 secretion and colonic tight junction protein (ZO-1 and claudin1) expression in the mouse model. Such inhibitory impact on tumorigenesis and mucosal barrier impairment was found to be associated with modulation of gut dysbiosis, particularly for suppressing lipopolysaccharide (LPS) producers. The FMT experiment confirmed the substantial contribution of SWHQ-reshaped microbiota to anti-tumor function and mucosal barrier protection. Moreover, LPS-activated TLR4/NF-κB signaling and its downstream pro-inflammatory factors were significantly suppressed in the colon of SWHQ-treated models and SWHQ-reshaped microbiota recipients. CONCLUSIONS: We demonstrated that the SWHQ effectively inhibited tumorigenesis and protect mucosal barrier in CRC at least partially by targeting gut microbiota. This study provides scientific basis for the clinical usage of SWHQ in CRC intervention and prevention.

Regulatory T cells induce polarization of pro-repair macrophages by secreting sFGL2 into the endometriotic milieu.

An increased number of highly active regulatory T cells (Tregs) and macrophages has been found in peritoneal fluid from women with endometriosis. Here, we show that the level of Tregs-derived soluble fibrinogen-like protein 2 (sFGL2) increases in the peritoneal fluid of women with endometriosis. Higher expression of FGL2 and its receptor CD32B is observed in eutopic endometrium and ectopic tissues. The production of sFGL2 in Tregs may be enhanced by several cytokines. sFGL2 selectively induces pro-repair macrophage polarization mainly through the activation of the SHP2-ERK1/2-STAT3 signaling pathway, and the suppression of the NF-κB signaling pathway. Furthermore, sFGL2 induces a much higher level of metallothionein (MT) expression that in turn facilitates pro-repair macrophages polarization. sFGL2-induced pro-repair macrophages promote Th2 and Tregs differentiation, creating a positive feedback loop. These findings suggest that sFGL2 secreted by Tregs skews macrophages toward a pro-repair phenotype via SHP2-ERK1/2-STAT3 signaling pathway, which is involved in the progression of endometriosis.

Sl-lncRNA15492 interacts with Sl-miR482a and affects Solanum lycopersicum immunity against Phytophthora infestans.

Long non-coding RNAs (lncRNAs) are involved in the resistance of plants to infection by pathogens via interactions with microRNAs (miRNAs). Long non-coding RNAs are cleaved by miRNAs to produce phased small interfering RNAs (phasiRNAs), which, as competing endogenous RNAs (ceRNAs), function as decoys for mature miRNAs, thus inhibiting their expression, and contain pre-miRNA sequences to produce mature miRNAs. However, whether lncRNAs and miRNAs mediate other molecular mechanisms during plant resistance to pathogens is unknown. In this study, as a positive regulator, Sl-lncRNA15492 from tomato (Solanum lycopersicum Zaofen No. 2) plants affected tomato resistance to Phytophthora infestans. Gain- and loss-of-function experiments and RNA ligase-mediated 5'-amplification of cDNA ends (RLM-5' RACE) also revealed that Sl-miR482a was negatively involved in tomato resistance by targeting Sl-NBS-LRR genes and that silencing of Sl-NBS-LRR1 decreased tomato resistance. Sl-lncRNA15492 inhibited the expression of mature Sl-miR482a, whose precursor was located within the antisense sequence of Sl-lncRNA15492. Further degradome analysis and additional RLM-5' RACE experiments verified that mature Sl-miR482a could also cleave Sl-lncRNA15492. These results provide a mechanism by which lncRNAs might inhibit precursor miRNA expression through antisense strands of lncRNAs, and demonstrate that Sl-lncRNA15492 and Sl-miR482a mutually inhibit the maintenance of Sl-NBS-LRR1 homeostasis during tomato resistance to P. infestans.

Identification of lncRNAs and their regulatory relationships with target genes and corresponding miRNAs in melon response to powdery mildew fungi.

Melon (Cucumis melo L.), an economically beneficial crop widely cultivated around the world, is vulnerable to powdery mildew (PM). However, the studies on molecular mechanism of melon response to PM fungi is still limited. Long non coding RNAs (lncRNAs) have emerged as new regulators in plants response to biotic stresses. We predicted and identified the intricate regulatory roles of lncRNAs in melon response to PM fungi. A total of 539 lncRNAs were identified from PM-resistant (MR-1) and susceptible melon (Top Mark), in which 254 were significantly altered after PM fungi infection. Multiple target genes of lncRNAs were found to be involved in the hydrolysis of chitin, callose deposition and cell wall thickening, plant-pathogen interaction and plant hormone signal transduction pathway. Additionally, a total of 42 lncRNAs possess the various functions with microRNAs (miRNAs), including lncRNAs that are targeted by miRNAs and function as miRNA precursors or miRNA sponges. These findings provide a comprehensive view of potentially functional lncRNAs, corresponding target genes and related lncRNA-miRNA pairs, which will greatly increase our knowledge of the mechanism underlying susceptibility and resistance to PM in melon.

Genome-Wide Identification of lncRNAs and Analysis of ceRNA Networks During Tomato Resistance to Phytophthora infestans.

Our previous studies have revealed the function of long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) in tomato in response to Phytophthora infestans infection. However, the interaction relationships between lncRNAs and miRNAs during tomato resistance to P. infestans infection are unknown. In this study, 9,011 lncRNAs were identified from tomato plants, including 115 upregulated and 81 downregulated lncRNAs. Among these, 148 were found to be differentially expressed and might affect the expression of 771 genes, which are composed of 887 matched lncRNA-mRNA pairs. In total, 88 lncRNAs were identified as endogenous RNAs (ceRNAs) and predicted to decoy 46 miRNAs. Degradome sequencing revealed that 11 miRNAs that were decoyed by 20 lncRNAs could target 30 genes. These lncRNAs, miRNAs, and target genes were predicted to form 10 regulatory modules. Among them, lncRNA42705/lncRNA08711, lncRNA39896, and lncRNA11265/lncRNA15816 might modulate MYB, HD-Zip, and NAC transcription factors by decoying miR159, miR166b, and miR164a-5p, respectively. Upon P. infestans infection, the expression levels of lncRNA42705 and lncRNA08711 displayed a negative correlation with the expression level of miR159 and a positive correlation with the expression levels of MYB genes. Tomato plants in which lncRNA42705 and lncRNA08711 were silenced displayed increased levels of miR159 and decreased levels of MYB, respectively. The result demonstrated that lncRNAs might function as ceRNAs to decoy miRNAs and affect their target genes in tomato plants, increasing resistance to disease.

LncRNA39026 Enhances Tomato Resistance to Phytophthora infestans by Decoying miR168a and Inducing PR Gene Expression.

Our previous study has indicated that a long noncoding RNA (lncRNA), lncRNA39026, can be responsive to Phytophthora infestans infection. However, the function and regulation mechanism of lncRNA39026 during tomato resistance to P. infestans are unknown. In this study, an lncRNA39026 sequence was cloned from tomato Zaofen No. 2, and this sequence contained an endogenous target mimicry for miR168a, which might suppress the expression of miR168a. LncRNA39026 was strongly downregulated at 3 h in the tomato plants infected with P. infestans, and its expression level displayed a negative correlation with the expression level of miR168a and a positive correlation with the expression levels of SlAGO1 genes (target gene of miR168a) upon P. infestans infection. Tomato plants in which lncRNA39026 was overexpressed displayed enhanced resistance to P. infestans, decreased level of miR168a, and increased level of SlAGO1, whereas the resistance was impaired, level of miR168a was increased, and level of SlAGO1 was decreased after lncRNA39026 silencing. In addition, lncRNA39026 could also induce the expression of pathogenesis-related (PR) genes, as shown by increased and decreased expression levels of PR genes in tomato plants with overexpressed and silenced lncRNA39026, respectively. The result demonstrated that lncRNA39026 might function to decoy miR168a and affect the expression of PR genes in tomato plants, increasing resistance to disease.

Enhanced shRNA delivery by the combination of polyethylenimine, ultrasound, and nanobubbles in liver cancer.

BACKGROUND: Traditional cancer treatments such as surgery, radiation, and chemotherapy destroy both cancer and normal cells, which limit their clinical application. It is difficult to achieve the best results for any liver cancer patients using any single treatment method. Gene therapy for HCC demands non-invasive, efficient, targeted and safe gene transfection strategies. OBJECTIVE: In this study, a nonviral shRNA gene delivery system utilizing a combination of PEI, US, and NBs was developed for targeting survivin in liver Cancer. METHODS AND RESULTS: The PEI-shRNA-NBs cumulated in the tumor tissue because of the EPR effect. By exposure to the US, micelles shRNA may be released from PEI-shRNA-NBs in tumor tissues and the shRNA then transmitted efficiently to cancer cells. Considerably enhanced therapeutic outcome was obtained with the gene silencing effect enhanced. CONCLUSIONS: PEI-shRNA-NBs possess the potential to become promising tools intended for shRNA delivery.

Tomato lncRNA23468 functions as a competing endogenous RNA to modulate NBS-LRR genes by decoying miR482b in the tomato-Phytophthora infestans interaction.

Our previous studies indicated that tomato miR482b could negatively regulate the resistance of tomato to Phytophthora infestans and the expression of miR482b was decreased after inoculation with P. infestans. However, the mechanism by which the accumulation of miR482b is suppressed remains unclear. In this study, we wrote a program to identify 89 long noncoding RNA (lncRNA)-originated endogenous target mimics (eTMs) for 46 miRNAs from our RNA-Seq data. Three tomato lncRNAs, lncRNA23468, lncRNA01308 and lncRNA13262, contained conserved eTM sites for miR482b. When lncRNA23468 was overexpressed in tomato, miR482b expression was significantly decreased, and the expression of the target genes, NBS-LRRs, was significantly increased, resulting in enhanced resistance to P. infestans. Silencing lncRNA23468 in tomato led to the increased accumulation of miR482b and decreased accumulation of NBS-LRRs, as well as reduced resistance to P. infestans. In addition, the accumulation of both miR482b and NBS-LRRs was not significantly changed in tomato plants that overexpressed lncRNA23468 with a mutated eTM site. Based on the VIGS system, a target gene of miR482b, Solyc02g036270.2, was silenced. The disease symptoms of the VIGS-Solyc02g036270.2 tomato plants were in accordance with those of tomato plants in which lncRNA23468 was silenced after inoculation with P. infestans. More severe disease symptoms were found in the modified plants than in the control plants. Our results demonstrate that lncRNAs functioning as eTMs may modulate the effects of miRNAs in tomato and provide insight into how the lncRNA23468-miR482b-NBS-LRR module regulates tomato resistance to P. infestans.

Correction: Trophoblast-derived CXCL16 induces M2 macrophage polarization that in turn inactivates NK cells at the maternal-fetal interface.

In this article, published online 27 March 2018, in the "ACKNOWLEDGEMENTS", it should be supplemented as follows: "This study was funded by a grant from the National Natural Science Foundation of China, number 81490744, awarded to Da-Jin Li." The authors regret the omission.

LncRNA33732-respiratory burst oxidase module associated with WRKY1 in tomato- Phytophthora infestans interactions.

Our previous studies indicated that tomato WRKY1 transcription factor acts as a positive regulator during tomato resistance to Phytophthora infestans. However, the molecular mechanism of WRKY1-mediated resistance regulation remains unclear. Here, we used a comparative transcriptome analysis between wild-type and WRKY1-overexpressing tomato plants to identify differentially expressed genes (DEGs) and long non-coding RNAs (DELs), and we examined long non-coding RNA (lncRNA)-gene networks. The promoter sequences of the upregulated DEGs and DELs were analyzed. Among 1073 DEGs and 199 DELs, 1 kb 5'-upstream regions of 59 DEGs and 22 DELs contain the W-box, the target sequence of the WRKY1. The results of promoter-ß-glucuronidase (GUS) fusion and yeast one-hybrid assay showed that lncRNA33732 was activated by WRKY1 through sequence-specific interactions with the W-box element in its promoter. The overexpression and silencing analysis of lncRNA33732 in tomato showed that lncRNA33732 acts as a positive regulator and enhanced tomato resistance to P. infestans by induction of the expression of respiratory burst oxidase (RBOH) and increase in the accumulation of H2 O2 . When the expression of RBOH gene was inhibited in tomato plants, H2 O2 accumulation decreased and resistance were impaired. These findings suggest that lncRNA33732 activated by WRKY1 induces RBOH expression to increase H2 O2 accumulation in early defense reaction of tomato to P. infestans attack. Our results provide insights into the WRKY1-lncRNA33732-RBOH module involved in the regulation of H2 O2 accumulation and resistance to P. infestans, as well as provide candidates to enhance broad-spectrum resistance to pathogens in tomato.

Tomato MYB49 enhances resistance to Phytophthora infestans and tolerance to water deficit and salt stress.

MAIN CONCLUSION: MYB49-overexpressing tomato plants showed significant resistance to Phytophthora infestans and tolerance to drought and salt stresses. This finding reveals the potential application of tomato MYB49 in future molecular breeding. Biotic and abiotic stresses severely reduce the productivity of tomato worldwide. Therefore, it is necessary to find key genes to simultaneously improve plant resistance to pathogens and tolerance to various abiotic stresses. In this study, based on homologous relationships with Arabidopsis R2R3-MYBs (AtMYBs) involved in responses to biotic and abiotic stresses, we identified a total of 24 R2R3-MYB transcription factors in the tomato genome. Among these tomato R2R3-MYBs, MYB49 (Solyc10g008700.1) was clustered into subgroup 11 by phylogenetic analysis, and its expression level was significantly induced after treatment with P. infestans, NaCl and PEG6000. Overexpression of MYB49 in tomato significantly enhanced the resistance of tomato to P. infestans, as evidenced by decreases in the number of necrotic cells, sizes of lesion, abundance of P. infestans, and disease index. Likewise, MYB49-overexpressing transgenic tomato plants also displayed increased tolerance to drought and salt stresses. Compared to WT plants, the accumulation of reactive oxygen species (ROS), malonaldehyde content, and relative electrolyte leakage was decreased, and peroxidase activity, superoxide dismutase activity, chlorophyll content, and photosynthetic rate were increased in MYB49-overexpressing tomato plants under P. infestans, salt or drought stress. These results suggested that tomato MYB49, as a positive regulator, could enhance the capacity to scavenge ROS, inhibit cell membrane damage and cell death, and protect chloroplasts, resulting in an improvement in resistance to P. infestans and tolerance to salt and drought stresses, and they provide a candidate gene for tomato breeding to enhance biotic stress resistance and abiotic stress tolerance.

Trophoblast-derived CXCL16 induces M2 macrophage polarization that in turn inactivates NK cells at the maternal-fetal interface.

Decidual macrophages (dMΦ) are distinct from the conventional macrophages present in other tissues and express M2 macrophage markers, but the molecular mechanisms of formation and the roles of M2 MΦ during pregnancy have not been completely elucidated. The crosstalk between decidual natural killer cells (dNK) and dMΦ plays an important role in the maintenance of maternal-fetal immune tolerance. Here, CXCL16 derived from first-trimester trophoblast cells induces the polarization of human M2 macrophages. The M2 MΦ polarized by CXCL16 exhibit decreased interleukin-15 production, which facilitates the inactivation of NK cells. The cytotoxicity of NK cells is attenuated by the CXCL16-polarized M2 MΦ. The data shown in the present study provide evidence to support the hypothesis that CXCL16 secreted by trophoblast cells is a key molecule involved in decidual M2 MΦ polarization, which in turn regulates the killing ability of NK cells, thereby contributing to the homeostatic and immune-tolerant milieu required for successful fetal development.