Genome-Wide Analysis of R2R3-MYB Genes and Functional Characterization of SmMYB75 in Eggplant Fruit Implications for Crop Improvement and Nutritional Enhancement.

R2R3-MYB represents a substantial gene family that plays diverse roles in plant development. In this study, 102 SmR2R3-MYB genes were identified from eggplant fruit and classified into 31 subfamilies. Analysis indicated that segmental duplication events played a pivotal role in the expansion of the SmR2R3-MYB gene family. Furthermore, the prediction of miRNAs targeting SmR2R3-MYB genes revealed that 60 SmR2R3-MYBs are targeted by 57 miRNAs, with specific miRNAs displaying varying numbers of target genes, providing valuable insights into the regulatory functions of miRNAs in plant growth, development, and responses to stress conditions. Through expression profile analysis under various treatment conditions, including low temperature (4 °C), plant hormone (ABA, Abscisic acid), and drought stress (PEG, Polyethylene glycol), diverse and complex regulatory mechanisms governing SmR2R3-MYB gene expression were elucidated. Notably, EGP21875.1 and EGP21874.1 exhibited upregulation in expression under all treatment conditions. Transcriptome and metabolome analyses demonstrated that, apart from anthocyanins (delphinidin-3-O-glucoside, cyanidin-3-O-(6-O-p-coumaroyl)-glucoside, and malvidin-3-O-(6-O-p-coumaroyl)-glucoside), overexpression of SmMYB75 could also elevate the content of various beneficial compounds, such as flavonoids, phenolic acids, and terpenes, in eggplant pulp. This comprehensive study enhances our understanding of SmR2R3-MYB gene functions and provides a strong basis for further research on their roles in regulating anthocyanin synthesis and improving eggplant fruit quality.

Dexamethasone Suppresses IL-33-exacerbated Malignant Phenotype of U87MG Glioblastoma Cells via NF-κB and MAPK Signaling Pathways.

BACKGROUND: Interleukin (IL)-33 is highly expressed in glioblastoma (GBM) and promotes tumor progression. Targeting IL-33 may be an effective strategy for the treatment of GBM. Dexamethasone (DEX) is a controversial drug routinely used clinically in GBM therapy. Whether DEX has an effect on IL-33 is unknown. This study aimed to investigate the effect of DEX on IL-33 and the molecular mechanisms involved. METHODS: U87MG cells were induced by tumor necrosis factor (TNF)-α to express IL-33 and then treated with DEX. The mRNA levels of IL-33, NF-κB p65, ERK1/2, and p38 were determined by real-time quantitative PCR. The expression of IL-33, IkBα (a specific inhibitor of NF-κB) and MKP-1 (a negative regulator of MAPK), as well as the phosphorylation of NF-κB, ERK1/2 and p38 MAPK, were detected by Western blotting. The secretion of IL-33 was measured by ELISA. The proliferation, migration and invasion of U87MG cells were detected by CCK8 and transwell assays, respectively. RESULTS: DEX significantly reduced TNF-α-induced production of IL-33 in U87MG cells, which was dependent on inhibiting the activation of the NF-κB, ERK1/2 and p38 MAPK signaling pathways, and was accompanied by the increased expression of IkBα but not MKP-1. Furthermore, the proliferation, migration and invasion of U87MG cells exacerbated by IL-33 were suppressed by DEX. CONCLUSION: DEX inhibited the production and tumor-promoting function of IL-33. Whether DEX can benefit GBM patients remains controversial. Our results suggest that GBM patients with high IL-33 expression may benefit from DEX treatment and deserve further investigation.

Eggplant transcription factor SmMYB5 integrates jasmonate and light signaling during anthocyanin biosynthesis.

Low light conditions severely suppress anthocyanin synthesis in fruit skins, leading to compromised fruit quality in eggplant (Solanum melongena L.) production. In this study, we found that exogenous methyl-jasmonate (MeJA) application can effectively rescue the poor coloration of the eggplant pericarp under low light conditions. However, the regulatory relationship between jasmonate and light signaling for regulating anthocyanin synthesis remains unclear. Here, we identified a JA response factor, SmMYB5, as an anthocyanin positive regulator by applying RNA-sequencing and characterization of transgenic plants. Firstly, we resolved that SmMYB5 can interact with TRANSPARENT TESTA8 (SmTT8), an anthocyanin-promoted BASIC HELIX-LOOP-HELIX (bHLH) transcription factor, to form the SmMYB5-SmTT8 complex and activate CHALCONE SYNTHASE (SmCHS), FLAVANONE-3-HYDROXYLASE (SmF3H), and ANTHOCYANIN SYNTHASE (SmANS) promoters by direct binding. Secondly, we revealed that JA signaling repressors JASMONATE ZIM DOMAIN5 (SmJAZ5) and SmJAZ10 can interfere with the stability and transcriptional activity of SmMYB5-SmTT8 by interacting with SmMYB5. JA can partially rescue the transcriptional activation of SmF3H and SmANS promoters by inducing SmJAZ5/10 degradation. Thirdly, we demonstrated that the protein abundance of SmMYB5 is regulated by light. CONSTITUTIVELY PHOTOMORPHOGENIC1 (SmCOP1) interacts with SmMYB5 to trigger SmMYB5 degradation via the 26S proteasome pathway. Finally, we delineated a light-dependent JA-SmMYB5 signaling pathway that promotes anthocyanin synthesis in eggplant fruit skins. These results provide insights into the mechanism of the integration of JA and light signals in regulating secondary metabolite synthesis in plants.

Association between miR-365 polymorphism and ischemic stroke in a Chinese population.

Background: Ischemic stroke (IS) represents a major cause of morbidity and mortality across the globe. The aberrant expression of miR-365 has been found to be implicated in a wide array of human diseases, including atherosclerosis and cancer. Studies on single-nucleotide polymorphisms (SNPs) in miRNA genes can help gain insight into the susceptibility to the condition. This study aimed to examine the relationship between miR-365 SNPs and the risk of IS. Methods: The study recruited 215 IS patients and 220 controls. The SNPscans genotyping was employed to genotype three polymorphic loci (rs121224, rs30230, and rs178553) of miR-365. The relative expression of miR-365 in peripheral blood mononuclear cells of the patients and controls was determined by using real-time quantitative PCR. Results: The miR-365 rs30230 polymorphism exhibited a significant association with the risk of developing IS (TC vs. CC: adjusted OR = 0.55, 95% CI: 0.33-0.92, P = 0.022; TT vs. CC: adjusted OR = 0.34, 95% CI: 0.14-0.85, P = 0.021; TC +TT vs. CC: adjusted OR = 0.51, 95% CI: 0.31-0.83, P = 0.007; T vs. C: adjusted OR = 0.57, 95% CI: 0.39-0.83, P = 0.004). Haplotype analysis revealed that the C-T-G haplotype was associated with a decreased risk of IS (OR = 0.68, 95% CI: 0.46-1.00, P = 0.047). Furthermore, miR-365 expression was significantly higher in IS patients than in controls (P < 0.001). Interestingly, patients with rs30230 TC or TT genotypes had lower miR-365 levels compared to their counterparts with CC genotypes (P < 0.001). Conclusions: The miR-365 rs30230 polymorphism might bear an association with IS susceptibility in the Chinese population, and the rs30230 TC/TT genotype might be a protective factor against IS.

IL-33 and HMGB1 modulate the progression of EAE via oppositely regulating each other.

Interleukin-33 (IL-33) and high mobility group box 1 (HMGB1) have been reported to play crucial and distinct roles in experimental autoimmune encephalomyelitis (EAE). However, little is known about their interaction in the progression of EAE. In this study, the dynamic expression and release of IL-33 and HMGB1 in different stages of EAE in vivo, and their interaction in vitro were explored. We found that HMGB1 was dominant in pre-onset stage of EAE, while IL-33 was dominant in peak stage. Moreover, both blockade of extracellular HMGB1 in the central nervous system (CNS) and conditional knockout of HMGB1 in astrocytes decreased IL-33 release. HMGB1 promoted the release of IL-33, while IL-33 reduced the release of HMGB1 from primary astrocytes in vitro. Taken together, IL-33 and HMGB1 in the CNS jointly participate in the EAE progression and the inhibitory effect of IL-33 on HMGB1 may be involved in the self-limiting of EAE.

IL-33 Contributes to the Pathological Changes of Hair Follicles in Psoriasis: A Potential Target for Psoriatic Alopecia.

Purpose: IL-33 is constitutively expressed in skin tissues. Alopecia, a T cells-driven disorder of the hair follicles (HFs), is a common complication in the development of psoriasis. However, the role of IL-33 in psoriatic alopecia remains uncovered. Here, we investigated the roles of IL-33 in inducing pathological changes of hair follicles in psoriasis. Patients and Methods: Clinical samples and imiquimod (IMQ)-induced psoriatic mice samples were used to investigate the pathological changes and T-cell infiltration of HFs. By using immunohistochemistry staining, the distribution and expression alteration of IL-33 in HFs were determined. Next, by using IL-33 and ST2 knockout mice, we investigated the role of IL-33/ST2 axis in the pathological changes of HFs in psoriasis. Meanwhile, recombinant IL-33 protein was subcutaneous injected to confirm its effect. Finally, RNA sequencing was used to clarify the genes and signaling pathways that involved in this process. Differentially expressed genes were further verified by RT-PCR in cultured HFs in vitro. Results: We found that the pathological changes of HFs and T cells infiltration in imiquimod-induced psoriatic mice were similar to that in psoriasis patients. The IL-33 positive keratinocytes in the outer root sheath of HFs were increased in both psoriasis patients and psoriatic model mice compared with the controls. By using gene knockout mice, we found that the pathological changes and T cell infiltration were attenuated in IL-33-/- and ST2-/- psoriatic model mice. In addition, subcutaneous injection of recombinant IL-33 exacerbated the pathological changes of HFs and T cell infiltration. RNA sequencing and RT-RCR revealed that IL-33 upregulated the transcription of genes related to keratinocytes proliferation and T lymphocytes chemotaxis. Conclusion: Our study identifies that IL-33 promotes the pathological changes of HFs in psoriasis, which contributes to psoriatic alopecia. Inhibition of IL-33 may be a potential therapeutic approach for psoriatic alopecia.

Comparative transcriptomic analysis of early fruit development in eggplant (Solanum melongena L.) and functional characterization of SmOVATE5.

KEY MESSAGE: Comparative transcriptome analysis of early fruits of long and round eggplants, SmOVATE5, is involved in regulating fruit development. Eggplant, a solanaceous crop that has undergone a long period of domestication, is one of the most important vegetables worldwide. The shape of its fruit is an important agronomic trait and consumers in different regions have different preferences. However, a limited understanding of the molecular mechanisms regulating fruit development and shape has hindered eggplant breeding. In this study, we performed morphological observations and transcriptome analysis of long- and round-fruited eggplant genotypes to understand the molecular regulation during the early development of different fruit shapes. Morphological studies revealed that the two varieties already exhibited distinctly different phenotypes at the initial stage of fruit development before flowering, with rapid fruit enlargement beginning on the sixth day after flowering. Comparative transcriptome analysis identified phytohormone-related genes that were significantly upregulated on the day of flowering, indicating they may be involved in regulating the initial stages of fruit development. Notably, SmARF1 showed a sustained upregulation pattern in both varieties, suggesting that it may promote eggplant fruit growth. In addition, several differentially expressed genes of the SUN, YABBY, and OVATE families are potentially involved in the regulation of fruit development or fruit shape. We demonstrated that the SmOVATE5 gene has a negative regulatory function suppressing plant growth and development. In conclusion, this study provides new insights into the molecular regulatory mechanisms of eggplant fruit development, and the genes identified may provide valuable references for different fruit shape breeding programs.

Genetic recombination of Orientia tsutsugamushi strains from scrub typhus patients in Guangxi, Southwest China, and the analysis of clinical features.

Three Orientia tsutsugamushi genotypic groups belonging to two prototypes (Gilliam and Karp) were identified in scrub typhus patients from Guangxi, Southwest China. Fever, headache, pneumonia, fatigue, chill, and anorexia were the most common clinical signs. Frequent recombination was observed for their 47-kDa gene compared to 56-kDa and 16S genes. Furthermore, patients infected with the Gilliam prototype represent a much higher proportion of pneumonia (6/6, 100%) than those infected with the Karp prototype (4/8, 50%) (p-value = 0.040). This discrepancy is consistent with recent animal tests on rhesus and may indicate different virulence and tissue tropism between different O. tsutsugamushi prototypes.

Comparative genomic investigation of TCP gene family in eggplant (Solanum melongena L.) and expression analysis under divergent treatments.

KEY MESSAGE: The putative TCP genes and their responses to abiotic stress in eggplant were comprehensively characterized, and SmTCP genes (Smechr0202855.1 and Smechr0602431.1) may be involved in anthocyanin synthesis. The Teosinte branched1/Cycloidea/Proliferating cell factors (TCPs), a family of plant-specific transcription factors, plays paramount roles in a plethora of developmental and physiological processes. We here systematically characterized putative TCP genes and their response to abiotic stress in eggplant. In total, 30 SmTCP genes were categorized into two subfamilies based on the classical TCP conserved domains. Chromosomal location analysis illustrated the random distribution of putative SmTCP genes along 12 eggplant chromosomes. Cis-acting elements and miRNA target prediction suggested that versatile and complicated regulatory mechanisms that control SmTCPs gene expression, and 3 miRNAs (miR319a, miR319b, and miR319c-3p) might act as major regulators targeting SmTCPs. Tissue expression profiles indicated divergent spatiotemporal expression patterns of SmTCPs. qRT-PCR assays demonstrated different expression profiles of SmTCP under 4 °C, drought and ABA treatment conditions, suggesting the possible participation of SmTCP genes in multiple signaling pathways. Furthermore, RNA-seq data of eggplant anthocyanin synthesis coupled with yeast one-hybrid and dual-luciferase assays suggested the involvement of SmTCP genes (Smechr0202855.1 and Smechr0602431.1) in the mediation of anthocyanin synthesis. Our study will facilitate further investigation on the putative functional characterization of eggplant TCP genes and lay a solid foundation for the in-depth study of the involvement of SmTCP genes in the regulation of anthocyanin synthesis.

Fine mapping and characterization of the dominant gene SmFTSH10 conferring non-photosensitivity in eggplant (Solanum melongena L.).

KEY MESSAGE: A candidate non photosensitive gene S m F TS H10 was identified by combining bulked segregant analysis and map­based cloning. Low light condition often leads to poor coloration of photosensitive eggplant. Here, we obtained a non-photosensitive eggplant that can synthesize large amount of anthocyanin under shading conditions. Genetic analysis of F1 and F2 populations revealed that the phenotype of non-photosensitivity was regulated by a single dominant nuclear gene, herein temporarily designated SmFTSH10. Through Bulked segregant analysis (BSA), SNP haplotyping and fine genetic mapping delimited SmFTSH10 to a 290 kb region of eggplant chromosome 10 flanking by markers dCAPS21 and dCAPS32. Sequence analysis revealed C-base deletion in the fourth exon of SmFTSH10 resulted in premature termination of translation. The expression level of SmFTSH10 decreased significantly in anthocyanin-rich parts of mutant '145' compared with the wild-type 'LSHX'. Sequencing of 10 recombinants revealed that the C-base deletion in the 4th exon of SmFTSH10 was co-segregated with the non-photosensitive phenotype, and the sequencing analysis of the natural population of eggplant also showed that the Indel in SmFTSH10 had a high accuracy in the identification of the photosensitivity of eggplant. Light-responsive expression patterns analysis suggests that it has the same expression trend as the genes involved in eggplant anthocyanin biosynthesis, which supports SmFTSH10 as the most possible candidate gene of non-photosensitivity. These findings provide a new insight into understanding the molecular mechanisms of anthocyanin biosynthesis in non-photosensitive eggplant.

A light-responsive transcription factor SmMYB35 enhances anthocyanin biosynthesis in eggplant (Solanum melongena L.).

MAIN CONCLUSION: SmMYB35, a light-responsive R2R3-MYB transcription factor, positively regulates anthocyanin biosynthesis in eggplant by binding to the promoters of SmCHS, SmF3H, SmDFR, and SmANS and enhancing their activities. In addition, SmMYB35 interacts with SmTT8 and SmTTG1 to form a MBW complex, thereby enhancing anthocyanin biosynthesis. Eggplant is a vegetable rich in anthocyanins. SmMYB35, a light-responsive R2R3-MYB transcription factor, was isolated from eggplant and investigated for its biological functions. The results suggested that the expression of SmMYB35 was regulated by SmHY5 through directly binding to G-box in the promoter region, and the overexpression of SmMYB35 could increase the anthocyanin content in the stems and petals of the transgenic eggplants. SmMYB35 could also bind to the promoters of SmCHS, SmF3H, SmDFR, and SmANS and enhance their activities. In addition, SmMYB35 interacted with SmTT8 and SmTTG1 to form a MBW complex which enhanced anthocyanin biosynthesis. Taking together, we firstly verified that SmMYB35 promoted anthocyanin biosynthesis in plants. The results provide new insights into the regulatory effects of SmMYB35 on key anthocyanin biosynthetic genes and advance our understanding of the molecular mechanism of light-induced anthocyanin synthesis in eggplants.

Genome-wide characterization and expression analysis of AP2/ERF genes in eggplant (Solanum melongena L.).

The AP2/ERF (APETALA2/Ethylene Response Factor) transcription factor superfamily plays crucial roles in a slew of physiological processes, such as plant growth and development, stress response, and secondary metabolites biosynthesis. Eggplant, especially the one rich with anthocyanins, is an economically important horticultural vegetable cultivated worldwide. In this study, we comprehensively analyzed the putative AP2/ERF gene family members and their response to abiotic stress in eggplant. As per the phylogenetic, conserved domains, and motif analysis, 178 AP2/ERF genes in this study belonged to five subfamilies. Chromosomal distributions analysis elucidated stochastic distribution of 178 putative SmAP2/ERF genes across the twelve chromosomes of eggplant. Expression profiles of sixteen selected AP2/ERF genes response to low temperature, drought, salt, abscisic acid, and ethylene treatments were analyzed, which revealed the involvement of SmAP2/ERF genes in diverse signaling pathways. In addition, we integrated RNA-Seq data on anthocyanin biosynthesis in eggplant with yeast one-hybrid and dual-luciferase assays and identified involvement of the SmAP2/ERF genes (Smechr0902114.1 and Smechr1102075.1) in the regulation of anthocyanin biosynthesis. This study will enable further functional characterization of AP2/ERF genes in eggplant and extend the current understanding of the role played by AP2/ERF genes in anthocyanin biosynthesis regulation.

HMGB1 Translocation is Associated with Tumor-Associated Myeloid Cells and Involved in the Progression of Fibroblastic Sarcoma.

The morphological variability and genetic complexity of fibroblastic sarcoma makes its diagnosis and treatment a challenge. High-mobility group box 1 protein (HMGB1), which functions as a DNA chaperone and a prototypical damage-associated molecular pattern, plays a paradoxical role in cancer. However, the expression pattern and role of HMGB1 in fibroblastic sarcomas is ill defined. By immunostaining of 95 tissue microarray cores of fibroblastic sarcomas, HMGB1 was found to be expressed in most tumor tissues. Nuclear HMGB1 translocation to cytoplasm was observed both in tumor cells and vascular endothelial cells. A visible number of tumor-associated myeloid cells including CD68+ and CD163+ macrophages and CD33+ myeloid cells were also detected in most tumor tissues. HMGB1 translocation was not only associated with CD68, CD163, and CD33 density, but also with disease progression. These results imply that HMGB1, an important regulator of the tumor microenvironment, is associated with tumor-associated myeloid cells and involved in the progression of fibroblastic sarcomas; HMGB1 may serve as a promising prognostic biomarker and a potential therapeutic target for fibroblastic sarcoma.

Weighted gene co-expression network analysis identifies genes related to anthocyanin biosynthesis and functional verification of hub gene SmWRKY44.

Eggplant is rich in anthocyanins, which are thought to be highly beneficial for human health. There is no study on weighted gene co-expression network analysis (WGCNA) of anthocyanin biosynthesis in eggplant. Here, transcriptome data of 33 eggplant pericarp samples treated with light were used for WGCNA to identify significant modules. Total 13000 DEGs and 12 modules were identified, and the most significant module was associated with the secondary metabolites pathways. In addition, the hub gene SmWRKY44 with high connectivity was selected and its function was verified. The expression of SmWRKY44 showed a significant correlation with anthocyanin accumulation in the eggplant peels, leaves, and flowers. SmWRKY44-OE Arabidopsis significantly increased the accumulation of anthocyanins. Yeast two-hybrid and BiFC assays showed that SmWRKY44 could interact with SmMYB1, and it was also found that they could jointly promote the biosynthesis of anthocyanins in eggplant leaves through transient expression analysis. Our work provides a new direction for studying the molecular mechanism of light-induced anthocyanin biosynthesis in eggplant.

SmBICs Inhibit Anthocyanin Biosynthesis in Eggplant (Solanum melongena L.).

Eggplant is rich in anthocyanins, which are thought to be highly beneficial for human health. It has been reported that blue light inhibitors of cryptochromes (BICs) act as negative regulators in light signal transduction, but little is known about their role in anthocyanin biosynthesis. In this study, yeast one-hybrid analysis showed that SmBICs could bind to the promoter of SmCHS, indicating that they could directly participate in eggplant anthocyanin biosynthesis. In SmBICs-silenced eggplants, more anthocyanins were accumulated, while SmBIC1-overexpression (OE) and SmBIC2-OE Arabidopsis and eggplants synthesized less anthocyanin. Quantitative real-time polymerase chain reaction also revealed that the anthocyanin structural genes, which were downregulated in SmBIC1-OE and SmBIC2-OE lines, were upregulated in SmBICs-silenced eggplants. In addition, transcriptome analysis further confirmed that differentially expressed genes of SmBICs-OE plants were enriched mainly in the pathways related to anthocyanin biosynthesis and the key transcription factors and structural genes for anthocyanin biosynthesis, such as SmMYB1, SmTT8, SmHY5, SmCHS, SmCHI, SmDFR and SmANS, were suppressed significantly. Finally, bimolecular fluorescence complementation and blue-light-dependent degradation assay suggested that SmBICs interacted with photo-excited SmCRY2 to inhibit its photoreaction, thereby inhibiting the expression of genes related to anthocyanin biosynthesis and reducing anthocyanin accumulation. Collectively, our study suggests that SmBICs repress anthocyanin biosynthesis by inhibiting photoactivation of SmCRY2. This study provides a new working model for anthocyanin biosynthesis in eggplant.

HMGB1 Promotes the Release of Sonic Hedgehog From Astrocytes.

High mobility group box 1 protein (HMGB1) is known to be a trigger of inflammation in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). However, it may play a different role in some way. Here we investigated the effect of HMGB1 on promoting sonic hedgehog (shh) release from astrocytes as well as the possible signal pathway involved in it. Firstly, shh increased in astrocytes after administration of recombinant HMGB1 or decreased after HMGB1 was blocked when stimulated by homogenate of the onset stage of EAE. Moreover, the expression of HMGB1 receptors, toll-like receptor (TLR) 2 and receptor for advanced glycation end products (RAGE) increased after HMGB1 administration in primary astrocytes. However, the enhancing effect of HMGB1 on shh release from astrocytes was suppressed only after RAGE was knocked out or blocked. Mechanistically, HMGB1 functioned by activating RAGE-mediated JNK, p38, stat3 phosphorylation. Moreover, HMGB1 could induce shh release in EAE. Additionally, intracerebroventricular injection of recombinant shh protein on the onset stage of EAE alleviated the progress of disease and decreased demylination, compared to the mice with normal saline treatment. Overall, HMGB1 promoted the release of shh from astrocytes through signal pathway JNK, p38 and stat3 mediated by receptor RAGE, which may provide new insights of HMGB1 function in EAE.

Dual role of interleukin-33 in tumors. / ç™½ç»†èƒžä»‹ç´ -33在肿瘤中的双重作用.

Interleukin-33 (IL-33) is a new member of the IL-1 cytokine family which plays roles in the nucleus as a nuclear factor and is released by damaged or necrotic cells to act as a cytokine. It can be released via damaged or necrotic cells and functions as a cytokine. The released IL-33 activates the downstream NF-κB and MAPKs signaling pathways through the isomers of the specific receptor ST2 and the interleukin-1 receptor accessory protein (IL-1RAcP), resulting in danger signals and the activated multiple immune responses. IL-33 is abnormally expressed in various tumors and involves in tumorigenesis, development, and metastasis. Moreover, IL-33 can play both pro-tumor and anti-tumor roles in the same type of tumor.

Frequent amplification of HDAC genes and efficacy of HDAC inhibitor chidamide and PD-1 blockade combination in soft tissue sarcoma.

BACKGROUND: The advent of immune checkpoint therapy has been a tremendous advance in cancer treatment. However, the responses are still insufficient in patients with soft tissue sarcoma (STS). We aimed to identify rational combinations to increase the response to immune checkpoint therapy and improve survival. METHODS: Whole-exome sequencing (WES) was performed in 11 patients with liposarcoma. Somatic copy number alterations (SCNAs) were analyzed at the gene level to identify obvious amplification patterns in drug-target genes. The expression and prognostic value of class I histone deacetylases (HDACs) was evaluated in 49 patients with sarcoma in our center and confirmed in 263 sarcoma samples from The Tumor Cancer Genome Atlas (TCGA) database. Q-PCR, flow cytometry and RNA-seq were performed to determine the correlations between class I HDACs, chidamide and PD-L1 in vitro and in vivo. The efficacy of combining chidamide with PD-1 blockade was explored in an immunocompetent murine model and a small cohort of patients with advanced sarcoma. Western blot, ChIP assay and dual luciferase assessment were applied in the mechanistic study. RESULTS: The HDAC gene family was frequently amplified in STS. SCNAs in the HDAC gene family were extensively amplified in 8 of 11 (73%) patients with liposarcoma, based on a drug-target gene set, and we verified amplification in 76.65% (197/257) of cases by analyzing TCGA sarcoma cohort. Class I HDAC expression is associated with a poor prognosis for patients with STS, and its inhibition is responsible for promoting apoptosis and upregulating of programmed cell death ligand 1 (PD-L1). The HDAC class I inhibitor chidamide significantly increases PD-L1 expression, increased the infiltration of CD8+ T cells and reduced the number of MDSCs in the tumor microenvironment. The combination of chidamide with an anti-PD-1 antibody significantly promotes tumor regression and improves survival in a murine model. Moreover, chidamide combined with the anti-PD-1 antibody toripalimab is effective in patients with advanced and metastatic sarcoma, and the side effects are tolerable. Mechanistically, chidamide increases histone acetylation at the PD-L1 gene through the activation of the transcriptional factor STAT1. CONCLUSIONS: The combination of chidamide and anti-programmed cell death 1 (PD-1) therapy represents a potentially important strategy for STS.

Expression of Tomato UVR8 in Arabidopsis reveals conserved photoreceptor function.

UV RESISTANCE LOCUS 8 (UVR8) is a photoreceptor that regulates UV-B photomorphogenesis in plants. UV-B photon perception promotes UVR8 homodimer dissociation into monomer, which is reverted to homodimer post UV-B, forming a complete photocycle. UVR8 monomer interacts with CONSTITUTIVELY PHOTOMORPHOGENEIC 1 (COP1) to initiate UV-B signaling. The function and mechanism of Arabidopsis UVR8 (AtUVR8) are extensively investigated, however, little is known about UVR8 and its signaling mechanisms in other plant species. Tomato is a widely used model plant for horticulture research. In this report we tested whether an ortholog of AtUVR8 in Tomato (SIUVR8) can complement Arabidopsis uvr8 mutant and whether the above-mentioned key signaling mechanisms of UVR8 are conserved. Heterologous expressed SIUVR8 in an Arabidopsis uvr8 null mutant rescued the uvr8 mutant in the tested UV-B responses including hypocotyl elongation, UV-B target gene expression and anthocyanin accumulation, demonstrating that the SIUVR8 is a putative UV-B photoreceptor. Moreover, in response to UV-B, SIUVR8 forms a protein complex with Arabidopsis COP1 in plants, suggesting conserved signaling mechanism. SIUVR8 exhibits similar photocycle as AtUVR8 in plants, which highlights conserved photoreceptor activation and inactivation mechanisms.

An Autocrine Circuit of IL-33 in Keratinocytes Is Involved in the Progression of Psoriasis.

IL-33 is constitutively expressed in the skin. Psoriasis is a common skin inflammatory disease. The roles of IL-33 in psoriasis have not been well-elucidated. We identified that keratinocytes (KCs) are the predominant cells expressing IL-33 and its receptor, suppression of tumorigenicity 2, in the skin. KCs actively released IL-33 on psoriasis inflammatory stimuli and induced psoriasis-related cytokine, chemokine, and inflammatory molecules genes transcription in KCs in an autocrine manner. IL-33‒specific deficiency in KCs ameliorated imiquimod-induced psoriatic dermatitis. In addition, intradermal injection of recombinant IL-33 alone induced psoriasis-like dermatitis, which is attributed to the transcriptional upregulation of genes enriched in IL-17, TNF, and chemokine signaling pathway in KCs on recombinant IL-33 stimulation. Our data demonstrate that the autocrine circuit of IL-33 in KCs promotes the progression of psoriatic skin inflammation, and IL-33 is a potential therapeutic target for psoriasis.