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The Pin1 prolyl isomerase regulates phosphorylation signaling by controlling protein conformation after phosphorylation, and its upregulation promotes oncogenesis via acting on numerous oncogenic molecules. SUMOylation and deSUMOylation are dynamic mechanisms regulating a spectrum of protein activities. The SUMO proteases (SENP) remove SUMO conjugate from proteins, and their expression is deregulated in cancers. However, nothing is known about the role of SUMOylation in regulating Pin1 function. Here, we show that Pin1 is SUMOylated on Lys6 in the WW domain and on Lys63 in the PPIase domain. Pin1 SUMOylation inhibits its protein activity and oncogenic function. We further identify that SENP1 binds to and deSUMOylates Pin1. Importantly, either overexpression of SENP1 or disruption of Pin1 SUMOylation promotes the ability of Pin1 to induce centrosome amplification and cell transformation. Moreover, SENP1 also increases Pin1 protein stability in cell cultures, and Pin1 levels are positively correlated with SENP1 levels in human breast cancer specimens. These results not only uncover Pin1 SUMOylation on Lys6/63 as a novel mechanism to inhibit its activity and function but also identify a critical role for SENP1-mediated deSUMOylation in promoting Pin1 function during tumorigenesis. Cancer Res; 73(13); 3951–62. ©2013 AACR.

Supplementary Figures - PDF file 635K, Supplementary Figure S1. Pin1 is modified on Lys6 and Lys63 by SUMO1 in vitro and in vivo. Supplementary Figure S2. Pin1 Lys6 and Lys63 mutations increase its ability to active cyclin D1 promoter and stabilize cyclin D1 protein in cells. Supplementary Figure S3. SENP1 binds Pin1 and thereby positively regulates cyclin D1 activation

Supplementary Text- PDF file 135K, Text for the supplementary information

Most cases of hepatocellular carcinoma (HCC) arise with the fibrotic microenvironment where hepatic stellate cells (HSCs) and carcinoma-associated fibroblasts (CAFs) are critical components in HCC progression. Therefore, CAF normalization could be a feasible therapy for HCC. Galectin-1 (Gal-1), a β-galactoside-binding lectin, is critical for HSC activation and liver fibrosis. However, few studies has evaluated the pathological role of Gal-1 in HCC stroma and its role in hepatic CAF is unclear. Here we showed that Gal-1 mainly expressed in HCC stroma, but not cancer cells. High expression of Gal-1 is correlated with CAF markers and poor prognoses of HCC patients. In co-culture systems, targeting Gal-1 in CAFs or HSCs, using small hairpin (sh)RNAs or an therapeutic inhibitor (LLS30), downregulated plasminogen activator inhibitor-2 (PAI-2) production which suppressed cancer stem-like cell properties and invasion ability of HCC in a paracrine manner. The Gal-1-targeting effect was mediated by increased a disintegrin and metalloprotease 17 (ADAM17)-dependent TNF-receptor 1 (TNFR1) shedding/cleavage which inhibited the TNF-α → JNK → c-Jun/ATF2 signaling axis of pro-inflammatory gene transcription. Silencing Gal-1 in CAFs inhibited CAF-augmented HCC progression and reprogrammed the CAF-mediated inflammatory responses in a co-injection xenograft model. Taken together, the findings uncover a crucial role of Gal-1 in CAFs that orchestrates an inflammatory CSC niche supporting HCC progression and demonstrate that targeting Gal-1 could be a potential therapy for fibrosis-related HCC.

Medulloblastoma (MB) was classified into four molecular subgroups: WNT, SHH, group 3, and group 4. In 2017, 12 subtypes within 4 subgroups and 8 subtypes within non-WNT/non-SHH subgroups according to the differences of clinical features and biology were announced. In this study, we aimed to identify the heterogeneity of molecular features for discovering subtype specific factors linked to diagnosis and prognosis. We retrieved 70 MBs in children to perform RNA sequencing and a DNA methylation array in Taiwan. Integrated with clinical annotations, we achieved classification of 12 subtypes of pediatric MBs in our cohort series with reference to the other reported series. We analyzed the correlation of cell type enrichment in SHH MBs and found that M2 macrophages were enriched in SHH β, which related to good outcomes of SHH MBs. The high infiltration of M2 macrophages may be an indicator of a favorable prognosis and therapeutic target for SHH MBs. Furthermore, C11orf95-RELA fusion was observed to be associated with recurrence and a poor prognosis. These results will contribute to the establishment of a molecular diagnosis linked to prognostic indicators of relevance and help to promote molecular-based risk stratified treatment for MBs in children.

The molecular mechanisms contributing to the regulation of Th17-mediated inflammation remain underexplored. We here report a SUMO-specific protease (SENP)2-mediated pathway induced in pathogenic Th17 cells that restricts the pathogenesis of inflammatory colitis. SENP2 regulates the maturation of small ubiquitin-like modifiers (SUMO) and recycles SUMO from the substrate proteins. We found higher levels of SENP2 in pathogenic Th17 cells. By deleting Senp2 during T-cell development or in mature Th17 cells in mice, we demonstrated that the lack of Senp2 exacerbates the severity of experimental colitis, which is linked to elevated levels of GM-CSF+IL-17A+ pathogenic Th17 cells and more severe dysbiosis of the intestinal microbiome. Adoptive transfer experiments demonstrated the cell-autonomous effect of Senp2 in restraining Th17 differentiation and colitis. The enzymatic activity of SENP2 is important for deSUMOylation of Smad4, which prevents Smad4 nuclear entry and Rorc expression. Our findings reveal a SENP2-mediated regulatory axis in the pathogenicity of Th17 cells.

Around the globe, surges of bacterial diseases are causing serious health threats and related concerns. Recently, the metal ion release and photodynamic and photothermal effects of nanomaterials were demonstrated to have substantial efficiency in eliminating resistance and surges of bacteria. Nanomaterials with characteristics such as surface plasmonic resonance, photocatalysis, structural complexities, and optical features have been utilized to control metal ion release, generate reactive oxygen species, and produce heat for antibacterial applications. The superior characteristics of nanomaterials present an opportunity to explore and enhance their antibacterial activities leading to clinical applications. In this review, we comprehensively list three different antibacterial mechanisms of metal ion release, photodynamic therapy, and photothermal therapy based on nanomaterials. These three different antibacterial mechanisms are divided into their respective subgroups in accordance with recent achievements, showcasing prospective challenges and opportunities in clinical, environmental, and related fields., Graphical Abstract

Upregulation of death-domain-associated protein (Daxx) is strongly associated with diverse cancer types. Among these, the clinicopathological significance and molecular mechanisms of Daxx overexpression in colorectal cancer (CRC) remain unknown. Here, we showed that Daxx expression was increased in both clinical CRC samples and CRC cell lines. Daxx knockdown significantly reduced proliferation activity in CRC cells and tumor growth in a xenograft model. Further studies revealed that Daxx expression could be attenuated by either treatment with the PIK3CA inhibitor PIK-75 or PIK3CA depletion in CRC cells. Conversely, expression of PIK3CA constitutively active mutants could increase Daxx expression. These data suggest that PIK3CA positively regulates Daxx expression. Consistently, the expression levels of PIK3CA and Daxx were positively correlated in sporadic CRC samples. Interestingly, Daxx knockdown or overexpression yielded decreased or increased levels of PIK3CA, respectively, in CRC cells. We further demonstrated that Daxx activates the promoter activity and expression of PIK3CA. Altogether, our results identify a mechanistic pathway of Daxx overexpression in CRC and suggest a reciprocal regulation between Daxx and PIK3CA for CRC cell growth.

Arginine synthesis deficiency due to the suppressed expression of ASS1 (argininosuccinate synthetase 1) represents one of the most frequently occurring metabolic defects of tumor cells. Arginine-deprivation therapy has gained increasing attention in recent years. One challenge of ADI-PEG20 (pegylated ADI) therapy is the development of drug resistance caused by restoration of ASS1 expression and other factors. The goal of this work is to identify novel factors conferring therapy resistance. Methods: Multiple, independently derived ADI-resistant clones including derivatives of breast (MDA-MB-231 and BT-549) and prostate (PC3, CWR22Rv1, and DU145) cancer cells were developed. RNA-seq and RT-PCR were used to identify genes upregulated in the resistant clones. Unbiased genome-wide CRISPR/Cas9 knockout screening was used to identify genes whose absence confers sensitivity to these cells. shRNA and CRISPR/Cas9 knockout as well as overexpression approaches were used to validate the functions of the resistant genes both in vitro and in xenograft models. The signal pathways were verified by western blotting and cytokine release. Results: Based on unbiased CRISPR/Cas9 knockout screening and RNA-seq analyses of independently derived ADI-resistant (ADIR) clones, aberrant activation of the TREM1/CCL2 axis in addition to ASS1 expression was consistently identified as the resistant factors. Unlike ADIR, MDA-MB-231 overexpressing ASS1 cells achieved only moderate ADI resistance both in vitro and in vivo, and overexpression of ASS1 alone does not activate the TREM1/CCL2 axis. These data suggested that upregulation of TREM1 is an independent factor in the development of strong resistance, which is accompanied by activation of the AKT/mTOR/STAT3/CCL2 pathway and contributes to cell survival and overcoming the tumor suppressive effects of ASS1 overexpression. Importantly, knockdown of TREM1 or CCL2 significantly sensitized ADIR toward ADI. Similar results were obtained in BT-549 breast cancer cell line as well as castration-resistant prostate cancer cells. The present study sheds light on the detailed mechanisms of resistance to arginine-deprivation therapy and uncovers novel targets to overcome resistance. Conclusion: We uncovered TREM1/CCL2 activation, in addition to restored ASS1 expression, as a key pathway involved in full ADI-resistance in breast and prostate cancer models.

Tourism has become a leading modern service industry. Unfortunately, there are few studies focusing on consumers' perception and acceptance as well as the impact of service quality on tourism consulting. Besides, there has been no investigation of this industry service using two-dimensional gaps, along with importance and performance analysis along with quality function. This study applied the PZB service quality gap model to extend SERVQUAL to design a questionnaire. Through service quality gap analysis and IPA model presentation, it was found there are five projects in the fourth aspect, and priority should be given to the improving "travel planning", "agent's responsibility", "agent's executive ability", "unique style" and "professional travel host". In the hierarchical analysis, the weights of "agent's responsibility" and "unique style" were 0.34 and 0.3, respectively. In the quality house section, interviewers explored the correlation between quality technology execution projects and customers' needs, and obtained absolute weights. They found that "skill knowledge" and "creative idea" were above 4.0, while the "original knowledge" had the lowest absolute weight. Finally, this study provides implementation methods for assessing resource utilization and improving service quality, to enhance the competitiveness of tourism agent entrepreneurs.

Acute hepatopancreatic necrosis disease (AHPND) in shrimp is caused by

Medulloblastoma is the most common embryonic brain tumor in children. We investigated a cohort of 52 Asian medulloblastoma patients aged between 0 and 19 years old, who received surgical resections and post-resection treatments in the Taipei Medical University Hospital and the Taipei Veterans General Hospital. Genome-wide RNA sequencing was performed on fresh-frozen surgical tissues. These data were analyzed using the CIBERSORTx immune deconvolution software. Two external clinical and molecular datasets from United States (n = 62) and Canada (n = 763) were used to evaluate the transferability of the gene-signature scores across ethnic populations. The abundance of 13 genes, including DLL1, are significantly associated with overall survival (All Cox regression P

Retinoblastoma (Rb) is a malignant tumor of the developing retina that affects children before the age of five years in association with inherited or early germline mutations of the RB1 gene. The genetic predisposition is also a driver for other primary malignancies, which have become the leading cause of death in retinoblastoma survivors. Other malignancies can occur as a consequence of radiotherapy. We describe a patient with retinoblastoma in which we detected a novel RB1 c.2548C &gt, T, p.(Gln850Ter) and a synchronous MET c.3029C &gt, T, p.(Thr1010Ile) mutation as well. After presenting with bilateral retinoblastoma, the patient developed at least four different manifestations of two independent osteosarcomas. Our goal was to identify all germline and somatic genetic alterations in available tissue samples from different time periods and to reconstruct their clonal relations using next generation sequencing (NGS). We also used structural and functional prediction of the mutant RB and MET proteins to find interactions between the defected proteins with potential causative role in the development of this unique form of retinoblastoma. Both histopathology and NGS findings supported the independent nature of a chondroblastic osteosarcoma of the irradiated facial bone followed by an osteoblastic sarcoma of the leg (tibia).

Plasmonic nanomaterials have been intensively explored for applications in biomedical detection and therapy for human sustainability. Herein, plasmonic gold nanoisland (NI) film (AuNIF) was fabricated onto a glass substrate by a facile seed-mediated growth approach. The structure of the tortuous gold NIs of the AuNIF was demonstrated by scanning electron microscopy and energy-dispersive X-ray spectroscopy. Based on the ultraviolet-visible spectrum, the AuNIF revealed plasmonic absorption with maximum intensity at 624 nm. With the change to the surface topography created by the NIs, the capture efficiency of Escherichia coli (E. coli) by the AuNIF was significantly increased compared to that of the glass substrate. The AuNIF was applied as a surface-enhanced Raman scattering (SERS) substrate to enhance the Raman signal of E. coli. Moreover, the plasmonic AuNIF exhibited a superior photothermal effect under irradiation with simulated AM1.5 sunlight. For photothermal therapy, the AuNIF also displayed outstanding efficiency in the photothermal killing of E. coli. Using a combination of SERS detection and photothermal therapy, the AuNIF could be a promising platform for bacterial theranostics.

Predictive metabolic biomarkers for the recurrent luminal breast cancer (BC) with hormone receptor (HR)-positive and human epidermal growth factor receptor type 2 (HER2)-negative are lacking. High levels of O-GlcNAcylation (O-GlcNAc) and pyruvate kinase isoenzyme M2 (PKM2) are associated with malignancy in BC, however, the association with the recurrence risk remains unclear. We first conduct survival analysis by using the METABRIC dataset to assess the correlation of PKM2 expression with BC clinical outcomes. Next, patients with HR+/HER2- luminal BC were recruited for PKM2/O-GlcNAc testing. Logistic regression and receiver operating characteristic curve analysis were performed to evaluate the 10-year DFS predicted outcome. Survival analysis of the METABRIC dataset revealed that high expression of PKM2 was significantly associated with worse overall survival in luminal BC. The high expression of O-GlcNAc or PKM2 was a significant independent marker for poor 10-year DFS using immunohistochemical analysis. The PKM2 or O-GlcNAc status was a significant predictor of DFS, with the combination of PKM2–O-GlcNAc status and T stage greatly enhancing the predictive outcome potential. In summary, O-GlcNAc, PKM2, and T stage serve as good prognostic discriminators in HR+/HER2− luminal BC.

The technology in Taiwan’s panel industry is changing fast. However, after the financial tsunami and the increased price for raw materials, enterprises’ abilities to select suppliers and purchase have great influences on plan implementation. Therefore, with the prevailing issues of supply chain management, how to evaluate and select appropriate suppliers has become a very important topic for enterprises. Depending on customers’ needs, the requirements for suppliers vary from industry to industry. On this basis, this study summarizes and analyzes the literature on supplier selection to develop the supplier selection criteria, constructs the hierarchical network architecture by an expert interview, and proposes a complete supplier evaluation model by the fuzzy theory and network analysis. This study shows that the order of the important dimensions is as follows: performance evaluation, customer service, technology and competitiveness, cost benefits, and architecture, and the most important criterion is quality. Finally, the material suppliers of backlight modules in the panel industry are taken as the examples and ranked by VIKOR, based on their merits and demerits, to help related industries to understand their current advantages and disadvantages according to the selection results obtained by the fuzzy analytical network process and improve the gap between their actual situations and enterprises’ expectations and thus enhance their competitiveness.

Additional file 3. Supplementary methods.

Additional file 2: Fig. S1. Differential 4-hydroxy-2-nonenal (HNE)-modified peptide adducts were re-analyzed through PEAKS 7 using previous MS/MS spectra (ProteomeXchange: PXD004546). Acquired MS/MS spectra were obtained through pooled concanavalin (Con) A-captured serum proteins (nine rheumatoid arthritis (RA) and nine healthy control (HC) pooled samples), 1-D SDS-PAGE, in-gel digestion, and nano-LC-MS/MS (A). HNE reacts with amino acid residues of proteins to form HNE-protein adducts by Michael addition and Schiff base adducts, respectively (B). Representative MS/MS spectrum of the 1211-SHTLRTTCWDGKLEYPTCAK-1230 peptide sequence and the modified peptide bearing an HNE modification at the K1230 residue in RA patients (C). A representative MS/MS spectrum of the peptide sequence 78-AVGDKLPECEADDGCPKPPEIAHGYVEH SVR-108 and the modified peptide bearing the HNE modification at the C92 residue in RA patients (D). The MS/MS spectrum 2-TVAAPSVFIFPPSDEQLK-19 and the modified peptide bearing the HNE modification at the A5 residue in RA patients (E, upper panel); 2-TVAAPSVFIFPPSDEQLK-19 and the modified peptide bearing the HNE modification at the A4 residues in RA patients and HCs (E, bottom panel). Representative MS/MS spectrum of 328-TFGSGEADCGLRPLFEKK-345 and the modified peptide bearing the HNE modification at the K344 residue in RA (F). The MS/MS spectrum 284-HRTGDEITYQCRNGFYPATRGNTAK-308 and the modified peptide bearing the HNE modification at the K308 residue in HCs (G). A representative MS/MS spectrum of the peptide sequence 162-ILGGHLDAK-170 and the modified peptide bearing the HNE modification at the A169 residues in HCs (H). Representative MS/MS spectrum of 83-VYACEVTHQGLSSPVTKSFNR-103 and the modified peptide bearing the HNE modification at the Q91 residue in HCs (I). The MS/MS spectrum 328-TFGSGEADCGLRPLFEK-344 and the modified peptide bearing the HNE modification at the C336 and L341 residues in HCs (J).

Additional file 1: Table S1. Demographic and clinical characteristics of individual subjects contributing to serum for healthy controls (HCs), and patients with osteoarthritis (OA) and rheumatoid arthritis (RA).

Additional file 4: Fig. S2. Comparison of receiver operating characteristics (ROC) curves from unselected features and selected features in (A) decision tree, (B) random forest classifier, and (C) support vector machine classifier.

Atypical teratoid rhabdoid tumors (ATRTs) are among the most malignant brain tumors in early childhood and remain incurable. Myc-ATRT is driven by the Myc oncogene, which directly controls the intracellular protein synthesis rate. Proteasome inhibitor bortezomib (BTZ) was approved by the Food and Drug Administration as a primary treatment for multiple myeloma. This study aimed to determine whether the upregulation of protein synthesis and proteasome degradation in Myc-ATRTs increases tumor cell sensitivity to BTZ. We performed differential gene expression and gene set enrichment analysis on matched primary and recurrent patient-derived xenograft (PDX) samples from an infant with ATRT. Concomitant upregulation of the Myc pathway, protein synthesis and proteasome degradation were identified in recurrent ATRTs. Additionally, we found the proteasome-encoding genes were highly expressed in ATRTs compared with in normal brain tissues, correlated with the malignancy of tumor cells and were essential for tumor cell survival. BTZ inhibited proliferation and induced apoptosis through the accumulation of p53 in three human Myc-ATRT cell lines (PDX-derived tumor cell line Re1-P6, BT-12 and CHLA-266). Furthermore, BTZ inhibited tumor growth and prolonged survival in Myc-ATRT orthotopic xenograft mice. Our findings suggest that BTZ may be a promising targeted therapy for Myc-ATRTs.

The beam formation can be treated as the diffraction pattern. A 1-D light detection and ranging beam steering could be derived through a phase shifter array using Rayleigh&ndash, Sommerfeld Diffraction, which is then utilized to demonstrate grating lobe-free beam steering from the optical phase array emitter with half-wavelength pitches. The half-wavelength pitch cannot demonstrate beam formation without any evanescent coupling blocking between emitters. Here, two index-mismatched silicon wires in the emitter array are proposed by the optical phase compensation through waveguide width adjustment, to avoid the complex and addressable thermal control on the phase shifters. Moreover, the same output optical waveguide mode needs to be further considered to demonstrate the grating lobe-free beam steering. In order to get the adiabatic connection between two different pitches between the phase shifter and emitter, an optical path equalization will also be applied.

We design and compare the splitting ratio wavelength flatness of directional coupler (DC), Mach-Zehnder directional coupler (MZDC), and tandem MZDC. All coupler responses are analyzed, and tandem MZDC performance is the best in the wavelength insensitivity compared with the other two. An MZDC with any coupling ratio could be utilized to match the maximum flatness in a 40-nm wavelength range. To extend a broad flatness range, the tandem MZDC is proposed and still follows the Mach Zehnder structure taking two MZDCs as couplers connected through a decoupled region. Unlike DC, MZDC with the flat wavelength response has a non-linear output phase. Hence, using two wavelength-insensitive MZDCs as the coupling function in a tandem MZDC could demonstrate a more extensive decoupled phase term to maximize the flat wavelength response. The tandem MZDC theoretically demonstrates the splitting ratio with 100-nm flatness in the wavelength range from 1250 nm to 1350 nm. Finally, a point spread function through the tandem MZDC shows a 24-dB signal-to-noise ratio improvement in optical coherence tomography applications.

P-selectin overexpressed on activated endothelial cells and platelets is a new target for treatment of cancers and cardiovascular diseases such as atherosclerosis and thrombosis. In this study, depolymerized low molecular weight fucoidan (LMWF8775) and a thermolysin-hydrolyzed protamine peptide (TPP1880) were prepared. TPP1880 and LMWF8775 were able to form self-assembled complex nanoparticles (CNPs). The formation of TPP1880/LMWF8775 CNPs was characterized by Fourier-transform infrared spectra, circular dichroism spectra and isothermal titration calorimetry. The CNPs selectively targeted PMA-stimulated, inflamed endothelial cells (HUVECs) with high expression of P-selectin. Gd-DTPA MRI contrast agent was successfully loaded in the CNPs with better T1 relaxivity and selectively accumulated in the activated HUVECs with increased MRI intensity and reduced cytotoxicity as compared to free Gd-DTPA. Our results suggest that the TPP1880/LMWF8775 CNPs may have potential in future for early diagnosis of cardiovascular diseases and cancers in which the endothelium is inflamed or activated.

This paper used the fuzzy analytic hierarchy process (FAHP) model to investigate how family and individual affect the success of entrepreneurship. The results of statistical analysis show that indi...

Smad4, a common-mediator of Smads, plays a central role in forming complexes with receptor-phosphorylated Smads, and then transduces transforming growth factor (TGF)-β signals into the nuclei. Although many cellular factors are involved in TGF-β induced epithelial-to-mesenchymal transition (EMT) and cell migration, very little is known with the mechanism of Smad4 regulation on pro-oncogenes response by TGF-β. Herein, we demonstrate the interaction of Sentrin-specific protease 2 (SENP2) with Smad4 through SENP2 residue 363~400. The same segment is also important for desumoylation of Smad4, and able to relieve sumoylation-mediated TGF-β repression. The SENP2363~400 segment is critical for TGF-β-induced cell migration, which is correlated with SENP2363~400 deletion mutant failed to increase matrix metalloproteinase (MMP)-9 and EMT marker gene expression. Moreover, our results suggest that the interaction and desumoylation between SENP2 and Smad4 promote cell migration in triple-negative breast cancer cells. Altogether, our data show how SENP2 regulates its substrate for desumoylation, and also the role of SENP2 in TGF-β induced cancer cell migration.

The use of blood plasma biomarkers in gastric cancer (GC) management is limited due to a lack of reliable biomarkers. An LC‐MS/MS assay and a bioinformatic analysis were performed to identify blood plasma biomarkers in a GC discovery cohort. The data obtained were verified and validated by western blotting and an ELISA in an independent study cohort. A label‐free quantification analysis of the MS data using PEAKS7 software found that four plasma proteins of apolipoprotein C‐1, gelsolin, sex hormone‐binding globulin (SHBG), and complement component C4‐A were significantly overexpressed in GC patients. A western blot assay of these plasma proteins showed that only SHBG was consistently overexpressed in the patient group. ELISA measurement of SHBG blood plasma levels confirmed that the patient group had significantly higher SHBG levels than the control group. SHBG levels in the patient group remained significantly higher after being stratified by gender, age, and disease stage. These findings show that LC‐MS/MS is powerful and highly sensitive for plasma biomarker discovery, and SHBG could be a potential plasma biomarker for GC management.

Concomitant expressions of glycan-binding proteins and their bound glycans regulate many pathophysiologic processes, but this issue has not been addressed in liver fibrosis. Activation of hepatic stellate cells (HSCs) is a rate-limiting step in liver fibrosis and is an important target for liver fibrosis therapy. We previously reported that galectin (Gal)-1, a β-galactoside-binding protein, regulates myofibroblast homeostasis in oral carcinoma and wound healing, but the role of Gal-1 in HSC migration and activation is unclear. Herein, we report that Gal-1 and its bound glycans were highly expressed in fibrotic livers and activated HSCs. The cell-surface glycome of activated HSCs facilitated Gal-1 binding, which upon recognition of the N-glycans on neuropilin (NRP)-1, activated platelet-derived growth factor (PDGF)- and transforming growth factor (TGF)-β-like signals to promote HSC migration and activation. In addition, blocking endogenous Gal-1 expression suppressed PDGF- and TGF-β1-induced signaling, migration, and gene expression in HSCs. Methionine and choline-deficient diet (MCD)-induced collagen deposition and HSC activation were attenuated in Gal-1-null mice compared to wild-type mice. In summary, we concluded that glycosylation-dependent Gal-1/NRP-1 interactions activate TGF-β and PDGF-like signaling to promote the migration and activation of HSCs. Therefore, targeting Gal-1/NRP-1 interactions could be developed into liver fibrosis therapy.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Billions of people have obesity-related metabolic syndromes such as diabetes and hyperlipidemia. Promoting the browning of white adipose tissue has been suggested as a potential strategy, but a drug still needs to be identified. Here, genetic deletion of activating transcription factor 3 (ATF3−/−) in mice under a high-fat diet (HFD) resulted in obesity and insulin resistance, which was abrogated by virus-mediated ATF3 restoration. ST32da, a synthetic ATF3 inducer isolated from Salvia miltiorrhiza, promoted ATF3 expression to downregulate adipokine genes and induce adipocyte browning by suppressing the carbohydrate-responsive element-binding protein–stearoyl-CoA desaturase-1 axis. Furthermore, ST32da increased white adipose tissue browning and reduced lipogenesis in HFD-induced obese mice. The anti-obesity efficacy of oral ST32da administration was similar to that of the clinical drug orlistat. Our study identified the ATF3 inducer ST32da as a promising therapeutic drug for treating diet-induced obesity and related metabolic disorders., Ching-Feng Cheng et al. find that expression of the transcription factor ATF3 in mice provides protection from obesity and insulin resistance under a high-fat diet. They show that expression of ATF3 can be induced by ST32da, a compound derived from the Chinese sage plant, Salvia miltiorrhiza.

Background The Slug-E-cadherin axis plays a critical role in non-small-cell lung cancers (NSCLCs) where aberrant upregulation of Slug promotes cancer metastasis. Now, the post-translational modifications of Slug and their regulation mechanisms still remain unclear in lung cancer. Hence, exploring the protein linkage map of Slug is of great interest for investigating the scenario of how Slug protein is regulated in lung cancer metastasis. Methods The Slug associated proteins, Ubc9 and SUMO-1, were identified using yeast two-hybrid screening; and in vitro SUMOylation assays combined with immunoprecipitation and immunoblotting were performed to explore the detail events and regulations of Slug SUMOylation. The functional effects of SUMOylation on Slug proteins were examined by EMSA, reporter assay, ChIP assay, RT-PCR, migration and invasion assays in vitro, tail vein metastatic analysis in vivo, and also evaluated the association with clinical outcome of NSCLC patients. Results Slug protein could interact with Ubc9 and SUMO-1 and be SUMOylated in cells. Amino acids 130–212 and 33–129 of Slug are responsible for its binding to Ubc9 and protein inhibitor of activated STAT (PIAS)y, respectively. SUMOylation could enhance the transcriptional repression activity of Slug via recruiting more HDAC1, resulting in reduced expression of downstream Slug target genes and enhanced lung cancer metastasis. In addition, hypoxia could increase Slug SUMOylation through attenuating the interactions of Slug with SENP1 and SENP2. Finally, high expression Slug and Ubc9 levels were associated with poor overall survival among NSCLC patients. Conclusions Ubc9/PIASy-mediated Slug SUMOylation and subsequent HDAC1 recruitment may play a crucial role in hypoxia-induced lung cancer progression, and these processes may serve as therapeutic targets for NSCLC. Electronic supplementary material The online version of this article (10.1186/s13046-018-0996-8) contains supplementary material, which is available to authorized users.