A secreted glycoprotein YKL-40 also named chitinase-3-like-1 is normally expressed by multiple cell types such as macrophages, chondrocytes, and vascular smooth muscle cells. However, a prominently ...high level of YKL-40 was found in a wide spectrum of human diseases including cancers and chronic inflammatory diseases where it was strongly expressed by cancerous cells and infiltrating macrophages. Here, we summarized recent important findings of YKL-40 derived from cancerous cells and smooth muscle cells during tumor angiogenesis and development. YKL-40 is a potent angiogenic factor capable of stimulating tumor vascularization mediated by endothelial cells and maintaining vascular integrity supported by smooth muscle cells. In addition, YKL-40 induces FAK-MAPK signaling and up-regulates VEGF receptor 2 in endothelial cells; but a neutralizing antibody (mAY) against YKL-40 inhibits its angiogenic activity. While YKL-40 is essential for angiogenesis, little is known about its functional role in tumor-associated macrophage (TAM)-mediated tumor development. Therefore, significant efforts are urgently needed to identify pathophysiological function of YKL-40 in the dynamic interaction between tumor cells and TAMs in the tumor microenvironment, which may offer substantial mechanistic insights into tumor angiogenesis and metastasis, and also point to a therapeutic target for treatment of cancers and other diseases.
The use of antagonistic microorganisms and their volatile organic compounds (VOCs) to control plant fungal pathogens is an eco-friendly and promising substitute for chemical fungicides. In this work, ...endophytic bacterium ETR-B22, isolated from the root of
Gagnep., was found to exhibit strong antagonistic activity against 12 fungal pathogens found in agriculture. Strain ETR-B22 was identified as
based on 16S rRNA and
sequences. We evaluated the antifungal activity of VOCs emitted by ETR-B22. The VOCs from strain ETR-B22 also showed broad-spectrum antifungal activity against 12 fungal pathogens. The composition of the volatile profiles was analyzed based on headspace solid phase microextraction (HS-SPME) gas chromatography coupled to mass spectrometry (GC-MS). Different extraction strategies for the SPME process significantly affected the extraction efficiency of the VOCs. Thirty-two different VOCs were identified. Among the VOC of ETR-B22, dimethyl trisulfide, indole, methyl anthranilate, methyl salicylate, methyl benzoate, benzyl propionate, benzyl acetate, 3,5-di-tert-butylphenol, allyl benzyl ether and nonanoic acid showed broad-spectrum antifungal activity, and are key inhibitory compounds produced by strain ETR-B22 against various fungal pathogens. Our results suggest that the endophytic strain ETR-B22 and its VOCs have high potential for use as biological controls of plant fungal pathogens.
Deposition of H2A.Z in chromatin is known to be mediated by a conserved SWR1 chromatin‐remodeling complex in eukaryotes. However, little is known about whether and how the SWR1 complex cooperates ...with other chromatin regulators. Using immunoprecipitation followed by mass spectrometry, we found all known components of the Arabidopsis thaliana SWR1 complex and additionally identified the following three classes of previously uncharacterized plant‐specific SWR1 components: MBD9, a methyl‐CpG‐binding domain‐containing protein; CHR11 and CHR17 (CHR11/17), ISWI chromatin remodelers responsible for nucleosome sliding; and TRA1a and TRA1b, accessory subunits of the conserved NuA4 histone acetyltransferase complex. MBD9 directly interacts with CHR11/17 and the SWR1 catalytic subunit PIE1, and is responsible for the association of CHR11/17 with the SWR1 complex. MBD9, TRA1a, and TRA1b function as canonical components of the SWR1 complex to mediate H2A.Z deposition. CHR11/17 are not only responsible for nucleosome sliding but also involved in H2A.Z deposition. These results indicate that the association of the SWR1 complex with CHR11/17 may facilitate the coupling of H2A.Z deposition with nucleosome sliding, thereby co‐regulating gene expression, development, and flowering time.
Synopsis
Cooperation of the SWR1 remodeler, responsible for histone H2A.Z deposition, with other chromatin regulators is incompletely understood. Here, proteomic identification of plant SWR1 complex components reveals its coupling to nucleosome sliding activities.
Characterization of the Arabidopsis SWR1 complex identifies CHR11, CHR17, TRA1A, TRA1B, and MBD9 as plant‐specific components.
ISWI remodeler catalytic subunits CHR11 and CHR17 associate with the SWR1 complex to couple nucleosome sliding and H2A.Z deposition.
MBD9 bridges CHR11 and CHR17 to the core SWR1 complex.
Together with other SWR1 components, MBD9 and CHR11/17 co‐regulate gene expression, development, and flowering time.
Proteomic analysis of Arabidopsis thaliana SWR1 complex components implicates nucleosome‐sliding ISWI remodeler subunits CHR11 and CHR17 also in histone deposition.
Background and Purpose
Dihydrotanshinone I (DHI), a lipophilic component of traditional Chinese medicine Salvia miltiorrhiza Bunge, has various therapeutic effects. We investigated the anti‐fibrotic ...effect of DHI and its underlying mechanisms in vitro and in vivo.
Experimental Approach
Rats subjected to bile duct ligation (BDL) were treated with DHI (25 mg·kg−1·day−1, i.p.) for 14 days. Serum biochemical and liver tissue morphological analyses were performed. The human hepatic stellate cell line LX‐2 served as a liver fibrosis model in vitro. Liver fibrogenic genes, yes‐associated protein (YAP) downstream genes and autophagy markers were examined using western blot and real‐time PCR analyses. Similar analyses were done in rat primary hepatic stellate cells (pHSCs). Autophagy flux was assessed by immunofluorescence.
Key Results
In BDL rats, DHI administration attenuated liver necrosis, bile duct proliferation and collagen accumulation and reduced the expression of genes associated with fibrogenesis, including Tgfb1, Mmp‐2, Acta2 and Col1a1. DHI (1, 5, 10 μmol·L−1) time‐ and dose‐dependently suppressed the protein level of COL1A1, TGFβ1 and α‐SMA in LX‐2 cells and rat pHSCs. Furthermore, DHI blocked the nuclear translocation of YAP, which inhibited the YAP/TEAD2 interaction and its downstream fibrogenic genes, connective tissue growth factor, SOX4 and survivin. This stimulated autophagic flux and accelerated the degradation of liver collagen.
Conclusions and Implications
DHI exerts anti‐fibrotic effects in BDL rats, LX‐2 cells and rat pHSCs by inhibiting the YAP and TEAD2 complex and stimulating autophagy. These findings indicate that DHI may be a potential therapeutic for the treatment of liver fibrosis.
Primary ovarian insufficiency (POI) is a rare gynecological condition. This disease causes menstrual disturbances, infertility, and various health problems. Historically, hormone replacement therapy ...is the first-line treatment for this disorder. Women diagnosed with POI are left with limited therapeutic options. In order to remedy this situation, a new generation of therapeutic approaches, such as in vitro activation, mitochondrial activation technique, stem cell and exosomes therapy, biomaterials strategies, and platelet-rich plasma intra-ovarian infusion, is being developed. However, these emerging therapies are yet in the experimental stage and require precise design components to accelerate their conversion into clinical treatments. Thus, each medical practitioner bears responsibility for selecting suitable therapies for individual patients. In this article, we provide a timely analysis of the therapeutic strategies that are available for POI patients and discuss the prospects of POI therapy.
Objective
Neonatal status epilepticus (SE) is a life‐threatening medical emergency. Unfortunately, up to 50% of neonates with SE are resistant to current antiseizure drugs, highlighting the need for ...better treatments. This study aims to explore a novel metabolic approach as a potential alternative treatment to control neonatal SE, using the glycolytic inhibitor 2‐deoxyglucose (2‐DG).
Methods
SE was induced by pilocarpine (300 mg/kg, intraperitoneally ip) in neonatal Sprague Dawley rats (postnatal day 10 P10‐P17) and was monitored by video‐electroencephalography (V‐EEG). After 30 minutes of SE, 2‐DG or one of two conventional antiseizure drugs with different mechanisms of action, phenobarbital or levetiracetam, was administrated ip, and V‐EEG recording was continued for ~60 additional minutes. The time to seizure cessation after drug injection, EEG scores, and power spectra before and after drug or saline treatment were used to assess drug effects.
Results
Once SE became sustained, administration of 2‐DG (50, 100, or 500 mg/kg, ip) consistently stopped behavioral and electrographic seizures within 10‐15 minutes; lower doses took longer (25‐30 minutes) to stop SE, demonstrating a dose‐dependent effect. Administration of phenobarbital (30 mg/kg, ip) or levetiracetam (100 mg/kg, ip) also stopped SE within 10‐15 minutes in neonatal rats.
Significance
Our results suggest that the glycolysis inhibitor 2‐DG acts quickly to reduce neuronal hyperexcitability and effectively suppress ongoing seizure activity, which may provide translational value in the treatment of neonatal SE.
Background and Purpose
This study investigates the antifibrotic activities and potential mechanisms of costunolide (COS), a natural sesquiterpene compound.
Experimental Approach
Rats subjected to ...bile duct ligation and mice challenged with CCl4 were used to study the antifibrotic effects of COS in vivo. Mouse primary hepatic stellate cells (pHSCs) and human HSC line LX‐2 also served as an in vitro liver fibrosis models. The expression of fibrogenic genes and signaling proteins in the neurogenic locus notch homologue protein 3 (Notch3)–hairy/enhancer of split‐1 (HES1) pathway was examined using western blot and/or real‐time PCR. Notch3 degradation was analysed using immunofluorescence and coimmunoprecipitation.
Key Results
In animals, COS administration attenuated hepatic histopathological injury and collagen accumulation and reduced the expression of fibrogenic genes. COS time‐ and dose‐dependently suppressed the levels of fibrotic markers in LX‐2 cells and mouse pHSCs. Mechanistic studies showed COS destabilized Notch3 and subsequently inhibited the Notch3–HES1 pathway, thus inhibiting HSC activation. Furthermore, COS blocked the WW domain‐containing protein 2 (WWP2)/protein phosphatase 1G (PPM1G) interaction and enhanced the effect of WWP2 on Notch3 degradation.
Conclusions and Implications
COS exerted potent antifibrotic effects in vitro and in vivo by disrupting the WWP2/PPM1G complex, promoting Notch3 degradation and inhibiting the Notch3/HES1 pathway. This indicates that COS may be a potential therapeutic candidate for the treatment of liver fibrosis.
Display omitted
•Dehydration of glycerol was studied over H6P2W18O62/MCM-41 and H3PW12O40/MCM-41.•The value of Brønsted/Lewis had a significant impact on the product distribution.•Leaching of HPW and ...coke deposition decreased the catalytic activity.•The reaction mechanism on H6P2W18O62/MCM-41 and H3PW12O40/MCM-41 was shown.
Gas phase dehydration of glycerol to acrolein was studied using the Wells–Dawson and Keggin type phosphotungstic acids supported on MCM-41 catalysts. The samples were characterized using XRD, FTIR, pyridine-FTIR, UV–Vis, N2 adsorption, NH3-TPD, ICP, SEM and elemental analysis. FT-IR and UV–Vis spectra results confirmed the presence of Wells–Dawson and Keggin type phosphotungstic acids on the support. XRD results suggested that the active phases were highly dispersed on MCM-41. N2 adsorption results showed that the mesoporous structure of MCM-41 was retained after loading of phosphotungstic acids. H3PW12O40/MCM-41 showed higher total acid sites than H6P2W18O62/MCM-41, but the number of Brønsted acid sites on H6P2W18O62/MCM-41 was higher than that of H3PW12O40/MCM-41. Glycerol conversion increased with the total amount of acid sites. The acid type also influenced catalytic performance. The selectivity to acrolein increased with increasing the ratio of Brønsted and Lewis acid, and lower value of Brønsted/Lewis acid favored the production of hydroxyacetone. H6P2W18O62/MCM-41 owned more Brønsted acid sites, the dehydration reaction was more likely to occur via the Brønsted acid sites dehydration route, thus generating more acrolein and formaldehyde. Meanwhile, H3PW12O40/MCM-41 exhibited more Lewis acid sites, the dehydration reaction was more likely proceeding via the Lewis acid sites dehydration route and generating more hydroxyacetone and acetaldehyde. Furthermore, we concluded that the reasons for decrease of catalytic performance in glycerol conversion were leaching of HPW and coke deposition.
To assess the moderated mediation effect of normative beliefs about aggression and family environment on exposure to violent video games and adolescent aggression, the subjects self-reported their ...exposure to violent video games, family environment, normative beliefs about aggression, and aggressive behavior. The results showed that there was a significant positive correlation between exposure to violent video games and adolescent aggression; normative beliefs about aggression had a mediation effect on exposure to violent video games and adolescent aggression, while family environment moderated the first part of the mediation process. For individuals with a good family environment, exposure to violent video games had only a direct effect on aggression; however, for those with poor family environment, it had both direct and indirect effects mediated by normative beliefs about aggression. This moderated mediation model includes some notions of General Aggression Model (GAM) and Catalyst Model (CM), which helps shed light on the complex mechanism of violent video games influencing adolescent aggression.
The formation of zygote is the beginning of mammalian life, and dynamic epigenetic modifications are essential for mammalian normal development. H3K27 di-methylation (H3K27me2) and H3K27 ...tri-methylation (H3K27me3) are marks of facultative heterochromatin which maintains transcriptional repression established during early development in many eukaryotes. However, the mechanism underlying establishment and regulation of epigenetic asymmetry in the zygote remains obscure. Here we show that maternal EZH2 is required for the establishment of H3K27me3 in mouse zygotes. However, combined immunostaining with ULI-NChIP-seq (ultra-low-input micrococcal nuclease-based native ChIP-seq) shows that EZH1 could partially safeguard the role of EZH2 in the formation of H3K27me2. Meanwhile, we identify that EHMT1 is involved in the establishment of H3K27me2, and that H3K27me2 might be an essential prerequisite for the following de novo H3K27me3 modification on the male pronucleus. In this work, we clarify the establishment and regulatory mechanisms of H3K27me2 and H3K27me3 in mouse zygotes.
PDF
