TMEM215 Prevents Endothelial Cell Apoptosis in Vessel Regression by Blunting BIK-Regulated ER-to-Mitochondrial Ca Influx.

BACKGROUND: In developmental and pathological tissues, nascent vessel networks generated by angiogenesis require further pruning/regression to delete nonfunctional endothelial cells (ECs) by apoptosis and migration. Mechanisms underlying EC apoptosis during vessel pruning remain elusive. TMEM215 (transmembrane protein 215) is an endoplasmic reticulum-located, 2-pass transmembrane protein. We have previously demonstrated that TMEM215 knockdown in ECs leads to cell death, but its physiological function and mechanism are unclear. METHODS: We characterized the role and mechanism of TMEM215 in EC apoptosis using human umbilical vein endothelial cells by identifying its interacting proteins with immunoprecipitation-mass spectrometry. The physiological function of TMEM215 in ECs was assessed by establishing a conditional knockout mouse strain. The role of TMEM215 in pathological angiogenesis was evaluated by tumor and choroidal neovascularization models. We also tried to evaluate its translational value by delivering a Tmem215 small interfering RNA (siRNA) using nanoparticles in vivo. RESULTS: TMEM215 knockdown in ECs induced apoptotic cell death. We identified the chaperone BiP as a binding partner of TMEM215, and TMEM215 forms a complex with and facilitates the interaction of BiP (binding immunoglobin protein) with the BH (BCL-2 [B-cell lymphoma 2] homology) 3-only proapoptotic protein BIK (BCL-2 interacting killer). TMEM215 knockdown triggered apoptosis in a BIK-dependent way and was abrogated by BCL-2. Notably, TMEM215 knockdown increased the number and diminished the distance of mitochondria-associated endoplasmic reticulum membranes and increased mitochondrial calcium influx. Inhibiting mitochondrial calcium influx by blocking the IP3R (inositol 1,4,5-trisphosphate receptor) or MCU (mitochondrial calcium uniporter) abrogated TMEM215 knockdown-induced apoptosis. TMEM215 expression in ECs was induced by physiological laminar shear stress via EZH2 downregulation. In EC-specific Tmem215 knockout mice, induced Tmem215 depletion impaired the regression of retinal vasculature characterized by reduced vessel density, increased empty basement membrane sleeves, and increased EC apoptosis. Moreover, EC-specific Tmem215 ablation inhibited tumor growth with disrupted vasculature. However, Tmem215 ablation in adult mice attenuated lung metastasis, consistent with reduced Vcam1 expression. Administration of nanoparticles carrying Tmem215 siRNA also inhibited tumor growth and choroidal neovascularization injury. CONCLUSIONS: TMEM215, which is induced by blood flow-derived shear stress via downregulating EZH2, protects ECs from BIK-triggered mitochondrial apoptosis mediated by calcium influx through mitochondria-associated ER membranes during vessel pruning, thus providing a novel target for antiangiogenic therapy.

Integrating GWAS, RNA-Seq and functional analysis revealed that BnaA02.SE mediates silique elongation by affecting cell proliferation and expansion in Brassica napus.

Rapeseed (Brassica napus) silique is the major carbohydrate source for seed development, and the final silique length has attracted great attention from breeders. However, no studies had focused on the dynamic character of silique elongation length (SEL). Here, the dynamic SEL investigation in a natural population including 588 lines over two years indicate that dynamic SEL during 0-20 days after flowering was the most essential stage associated with seed number per silique (SPS) and thousand seed weight (TSW). Then, nine loci were identified to be associated with SEL based on GWAS analysis, among which five SNPs (over 50%) distributed on the A02 chromosome within 6.08 to 6.48 Mb. Subsequently, we screened 5078 differentially expressed genes between two extreme materials. An unknown protein, BnaA02.SE, was identified combining with GWAS and RNA-Seq analysis. Subcellular localization and expression profiles analysis demonstrated that BnaA02.SE is a chloroplast- and nucleus-localized protein mainly expressed in pericarps and leaves. Furthermore, transgenic verification and dynamic cytological observation reveal that overexpressed BnaA02.SE can promote silique elongation by regulating JA and IAA contents, affecting cell proliferation and expansion, respectively, and finally enhance seed yield by influencing SPS and TSW. Haplotype analysis reveal that the homologs of BnaA02.SE may also be involved in silique elongation regulation. Our findings provided comprehensive insights into a newly SEL trait, and cloned the first gene (BnaA02.SE) controlling silique elongation in B. napus. The identified BnaA02.SE and its homologs can offer a valuable target for improving B. napus yield.

Effects of polyethylene, polylactic acid, and tire particles on the sediment microbiome and metabolome at high and low temperatures.

Global warming has led to a high incidence of extreme heat events, and the frequent occurrence of extreme heat events has had extensive and far-reaching impacts on wetland ecosystems. The widespread distribution of plastics in the environment, including polyethylene (PE), polylactic acid (PLA), and tire particles (TPs), has caused various environmental problems. Here, high-throughput sequencing techniques and metabolomics were used for the first time to investigate the effects of three popular microplastic types: PE, PLA, and TP, on the sediment microbiome and the metabolome at both temperatures. The microplastics were incorporated into the sediment at a concentration of 3% by weight of the dry sediment (wt/wt), to reflect environmentally relevant conditions. Sediment enzymatic activity and physicochemical properties were co-regulated by both temperatures and microplastics producing significant differences compared to controls. PE and PLA particles inhibited bacterial diversity at low temperatures and promoted bacterial diversity at high temperatures, and TP particles promoted both at both temperatures. For bacterial richness, only PLA showed inhibition at low temperature; all other treatments showed promotion. PE, PLA, and TP microplastics changed the community structure of sediment bacteria, forming two clusters at low and high temperatures. Furthermore, PE, PLA, and TP changed the sediment metabolic profiles, producing differential metabolites such as lipids and molecules, organic heterocyclic compounds, and organic acids and their derivatives, especially TP had the most significant effect. These findings contribute to a more comprehensive understanding of the potential impact of microplastic contamination.IMPORTANCEIn this study, we added 3% (wt/wt) microplastic particles, including polyethylene, polylactic acid, and tire particles, to natural sediments under simulated laboratory conditions. Subsequently, we simulated the sediment microbial and ecosystem responses under different temperature conditions by incubating them for 60 days at 15°C and 35°C, respectively. After synthesizing these results, our study strongly suggests that the presence of microplastics in sediment ecosystems and exposure under different temperature conditions may have profound effects on soil microbial communities, enzyme activities, and metabolite profiles. This is important for understanding the potential hazards of microplastic contamination on terrestrial ecosystems and for developing relevant environmental management strategies.

Enhancing lipid production and sedimentation of Chlorella pyrenoidosa in saline wastewater through the addition of agricultural phytohormones.

In this study, the effect of external agricultural phytohormones (mixed phytohormones) addition (1.0, 5.0, 10.0, and 20.0 mg L-1) on the growth performance, lipid productivity, and sedimentation efficiency of Chlorella pyrenoidosa cultivated in saline wastewater was investigated. Among the different concentrations evaluated, the highest biomass (1.00 g L-1) and lipid productivity (11.11 mg L-1 d-1) of microalgae were obtained at 10.0 mg L-1 agricultural phytohormones addition. Moreover, exogenous agricultural phytohormones also improved the sedimentation performance of C. pyrenoidosa, which was conducive to the harvest of microalgae resources, and the improvement of sedimentation performance was positively correlated with the amount of agricultural phytohormones used. The promotion of extracellular polymeric substances synthesis by phytohormones in microalgal cells could be considered as the reason for its promotion of microalgal sedimentation. Transcriptome analysis revealed that the addition of phytohormones upregulated the expression of genes related to the mitogen-activated protein kinase (MAPK)-mediated phytohormone signaling pathway and lipid synthesis, thereby improving salinity tolerance and lipid production in C. pyrenoidosa. Overall, agricultural phytohormones provide an effective and inexpensive strategy for increasing the lipid productivity and sedimentation efficiency of microalgae cultured in saline wastewater.

Inhibition of Proliferation and Induction of Apoptosis in Prostatic Carcinoma DU145 Cells by Polysaccharides from Yunnan Rosa roxburghii Tratt.

OBJECTIVE: This study aimed to investigate methodologies for the extraction and purification of polysaccharides from Rosa roxburghii Tratt fruits and their impact on various cellular processes in prostate cancer DU145 cells, including survival rate, migration, invasion, cell cycle, and apoptosis. RESULTS: Compared to the control group, the polysaccharide exhibited a significant reduction in the viability, migration, and invasion rates of DU145 cells in a time- and dose-dependent manner within the polysaccharide-treated groups. Additionally, it effectively arrested the cell cycle of DU145 cells at the G0/G1 phase by downregulating the expressions of CDK-4, CDK-6, and Cyclin D1. Furthermore, it induced apoptosis by upregulating the expressions of Caspase 3, Caspase 8, Caspase 9, and BAX. METHODS: Polysaccharides were extracted from Rosa roxburghii Tratt sourced from Yunnan, China. Extraction and decolorization methods were optimized using response surface methodology, based on a single-factor experiment. Polysaccharide purification was carried out using DEAE-52 cellulose and Sephadex G-100 column chromatography. The optimal dosage of R. roxburghii Tratt polysaccharide affecting DU145 cells was determined using the CCK-8 assay. Cell migration and invasion were assessed using transwell and scratch assays. Flow cytometry was employed to analyze the effects on the cell cycle and apoptosis. Western blotting and Quantitative real-time PCR were utilized to examine protein and mRNA expressions in DU145 cells, respectively. CONCLUSIONS: Rosa roxburghii Tratt polysaccharides, consisting of D-mannose, L-rhamnose, N-acetyl-D-glucosamine, D-galacturonic acid, D-glucose, D-galactcose, D-xylose, L-arabinose, and L-fucose, possess the ability to hinder DU145 cell proliferation, migration, and invasion while inducing apoptosis through the modulation of relevant protein and gene expressions.

Unveiling the overlooked threat: antibiotic resistance in groundwater near an abandoned sulfuric acid plant in Xingyang, China.

Groundwater near a sulfuric acid plant in Xingyang, Henan, China was sampled from seven distinct sites to explore the prevalence of antibiotic resistance genes (ARGs) and mobile genetic elements (MGEs). Results showed that genes aadA, blaCTX-M, tetA, qnrA, and sul1 were detected with 100% frequency followed by aac(6')-Ib (85.71%), ermB (85.71%), and tetX (71.42%). Most abundant ARGs were sul1 in LSA2 (1.15 × 1011 copies/mL), tetA in LSA6 (4.95 × 1010 copies/mL), aadA in LSA2 (4.56 × 109 copies/mL), blaCTX-M in LSA4 (1.19 × 109 copies/mL), and ermB in LSA5 (1.07 × 109 copies/mL). Moreover, in LSA2, intl1 as a marker of class 1 integron emerged as the most abundant gene as part of MGE (2.25 × 1011 copies/mL), trailed by ISCR1 (1.57 × 109 copies/mL). Environmental factors explained 81.34% of ARG variations, with a strong positive correlation between the intl2 and blaCTX-M genes, as well as the ISCR1 gene and qnrA, tetA, intl2, and blaCTX-M. Furthermore, the intI1 gene had a strong positive connection with the aadA, tetA, and sul1 genes. Moreover, the aac(6')-Ib gene was associated with As, Pb, Mg, Ca, and HCO3-. The intl2 gene was also shown to be strongly associated with Cd. Notably, network analysis highlighted blaCTX-M as the most frequently appearing gene across networks of at least five genera. Particularly, Lactobacillus, Plesiomonas, and Ligilactobacillus demonstrated correlations with aadA, qnrA, blaCTX-M, intI2, and ISCR1. Based on 16S rRNA sequencing, the dominant phyla were Proteobacteria, Firmicutes, Bacteroidota, Acidobacteriota, and Actinobacteriota, with dominant genera including Pseudomonas, Ligilactobacillus, Azoarcus, Vogesella, Streptococcus, Plesiomonas, and Ferritrophicum. These findings enhance our understanding of ARG distribution in groundwater, signaling substantial contamination by ARGs and potential risks to public health.

Thalamocortical Mechanisms for Nostalgia-Induced Analgesia.

As a predominately positive emotion, nostalgia serves various adaptive functions, including a recently revealed analgesic effect. The current fMRI study aimed to explore the neural mechanisms underlying the nostalgia-induced analgesic effect on noxious thermal stimuli of different intensities. Human participants' (males and females) behavior results showed that the nostalgia paradigm significantly reduced participants' perception of pain, particularly at low pain intensities. fMRI analysis revealed that analgesia was related to decreased brain activity in pain-related brain regions, including the lingual and parahippocampal gyrus. Notably, anterior thalamic activation during the nostalgia stage predicted posterior parietal thalamus activation during the pain stage, suggesting that the thalamus might play a key role as a central functional linkage in the analgesic effect. Moreover, while thalamus-PAG functional connectivity was found to be related to nostalgic strength, periaqueductal gray-dorsolateral prefrontal cortex (PAG-dlPFC) functional connectivity was found to be associated with pain perception, suggesting possible analgesic modulatory pathways. These findings demonstrate the analgesic effect of nostalgia and, more importantly, shed light on its neural mechanism.SIGNIFICANCE STATEMENT Nostalgia is known to reduce individuals' perception of physical pain. The underlying brain mechanisms, however, are unclear. Our study found that the thalamus plays a key role as a functional linkage between nostalgia and pain, suggesting a possible analgesic modulatory mechanism of nostalgia. These findings have implications for the underlying brain mechanisms of psychological analgesia.

RNA-binding protein SPEN controls hepatocyte maturation via regulating Hnf4α expression during liver development.

Liver organogenesis is a complex process. Although many signaling pathways and key factors have been identified during liver development, little is known about the regulation of late liver development, especially liver maturation. As a transcriptional repressor, SPEN has been demonstrated to interact with lncRNAs and transcription factors to participate in X chromosome inactivation, neural development, and lymphocyte differentiation. General disruption of SPEN results in embryonic lethality accompanied by hampered liver development in mice. However, the function of SPEN in embryonic liver development has not been reported. In this study, we demonstrate that SPEN is required for hepatocyte maturation using hepatocyte-specific disruption of SPEN with albumin-Cre-mediated knockout. SPEN expression was upregulated in hepatocytes along with liver development in mice. The deletion of the SPEN gene repressed hepatic maturation, mainly by a decrease in hepatic metabolic function and disruption of hepatocyte zonation. Additional experiments revealed that transcription factors which control hepatocyte maturation were strongly downregulated in SPEN-deficient hepatocytes, especially Hnf4α. Furthermore, restoration of Hnf4α levels partially rescued the immature state of hepatocytes caused by SPEN gene deletion. Taken together, these results reveal an unexpected role of SPEN in liver maturation.

Novel gold-platinum nanoparticles serve as broad-spectrum antioxidants for attenuating ischemia reperfusion injury of the kidney.

Kidney ischemia reperfusion injury (IRI) is a common and inevitable pathological condition in routine urological practices, especially during transplantation. Severe kidney IRI may even induce systemic damage to peripheral organs, and lead to multisystem organ failure. However, no standard clinical treatment option is currently available. It has been reported that kidney IRI is predominantly associated with abnormally increased endogenous reactive oxygen species (ROS). Scavenging excessive ROS may reduce the damage caused by oxidative stress and subsequently alleviate kidney IRI. Here, we reported a simple and efficient one-step synthesis of gold-platinum nanoparticles (AuPt NPs) with a gold core having a loose and branched outer platinum shell with superior ROS scavenging capacity to possibly treat kidney IRI. These AuPt NPs exhibited multiple enzyme-like anti-oxidative properties simultaneously possessing catalase- and peroxidase-like activity. These particles showed excellent cell protective capability, and alleviated kidney IRI both in vitro and in vivo without obvious toxicity, by suppressing cell apoptosis, inflammatory cytokine release, and inflammasome formation. Meanwhile, AuPt NPs also had an effect on inhibiting the transition to chronic kidney disease by reducing kidney fibrosis in the long term. Thus, AuPt NPs might be a good therapeutic agent for kidney IRI management and may be helpful for the development of clinical treatments for kidney IRI.

EFEMP2 increases the invasion ability of cervical cancer cells by promoting EMT via the Raf/MEK/ERK signaling pathway.

EFEMP2 has been reported as a candidate oncogene. To investigate the role of EFEMP2 in cervical cancer cell proliferation and invasion, the mRNA and protein expressions of EFEMP2 in 5 different cervical cancer cell lines were detected. And then the effects of up- or down-regulation of EFEMP2 expression on the biological behavior of cervical cancer cells were further investigated by transfection experiments and cell function assays in vitro and in vivo. The results revealed that EFEMP2 was highly expressed in highly invasive Ca Ski cells and lowly expressed in less invasive HT-3 cells. When EFEMP2 was knocked down, the proliferation and invasion ability of cervical cancer cells were also reduced, accompanied by the decreased expression of MMP-1, MMP-13, MMP-3, and MMP-10, meanwhile, the EMT process was blocked and the Raf/MEK/ERK signaling pathway was inhibited. On the contrary, the upregulation of EFEMP2 could promote the proliferation and invasion of cervical cancer cells by inducing EMT and activating the Raf/MEK/ERK pathway. In conclusion, EFEMP2 could increase the invasion ability of cervical cancer cells by upregulating the expression of MMP-1, MMP-13, MMP-3, and MMP-10 and inducing the EMT process through the Raf/MEK/ERK pathway. EFEMP2 played a promoting role in the development of cervical cancer and provided a potential therapeutic target for inhibiting the invasion and metastasis of cancer cells and improving the prognosis of cervical cancer patients.

Novel Chemicals Derived from Tadalafil Exhibit PRMT5 Inhibition and Promising Activities against Breast Cancer.

Breast cancer seriously endangers women's health worldwide. Protein arginine methyltransferase 5 (PRMT5) is highly expressed in breast cancer and represents a potential druggable target for breast cancer treatment. However, because the currently available clinical PRMT5 inhibitors are relatively limited, there is an urgent need to develop new PRMT5 inhibitors. Our team previously found that the FDA-approved drug tadalafil can act as a PRMT5 inhibitor and enhance the sensitivity of breast cancer patients to doxorubicin treatment. To further improve the binding specificity of tadalafil to PRMT5, we chemically modified tadalafil, and designed three compounds, A, B, and C, based on the PRMT5 protein structure. These three compounds could bind to PRMT5 through different binding modes and inhibit histone arginine methylation. They arrested the proliferation and triggered the apoptosis of breast cancer cells in vitro and also promoted the antitumor effects of the chemotherapy drugs cisplatin, doxorubicin, and olaparib in combination regimens. Among them, compound A possessed the highest potency. Finally, the anti-breast cancer effects of PRMT5 inhibitor A and its ability to enhance chemosensitivity were further verified in a xenograft mouse model. These results indicate that the new PRMT5 inhibitors A, B, and C may be potential candidates for breast cancer treatment.

Lactobacillus paracasei R3 protects against dextran sulfate sodium (DSS)-induced colitis in mice via regulating Th17/Treg cell balance.

Inflammatory bowel diseases (IBD), mainly comprising ulcerative colitis (UC) and Crohn's Disease, are most often a polygenic disorder with contributions from the intestinal microbiome, defects in barrier function, and dysregulated host responses to microbial stimulation. Strategies that target the microbiota have emerged as potential therapies and, of these, probiotics have gained the greatest attention. Herein, we isolated a strain of Lactobacillus paracasei R3 (L.p R3) with strong biofilm formation ability from infant feces. Interestingly, we also found L.p R3 strain can ameliorate the general symptoms of murine colitis, alleviate inflammatory cell infiltration and inhibit Th17 while promote Treg function in murine dextran sulfate sodium (DSS)-induced colitis. Overall, this study suggested that L.p R3 strain significantly improves the symptoms and the pathological damage of mice with colitis and influences the immune function by regulating Th17/Treg cell balance in DSS-induced colitis in mice.

Oxytocin intensifies the mortality salience effect: Novel evidence for the social salience model of oxytocin.

Oxytocin plays an important role in human responses to threat processing. Few studies have directly examined the effects of oxytocin on our response to death-related stimuli. In the current study, 63 participants intranasally received either 32 IU of oxytocin or a placebo and thereafter completed a visual dot-probe task consisting of death-related and non-death related images. The results indicated that oxytocin enhanced participants' vigilance toward death-related images as well as increased their anxiety about and fear of death. Overall, oxytocin amplifies the defensive responses to a mortality threat, supporting the social salience model of oxytocin.

Meaning making helps cope with COVID-19: A longitudinal study.

Meaning making is a useful coping strategy in negative situations. We investigated whether making meaning in negative experiences (MINE) would help people cope with COVID-19. We conducted a three-wave longitudinal study (N = 2364) three months before, during, and after the COVID-19 outbreak in China. Results showed that participants reported increased tendency of MINE during the COVID-19 outbreak than three months before the outbreak. Moreover, both initial MINE and the increased MINE predicted less psychological distress including depression, anxiety and stress, during and three months after the outbreak. Perceived benefits and costs of the COVID-19 mediated the long-term effect of MINE. These findings not only provide novel evidence for meaning making model but also shed light on the underlying mechanism, suggesting an effective strategy to cope with stressful events such as the ongoing COVID-19 pandemic.

Transmembrane protein 215 promotes angiogenesis by maintaining endothelial cell survival.

Sprouting angiogenesis is a major form of neovascularization of tissues suffering from hypoxia and other related stress. Endothelial cells (ECs) undergo proliferation, differentiation, programmed death, and migration during angiogenic sprouting, but the underlying molecular mechanisms regulating ECs in angiogenesis have been incompletely elucidated. Here we report that the transmembrane protein 215 (TMEM215) is involved in angiogenesis by regulating EC survival. The murine TMEM215 gene, which possesses two transcriptional starting sites as determined by 5'-rapid amplification of complementary DNA (cDNA) ends (RACE), encodes a two-pass TMEM. The TMEM215 transcripts were detected in ECs in addition to other tissues by quantitative reverse transcription-polymerase chain reaction. Immunofluorescence showed that TMEM215 was expressed in the vasculature in retina, liver, and tumor, and colocalized with EC markers. We show that knockdown of TMEM215 in ECs induced strong cell death of ECs in vitro without affecting cell proliferation and migration, suggesting that TMEM215 was required for EC survival. Downregulation of TMEM215 expression compromised lumen formation and sprouting capacities of ECs in vitro. Moreover, intravitreous injection of TMEM215 small interfering RNA resulted in delayed and abnormal development of retinal vasculature with poor perfusion. These results identified TMEM215 as a novel molecule involved in angiogenesis by regulating the survival of ECs.

Self-affirmation enhances the processing of uncertainty: An event-related potential study.

We proposed that self-affirmation can endow people with more cognitive resource to cope with uncertainty. We tested this possibility with an event-related potential (ERP) study by examining how self-affirmation influences ambiguous feedback processing in a simple gambling task, which was used to investigate risk decision-making. We assigned 48 participants randomly to the affirmation and non-affirmation (i.e., control) groups. All participants accepted the manipulation first and then completed the gambling task with an electroencephalogram (EEG) recording, in which participants might receive a positive (winning), negative (losing), or ambiguous (unknown valence) outcome after they made a choice. We considered both the feedback-related negativity (FRN) and P3 components elicited by the outcome feedback, which reflected the amount of cognitive resources being invested in the early and late stages of the outcome feedback processing, respectively. ERP results showed that ambiguous feedback elicited a larger FRN among affirmed participants than unaffirmed participants but exerted no influence on the P3. This finding suggests that self-affirmation may help coping with uncertainty by enhancing the early processing of uncertainty.

Endothelial Notch activation reshapes the angiocrine of sinusoidal endothelia to aggravate liver fibrosis and blunt regeneration in mice.

Liver sinusoidal endothelial cells (LSECs) critically regulate liver homeostasis and diseases through angiocrine factors. Notch is critical in endothelial cells (ECs). In the current study, Notch signaling was activated by inducible EC-specific expression of the Notch intracellular domain (NIC). We found that endothelial Notch activation damaged liver homeostasis. Notch activation resulted in decreased fenestration and increased basement membrane, and a gene expression profile with decreased LSEC-associated genes and increased continuous EC-associated genes, suggesting LSEC dedifferentiation. Consistently, endothelial Notch activation enhanced hepatic fibrosis (HF) induced by CCl4 . Notch activation attenuated endothelial nitric oxide synthase (eNOS)/soluble guanylate cyclase (sGC) signaling, and activation of sGC by 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1) reversed the dedifferentiation phenotype. In addition, Notch activation subverted the hepatocyte-supporting angiocrine profile of LSECs by down-regulating critical hepatocyte mitogens, including Wnt2a, Wnt9b, and hepatocyte growth factor (HGF). This led to compromised hepatocyte proliferation under both quiescent and regenerating conditions. Whereas expression of Wnt2a and Wnt9b was dependent on eNOS-sGC signaling, HGF expression was not rescued by the sGC activator, suggesting heterogeneous mechanisms of LSECs to maintain hepatocyte homeostasis. CONCLUSION: Endothelial Notch activation results in LSEC dedifferentiation and accelerated liver fibrogenesis through eNOS-sGC signaling, and alters the angiocrine profile of LSECs to compromise hepatocyte proliferation and liver regeneration (LR). (Hepatology 2018).

SNAI1, an endothelial-mesenchymal transition transcription factor, promotes the early phase of ocular neovascularization.

Ocular neovascularization is a comprehensive process involved in retinal vascular development and several blinding diseases such as age-related macular degeneration and retinopathy of prematurity, with vascular endothelial growth factor (VEGF) regarded as the master regulator. However, the qualified effect of anti-VEGF therapy reveals that the underlying mechanisms are still not clearly identified. To initialize angiogenesis, endothelial cells undergo a phenotype switching to generate highly migratory and invasive cells. This process shares certain similar characters observed in endothelial-mesenchymal transition (EndMT). Here, we found that SNAI1, an EndMT transcription factor, was expressed by endothelial cells in both physiological and pathological ocular neovascularization. SNAI1 overexpression triggered cell morphological change and enhanced cell motility, while loss of SNAI1 attenuated migration, invasion and sprouting. RNA sequence analysis further revealed that SNAI1 knockdown decreased the expression of genes related to cytoskeleton rearrangement and ECM remodeling. Moreover, intravitreal injection of small interfering RNA of SNAI1 suppressed new vessel formation in developing retina as well as mice model of choroidal neovascularization and oxygen-induced retinopathy. Therefore, we propose that the EndMT transcription factor SNAI1 promotes the early phase of ocular neovascularization and may provide a potential therapeutic target.

The Notch ligand delta-like 3 promotes tumor growth and inhibits Notch signaling in lung cancer cells in mice.

Although it has been suggested that Dll3, one of the Notch ligands, promotes the proliferation and inhibits the apoptosis of cancer cells, the role of Dll3 in cancers remains unclear. In this study, we found that in the murine Lewis lung carcinoma (LLC) cells, the level of Dll3 mRNA changed upon tumor microenvironment (TME) stimulation, namely, decreased under hypoxia or stimulated with tumor necrosis factor (TNF)-α. Dll3 was also expressed at higher level in human lung carcinoma tissues than in the para-carcinoma tissues. Overexpression of Dll3 in LLC cells promoted cell proliferation and reduced apoptosis in vitro, and enhanced tumor growth when inoculated in vivo in mice. The Dll3-mediated proliferation could be due to increased Akt phosphorylation in LLC cells, because an Akt inhibitor counteracted Dll3-induced proliferation. Moreover, Dll3 overexpression promoted PI3K/Akt signaling through inhibiting Notch signaling.

Molecular cloning and characterization of a sigma-class glutathione S-transferase from the freshwater mussel Hyriopsis cumingii.

A full-length cDNA of a sigma-like glutathione S-transferase (GST) was identified from Hyriopsis cumingii (HcGSTS). The deduced amino acid sequence of HcGSTS was found to comprise 203 amino acid residues and to contain the distinct highly conserved glutathione binding site of N-terminal and the relatively diverse substrate binding site of C-terminal. Alignment analysis and phylogenetic relationship suggested that the HcGSTS is a sigma-class GST. The mRNA of HcGSTS was constitutively expressed in all tested tissues, the strongest expression being in the hepatopancreas. The mRNA expression of HcGSTS was significantly up-regulated (P < 0.05) in all assessed tissues after stimulation of the mussels with peptidoglycan (PGN) and LPS, the only exception being when the gills were challenged with PGN. The expression of HcGSTS mRNA in kidney and foot was also significantly up-regulated (P < 0.05) by microcystin-LR. Recombinant HcGSTS exhibited high activity towards the substrate 1-chloro-2,4-dinitrobenzene. The optimal pH was 8.0 and temperature 35 °C.