Novel biocompatible N-rich AIE fluorescent probe for live cell imaging and visual onsite detection of uranium.

A sensitive and biocompatible N-rich probe for rapid visual uranium detection was constructed by grafting two trianiline groups to 2,6-bis(aminomethyl)pyridine. Possessing excellent aggregation-induced emission (AIE) property and the advantages to form multidentate chelate with U selectively, the probe has been applied successfully to visualize uranium in complex environmental water samples and living cells, demonstrating outstanding anti-interference ability against large equivalent of different ions over a wide effective pH range. A large linear range (1.0 × 10-7-9.0 × 10-7 mol/L) and low detection limit (72.6 nmol/L, 17.28 ppb) were achieved for the visual determination of uranium. The recognition mechanism, photophysical properties, analytical performance and cytotoxicity were systematically investigated, demonstrating high potential for fast risk assessment of uranium pollution in field and in vivo.

Dental Implant Navigation System Based on Trinocular Stereo Vision.

Traditional dental implant navigation systems (DINS) based on binocular stereo vision (BSV) have limitations, for example, weak anti-occlusion abilities, as well as problems with feature point mismatching. These shortcomings limit the operators' operation scope, and the instruments may even cause damage to the adjacent important blood vessels, nerves, and other anatomical structures. Trinocular stereo vision (TSV) is introduced to DINS to improve the accuracy and safety of dental implants in this study. High positioning accuracy is provided by adding cameras. When one of the cameras is blocked, spatial positioning can still be achieved, and doctors can adjust to system tips; thus, the continuity and safety of the surgery is significantly improved. Some key technologies of DINS have also been updated. A bipolar line constraint algorithm based on TSV is proposed to eliminate the feature point mismatching problem. A reference template with active optical markers attached to the jaw measures head movement. A T-type template with active optical markers is used to obtain the position and direction of surgery instruments. The calibration algorithms of endpoint, axis, and drill are proposed for 3D display of the surgical instrument in real time. With the preoperative path planning of implant navigation software, implant surgery can be carried out. Phantom experiments are carried out based on the system to assess the feasibility and accuracy. The results show that the mean entry deviation, exit deviation, and angle deviation are 0.55 mm, 0.88 mm, and 2.23 degrees, respectively.

Acetyl-3-Aminoethyl Salicylate Ameliorates Hepatic Ischemia/Reperfusion Injury and Liver Graft Survival Through a High-Mobility Group Box 1/Toll-Like Receptor 4-Dependent Mechanism.

In liver transplant cases, severe hepatic ischemia/reperfusion injury (HIRI) is a strong predictor of adverse liver graft and overall outcomes. During HIRI, high-mobility group box 1 (HMGB1) promotes hepatocellular death and proinflammatory cytokine secretion by toll-like receptor 4 (TLR4). Because salicylates inhibit HMGB1/TLR4 interaction, we hypothesized that salicylates may ameliorate HIRI-induced liver damage by inhibiting HMGB1/TLR4 axis activation. Using a murine model of HIRI, we found that the salicylate acetyl-3-aminoethyl salicylic acid (ac3AESA) reduced serum alanine aminotransferase and aspartate aminotransferase as well as Suzuki scores and apoptotic cell counts after HIRI. Ac3AESA also down-regulated hepatocellular HMGB1 and TLR4 expression, phosphorylated inhibitor of κBα, extracellular signal-regulated kinase 1/2, c-Jun N-terminal kinase, p38 mitogen-activated protein kinase, cleaved caspase 3, and cleaved caspase 1 levels after HIRI. Ac3AESA reduced liver Kupffer cell transcription of proinflammatory mediators tumor necrosis factor α (TNF-α), interleukin (IL) 6, IL1ß, chemokine (C-X-C motif) ligand (CXCL) 1, CXCL2, and CXCL8 after HIRI. Ac3AESA also dose-dependently reduced in vitro release of Kupffer cell TNF-α. Employing a murine orthotopic liver transplantation model, we found daily ac3AESA administration up to day 10 after transplant improved liver graft survival, suppressed allograft damage, and down-regulated HMGB1/TLR4 signaling. These benefits to survival and allograft health were maintained for cold ischemia times of 12 and 18 hours. Notably, TLR4 knockout eliminated all foregoing ac3AESA-induced effects. In conclusion, ac3AESA partially rescues the negative effects of HIRI and prolongs liver graft survival in a TLR4-dependent manner.

Panax notoginseng saponins promote liver regeneration through activation of the PI3K/AKT/mTOR cell proliferation pathway and upregulation of the AKT/Bad cell survival pathway in mice.

BACKGROUD: The regenerative capacity of the liver is crucial for the host to survive after serious hepatic injuries, tumor resection, or living donor liver transplantation. Panax notoginseng saponins (PNS) have been reported to exert protective effects during organ injuries. The present study aimed to evaluate the effect of PNS on liver regeneration(LR) and on injuries induced by partial hepatectomy (PH). METHODS: We performed 70% partial PH on C57BL/6 J mice treated with or without PNS. LR was estimated by liver weight/body weight, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and cell proliferation, and the related cellular signals were analyzed by Western blot. RESULTS: Different concentrations of PNS promoted hepatocyte proliferation in vitro. Mice in the PNS group showed higher liver/body weight ratios at 2 d and 7 d (P < 0.05) after PH and lower levels of serum ALT and AST (P < 0.05) compared to those of mice in the normal control (NC) group. Histological analysis showed that the expression of proliferating cell nuclear antigen(PCNA) at 2 d and 7 d after PH was significantly higher in the PNS group than in the NC group (P < 0.05). Mechanistically, the AKT/mTOR cell proliferation pathway and AKT/Bad cell survival pathway were activated by PNS, which accelerated hepatocyte proliferation and inhibited apoptosis (P < 0.05). CONCLUSIONS: PNS promoted liver regeneration through activation of PI3K/AKT/mTOR and upregulated the AKT/Bad cell pathways in mice.

Icariin Improves Sepsis-Induced Mortality and Acute Kidney Injury.

OBJECTIVES: Icariin (ICA) is a bioactive flavonoid with renal protective actions. This study investigated the effects of ICA on renal injury, inflammation, oxidative damage, apoptosis, and survival in a mouse model of cecal ligation and perforation (CLP)-induced sepsis. METHODS: Sepsis was induced by CLP. Mice were treated with ICA (30 or 60 mg/kg) for 3 days before CLP. Renal functions, inflammatory responses, oxidative damage, histological changes, apoptosis, and vascular permeability were examined. The effects of ICA on CLP-induced expression of renal nuclear factor-κB (NF-κB), cleaved caspase-3, Bax, and Bcl-2 were evaluated. RESULTS: Mice in the CLP group had a low survival rate and increases in blood urea nitrogen and creatinine levels, proinflammatory cytokine levels, oxidative damage, apoptosis, and vascular permeability. These renal changes were dramatically improved by ICA treatment, especially in the 60 mg/kg ICA group. The detection of molecules involved in the inflammation and apoptosis of the kidney indicated that ICA reduced expression of NF-κB, cleaved caspase-3, and Bax but enhanced expression of Bcl-2. CONCLUSION: ICA improves CLP-induced mortality and acute kidney injury by inhibiting renal oxidant damage, inflammatory responses, apoptosis, and vascular permeability.

A Mussel-Inspired Conductive, Self-Adhesive, and Self-Healable Tough Hydrogel as Cell Stimulators and Implantable Bioelectronics.

A graphene oxide conductive hydrogel is reported that simultaneously possesses high toughness, self-healability, and self-adhesiveness. Inspired by the adhesion behaviors of mussels, our conductive hydrogel shows self-adhesiveness on various surfaces and soft tissues. The hydrogel can be used as self-adhesive bioelectronics, such as electrical stimulators to regulate cell activity and implantable electrodes for recording in vivo signals.

Exogenous vascular endothelial growth factor delivery prior to endothelial precursor cell transplantation in orthotopic liver transplantation-induced hepatic ischemia/reperfusion injury.

Vascular endothelial growth factor (VEGF) promotes angiogenesis in vivo. We hypothesized that exogenous delivery of VEGF prior to bone marrow-derived endothelial precursor cell (EPC) transplantation may improve orthotopic liver transplantation (OLT)-induced hepatic ischemia/reperfusion injury (HIRI). OLT between Sprague Dawley donor rats and inbred LEW Wistar recipient rats was performed in 6 experimental groups to comparatively assess the effects of the VEGF gene: an untreated normal control group, a surgical control group, a liposomal control group, a VEGF group receiving only the liposome-encapsulated VEGF plasmid, an EPC group receiving only EPCs, and an EPC+VEGF group receiving the liposome-encapsulated VEGF plasmid followed by EPCs. VEGF plasmid delivery to liver tissue, endogenous VEGF, and vascular endothelial growth factor receptor (VEGFR) expression, liver transaminase levels, hepatocellular injury levels, apoptosis, apoptotic biomarkers, hepatotrophic mitogens, angiogenesis, and nitric oxide synthase (NOS) activity were assayed after OLT. Exogenous VEGF gene delivery prior to EPC transplantation significantly increased endogenous VEGF and VEGFR expression, significantly reduced liver transaminase levels, significantly reduced hepatocellular injury levels, significantly reduced hepatic apoptosis levels, and significantly reduced several apoptotic biomarkers (ie, B cell lymphoma 2-associated X protein/B cell lymphoma 2 ratio, caspase 3 activity, and heat shock protein 70 expression) in post-OLT-induced HIRI. Moreover, VEGF gene delivery prior to EPC transplantation significantly increased hepatotrophic mitogen expression (ie, epidermal growth factor, heparin-binding epidermal growth factor-like growth factor, hepatocyte growth factor, and transforming growth factor α), angiogenesis, and NOS activity in post-OLT-induced HIRI. In conclusion, exogenous liposomal delivery of the VEGF gene prior to bone marrow-derived EPC transplantation may be an effective strategy in decreasing OLT-induced HIRI. Liver Transplantation 23 804-812 2017 AASLD.

Experimental study on the thermal performance of ultra-thin flat heat pipes with novel multiscale striped composite wick structures.

The rapid development of power-intensive and flexible electronic devices requires thinner heat-dissipation devices with better thermal performance. Ultra-thin flat heat pipe (UTFHP) with striped wick structure is a promising candidate for this application, but its wick structure and thermal performance have not yet been thoroughly studied and optimized for the small concentrated heat source, which is commonly encountered in electronics. In this study, several concentrated striped composite wick (CSCW) structures for 0.6 mm thick UTFHPs are proposed and experimentally investigated. The CSCW consists of copper foam with striped passages converging in the heating zone and double layers of copper screen mesh. The thermal performance of UTFHPs with various composite wick structures is experimentally evaluated. UTFHPs with the proposed structures are also compared with a UTFHP with a more conventional parallel passage composite wick structure. Experimental results show that the CSCW with the hollow structure at the evaporation section is preferred, due to the directed liquid working medium reflux and a large vapor-liquid evaporation interface. Besides, the passage width of the copper foam significantly affects the thermal performance. With the best-performing wick structure, the UTFHP gives the lowest thermal resistance of 0.79 °C/W at a heat load of 23.34 W. Its effective thermal conductivity is approximately 7 times that of copper. The proposed striped wick structure for UTFHPs provides an alternative to handle the hot-spot challenge of electronic devices.

Evaluation of flash drought under the impact of heat wave events in southwestern Germany.

Flash droughts are a recently recognised type of extreme drought defined by the rapid onset and strong intensification of drought conditions. Our understanding of flash drought processes under the influence of heat waves needs to be improved in the context of global warming. Here, we applied a physically based hydrological model, i.e., TRAnspiration and INterception (TRAIN) model to simulate root zone soil moisture (RZSM) and evapotranspiration (ET) with daily time steps and at a 1 × 1 km resolution to identify and assess flash droughts. Two states, Baden-Württemberg (BW) and Rhineland-Palatinate (RP), located in southwestern Germany, were selected as the study areas. Three datasets, the Global Land Evaporation Amsterdam Model (GLEAM) dataset, ERA5-Land (land component of the fifth generation of European ReAnalysis) dataset, and SMAP-L4 (Soil Moisture Active Passive Level-4) dataset, were selected to evaluate the TRAIN simulated RZSM and ET from 1961 to 2016. The results show that the simulated RZSM had the highest correlation with the ERA5-Land products, followed by SMAP-L4 and GLEAM, with regional average correlation coefficients (CC) of 0.765, 0.762, and 0.746, respectively. The CC of the TRAIN simulated ET with ERA5-Land and GLEAM ET were 0.828 and 0.803, respectively. The results of the trend analyses showed a significant increase (p < 0.05) in the number of flash droughts and heat waves in both the BW and RP states. A comparative analysis revealed that the mean duration and onset speed of flash droughts in BW (RP) without heat waves were 10.42 (10.67) pentads and 19.69th percentile/pentad (17.16th percentile/pentad), respectively, while associated with heat waves they were 8.95 (9.53) pentads and 21.77th percentile/pentad (19.91th percentile/pentad), respectively. This indicates that flash droughts under the influence of heat waves are generally shorter in duration but faster in occurrence. The findings of this study have important implications for flash drought assessment, monitoring, and mitigation under the impact of heat waves.

NAMPT inhibition reduces macrophage inflammation through the NAD+/PARP1 pathway to attenuate liver ischemia-reperfusion injury.

BACKGROUND: Liver ischemia-reperfusion injury (IRI) is a major complication in the perioperative period and often leads to liver failure and even systemic inflammation. Previous studies have suggested that the inflammatory response participated in the liver damage during liver IRI. Nicotinamide phosphoribosyl transferase (NAMPT) is required for the maintenance of cellular nicotinamide adenine dinucleotide (NAD+) levels, catalyzing the rate-limiting step in the NAD + salvage pathway. NAMPT is strongly upregulated during inflammation and constitutes an important mechanistic link between inflammatory, metabolic, and transcriptional pathways. The aim of our study was to investigate the role of NAMPT in liver IRI. METHODS: We investigated the effect of pharmacological inhibition of NAMPT with FK866 in models of liver IRI. Liver damage was assessed by HE staining, serum ALT/AST, and TUNEL staining. To examine the mechanism, primary hepatocytes, liver macrophages and RAW264.7 cells were treated with or without NAMPT inhibitors before hypoxia-reoxygenation. Liver macrophages and RAW 264.7 cells activation in vitro was evaluated by western blotting, flow cytometry, and ELISA. RESULT: We found that NAMPT was upregulated in liver IRI. Treatment with the NAMPT inhibitor FK866 ameliorated liver IRI and suppressed inflammation in mice. Although NAMPT plays an important role both in hepatocytes and liver macrophages, we focused on the impact of NAMPT on liver macrophages. The mechanism revealed that FK866 potently inhibited NAMPT activity, as demonstrated by reduced liver NAD+ and intracellular NAD+, resulting in reduced abundance and activity of NAD + -dependent enzymes, including poly (ADP-ribose) polymerase 1 (PARP1), thus inhibiting macrophage M1 polarization by reducing CD86, iNOS, TNF-α, and interleukin (IL)-1ß. Taken together, our data suggested that NAMPT can regulate macrophage polarization through NAD+/PARP1 to ameliorate liver injury, and that FK866-mediated NAMPT blockade may be a therapeutic approach in liver IRI.

P53/miR-34a/SIRT1 positive feedback loop regulates the termination of liver regeneration.

BACKGROUND: The capacity of the liver to restore its architecture and function assures good prognoses of patients who suffer serious hepatic injury, cancer resection, or living donor liver transplantation. Only a few studies have shed light on the mechanisms involved in the termination stage of LR. Here, we attempt to further verify the role of the p53/miR-34a/SIRT1 positive feedback loop in the termination of liver regeneration and its possible relationship with liver cancer. METHOD: We performed partial hepatectomy (PH) in mice transfected with adenovirus (Ade) overexpressing P53 and adenovirus-associated virus (AAV) overexpressing miR-34a. LR was analyzed by liver weight/body weight, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and cell proliferation, and the related cellular signals were investigated. Bile acid (BA) levels during LR were analyzed by metabolomics of bile acids. RESULTS: We found that the P53/miR-34a/SIRT1 positive feedback loop was activated in the late phase of LR. Overexpression of P53 or miR-34a terminated LR early and enhanced P53/miR-34a/SIRT1 positive feedback loop expression and its proapoptotic effect. T-ß-MCA increased gradually during LR and peaked at 7 days after PH. T-ß-MCA inhibited cell proliferation and promoted cell apoptosis via facilitating the P53/miR-34a/SIRT1 positive feedback loop during LR by suppressing FXR/SHP. The P53/miR-34a/SIRT1 positive feedback loop was abolished in HCC patients with P53 mutations. CONCLUSIONS: The P53/miR-34a/SIRT1 positive feedback loop plays an important role in the termination of LR. Our findings showed the molecular and metabolic mechanisms of LR termination and provide a potential therapeutic alternative for treating P53-wild-type HCC patients.

Identification of a Pyroptosis-Related Gene Signature and Effect of Silencing the CHMP4C and CASP4 in Pancreatic Adenocarcinoma.

Background: Pancreatic adenocarcinoma (PAAD) is a highly malignant tumor with an extremely poor prognosis. Pyroptosis has been demonstrated to play an important role in tumor prognosis. However, the expression of pyroptosis-related genes in PAAD and their correlations with prognosis remains unclear. Methods: In this study, the 36 pyroptosis-related genes that were differentially expressed between normal pancreatic tissues and PAAD tissues were identified via the "limma" R package. Based on these differentially expressed genes (DEGs), a five-gene signature was established by applying the least absolute shrinkage and selection operator Cox regression in the TCGA cohort and was validated in the GEO cohort. The Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses of DEGs based on the risk model indicated that immune-associated biological processes and pathways were enriched. In vivo, we detected the expressions of CASP4 and CHMP4C by immunohistochemistry in tumor tissues and adjacent normal tissues. In vitro, we silenced CASP4 and CHMP4C to explore their effects on pancreatic cancer cells. Results: PAAD patients in the low-risk group showed significantly higher survival possibilities than those in the high-risk group. The expressions of CASP4 and CHMP4C in tumor tissue were higher than those in the adjacent normal tissues in vivo. The knockdown of CASP4 significantly inhibited the invasion and migration but not the proliferation of PANC-1 cells. The knockdown of CHMP4C obviously inhibited the proliferation, migration, and invasion of PANC-1 cells. Conclusion: Pyroptosis-related genes play important roles in predicting the prognosis of PAAD, and CASP4 and CHMP4C affect the metastasis of PAAD.

Exploration on the Improvement of Cognitive Function and Inflammatory Response in Perimenopausal Patients with Mild Cognitive Impairment by Self-Prepared Ningshen Prescription.

Objective: To investigate the improvement of cognitive function and inflammatory response in perimenopausal patients with MCI by kidney-tonifying, blood-activating, and mind-nourishing. Methods: 80 perimenopausal patients with MCI who met the diagnostic criteria were divided into a therapy group (n = 40) and a control group (n = 40) according to the treatment method. The control group was given nimodipine (Bayer Pharmaceuticals) 30 mg, 3 times/day orally, while the therapy group was given a decoction of self-prepared Ningshen prescription on the top of the control group (glossy privet fruit, mulberry, aizoon stonecrop, dan-shen root, tuber fleeceflower stem, cyperus rotundus, citron). Patients in the 2 groups were assessed on the MocA scale, ADL scale, and TCM symptom score before and after 2 months of treatment, respectively, to observe whether there was any change in the scale scores and in the levels of inflammatory factors (hs-CRP, Hcy, and IL-1ß) Pre- and posttherapy in the 2 groups. Observe the improvement of clinical symptoms and their safety in both groups (liver and kidney function indicators such as ALT, AST and Cr, dizziness, headache, decrease in blood pressure, flushing, and gastrointestinal reactions). Results: The efficacy of the therapy group was better than that of the control group; the MocA scale and ADL scale scores improved and the TCM symptom score decreased in both groups posttherapy, with the MocA scale and ADL scale scores improving more and the TCM symptom score decreasing more in the therapy group compared with the control group during the same period (p < 0.05). The serum levels of hs-CRP, Hcy, and IL-1ß decreased in both groups posttherapy, with the serum levels of hs-CRP, Hcy, and IL-1ß decreasing more in the therapy group compared to the control group during the same period (p < 0.05). The difference in adverse events between the two groups was not statistically significant when compared by a chi-square test (p > 0.05). The differences in ALT, AST, and Cr levels between the control group and the treatment group before and after treatment were not significant (p > 0.05). Conclusion: Ning Shen prescription can effectively prevent the continued development of cognitive dysfunction in perimenopausal patients with MCI, delay its natural course, and can improve the patients' ability to perform daily activities and improve their TCM symptoms.

Infant Skin Friendly Adhesive Hydrogel Patch Activated at Body Temperature for Bioelectronics Securing and Diabetic Wound Healing.

Adhesive-caused injury is a great threat for infants with premature skin or diabetic patients with fragile skin because extra-strong adhesion might incur pain, inflammation, and exacerbate trauma upon removal. Herein, we present a skin-friendly adhesive hydrogel patch based on protein-polyphenol complexation strategy, which leads to a thermoresponsive network sensitive to body temperature. The adhesion of the hydrogel is smartly activated after contacting with warm skin, whereas the painless detachment is easily realized by placing an ice bag on the surface of the hydrogel. The hydrogel exhibits an immunomodulatory performance that prevents irritation and allergic reactions during long-period contact with the skin. Thus, the hydrogel patch works as a conformable and nonirritating interface to guarantee nondestructively securing bioelectronics on infant skin for healthcare. Furthermore, the hydrogel patch provides gentle adhesion to wounded skin and provides a favorable environment to speed up the healing process for managing diabetic wounds.

LncRNA Snhg1 Plays an Important Role via Sequestering rno-miR-139-5p to Function as a ceRNA in Acute Rejection After Rat Liver Transplantation Based on the Bioinformatics Analysis.

In order to explore the molecular mechanism of acute rejection after liver transplantation (ARLT) in rats, we employed the GSE36798 data set in the Gene Expression Omnibust (GEO) database to construct a related ceRNA network. This dataset contained a total of 16 samples (8 graft samples and 8 plasma samples). Each kind of sample was divided into acute rejection (AR) groups and non-acute rejection (NR) groups, and each group had 4 replicates. First, we performed principal component analysis (PCA) with downloaded data to compare the difference between samples in a macroscopic way. Then, we used the "limma" R package to screen out differentially expressed miRNAs among different groups and used the "pheatmap" R package to perform bidirectional hierarchical clustering analysis for these differentially expressed miRNAs. The miRWalk database and the LncBase V.2 database were applied to predict downstream target genes and upstream-related lncRNAs, respectively. Meanwhile, the String database was used to predict the relationship between target genes, and the aforementioned results were processed for visualization by Cytoscape software. In addition, we exhibited the ultimate ceRNA network, including two lncRNAs, two miRNAs, and 77 mRNAs. Finally, we constructed a rat model of ARLT and applied graft specimens to relevant experimental verification. We found that the lncRNA Snhg1/rno-miR-139-5p axis might be involved in the regulation of ARLT in rats. In short, we demonstrated the differentially expressed miRNA profile, constructed a related ceRNA network, and screened out a possible regulatory axis. In view of the conservation of genes among species, this work was expected to provide a new strategy for the treatment and prevention of ARLT in the clinical setting.

Glutathione-Depleting Organic Metal Adjuvants for Effective NIR-II Photothermal Immunotherapy.

Although photothermal immunotherapy (PTI) is a compelling strategy for tumor therapy, the development of promising photothermal agents to overcome the insufficient immunogenicity of tumor cells and the poor immune response encountered in PTI is still challenging. Herein, commercial small-molecule-based organic metal adjuvants (OMAs) are presented, with second near-infrared photoacoustic and photothermal properties as well as the ability to perturb redox homeostasis to potentiate immunogenicity and immune responsiveness. OMAs, assembled from charge-transfer complexes and characterized by a broad substrate scope, high accessibility, and flexibly tuned optical properties, demonstrate strong phototherapeutic and adjuvant abilities via the depletion of glutathione and cysteine, and subsequently elicit systemic immunity by evoking immunogenic cell death, promoting dendritic cell maturation, and increasing T cell infiltration. Furthermore, programmed cell death protein 1 antibody can be employed to synergize with OMAs to suppress tumor immune evasion and ultimately improve the treatment outcomes. This study unlocks new paradigms to provide a versatile OMA-based scaffold for future practical applications.

HTR1D functions as a key target of HOXA10-AS/miR-340-3p axis to promote the malignant outcome of pancreatic cancer via PI3K-AKT signaling pathway.

Competing endogenous RNAs (ceRNAs) are a newly discovered class of molecular regulators involved in many diseases, especially tumors. Therefore, exploration of the potential ceRNA regulatory network regarding the occurrence and development of pancreatic cancer will provide a new theoretical basis for its diagnosis and treatment. Based on the above background, we applied a bioinformatics approach to mine the public database The Cancer Genome Atlas (TCGA) and performed a series of subsequent molecular biology assays to confirm the hypothesis that HOXA10-AS/ miR-340-3p/HTR1D axis could modulate the malignant progression of pancreatic cancer. Here, our present study demonstrated that the expression level of HTR1D, positively correlated with the level of lncRNA HOXA10-AS and negatively associated with the level of miR-340-3p, was significantly increased in pancreatic cancer cell lines (PCs) compared with that in normal HPDE6-C7 cells. Knocking down HTR1D obviously inhibited the proliferation and migration of PCs and promoted apoptosis by upregulating p-AKT. Elevated miR-340-3p blocked the progression of pancreatic cancer by downregulating HTR1D. Lessened level of lncRNA HOXA10-AS reduced the sponging of miR-340-3p, resulting in an increase of miR-340-3p and a subsequent decrease of HTR1D to ultimately suppress the malignant biological behaviors of cancer. These data illustrated that the HOXA10-AS/miR-340-3p/HTR1D ceRNA axis acted a crucial part in the malignant biological behavior of pancreatic cancer in an AKT-dependent manner.

Effects of Sparassis latifolia neutral polysaccharide on immune activity via TLR4-mediated MyD88-dependent and independent signaling pathways in RAW264.7 macrophages.

Background: Sparassis latifolia (S. latifolia) is a precious edible fungus with multiple biological activities. To date, no study has been investigated the underlying molecular mechanism of immunoregulation caused by the neutral polysaccharide of S. latifolia. Materials and methods: To investigate immunomodulatory mechanism of S. latifolia neutral polysaccharide (SLNP), SLNP was obtained from S. latifolia and its structure, immune receptors and regulation mechanism were studied. Results: S. latifolia neutral polysaccharide consisted of arabinose, galactose, glucose, xylose, and mannose with a molar ratio of 6:12:63:10:5. SLNP was a pyran polysaccharide with a relative molecular weight of 3.2 × 105 Da. SLNP promoted the proliferation of RAW264.7, which further induced the secretions of nitric oxide, TNF-α, IL-6, and IFN-ß, and upregulated the immune receptor TLR4 expression. Moreover, SLNP increased remarkably the levels of TRAF6, IRF3, JNK, ERK, p38, and p38 mRNA and protein mediated by TLR4. Conclusion: S. latifolia neutral polysaccharide regulated the immune function of RAW264.7 through MyD88-dependent and -independent signaling pathways mediated by TLR4 receptor, which suggests that SLNP is a new immunomodulator.

XBP1s repression regulates Kupffer cell polarization leading to immune suppressive effects protecting liver allograft in rats.

BACKGROUND: Polarized kupffer cells (KCs) influence the immune response after liver transplantation. We report an undiscovered immune regulatory role of X-box binding protein 1 (XBP1) on immune function of kupffer cells (KCs). METHODS: Acute rejection model using rats. RESULTS: We found that suppression of XBP1s in lipopolysaccharide (LPS) -activated KCs could increase the expression of arginase-1 (Arg-1) and CD204 but also decrease the expression levels of MHC-II and CD40 and shift the phenotype markers of KCs toward M2 via the janus kinase (JAK) 3- Signal Transducer And Activator Of Transcription (STAT) 6 pathway, presenting an immunosuppressive function by enhancing anti-inflammatory cytokine secretion and accelerating apoptosis of activated T cells. XBP1s over-expression in KCs shift the phenotype markers on KCs towards M1 via the JAK1-STAT1 pathway and have shown a strong pro-inflammatory property. Down-regulation of XBP1s in KCs changed the phenotype and cytokine secretion profile towards M2 and markedly protected the function and structure of allograft liver, prolonging the recipient's survival compared with control and normal saline groups in rats. CONCLUSIONS: Our findings reveal a novel regulatory mechanism of XBP1 in an induced immuno-suppressive state to protect rat's liver allograft via JAK-STAT mediated KCs polarization.

SCARF1 promotes M2 polarization of Kupffer cells via calcium-dependent PI3K-AKT-STAT3 signalling to improve liver transplantation.

OBJECTIVES: This study aimed to investigate the protective effect of SCARF1 on acute rejection (AR), phagocytic clearance of Kupffer cells (KCs), M2 polarization and the exact mechanism underlying these processes. METHODS: AAV was transfected into the portal vein of rats, and AR and immune tolerance (IT) models of liver transplantation were established. Liver tissue and blood samples were collected. The level of SCARF1 was detected via WB and immunohistochemical staining. Pathological changes in liver tissue were detected using HE staining. Apoptotic cells were detected using TUNEL staining. KC polarization was assessed via immunohistochemical staining. Primary KCs were isolated and co-cultured with apoptotic T lymphocytes. Phagocytosis of apoptotic cells and polarization of KCs were both detected using immunofluorescence. Calcium concentration was determined using immunofluorescence and a fluorescence microplate reader. The levels of PI3K, p-AKT and P-STAT3 were assessed via WB and immunofluorescence. RESULTS: Compared to the IT group, the level of SCARF1 was significantly decreased in the AR group. Overexpression of SCARF1 in KCs improved AR and liver function markers. Enhanced phagocytosis mediated by SCARF1 is beneficial for improving the apoptotic clearance of AR and promoting M2 polarization of KCs. SCARF1-mediated enhancement of phagocytosis promotes increased calcium concentration in KCs, thus further activating the PI3K-AKT-STAT3 signalling pathway. CONCLUSIONS: SCARF1 promotes the M2 polarization of KCs by promoting phagocytosis through the calcium-dependent PI3K-AKT-STAT3 signalling pathway.