Hepatic macrophages have been considered as a therapeutic target for liver fibrosis treatment, and phosphatidylserine (PS)-containing nanoparticles are commonly used to mimic apoptotic cells that can specifically regulate macrophage functions, resulting in anti-inflammatory effects. This study was designed to test the efficacy of PS-modified nanostructured lipid carriers (mNLCs) containing curcumin (Cur) (Cur-mNLCs) in the treatment of liver fibrosis in a rat model. Carbon tetrachloride-induced liver fibrosis in rats was used as an experimental model, and the severity of the disease was examined by both biochemical and histological methods. Here, we showed that mNLCs were spherical nanoparticles with decreased negative zeta potentials due to PS decoration, and significantly increased both mean residence time and area under the curve of Cur. In the rats with liver fibrosis, PS-modification of NLCs enhanced the nanoparticles targeting to the diseased liver, which was evidenced by their highest accumulation in the liver. As compared to all the controls, Cur-mNLCs were significantly more effective at reducing the liver damage and fibrosis, which were indicated by in Cur-mNLCs-treated rats the least increase in liver enzymes and pro-inflammatory cytokines in the circulation, along with the least increase in collagen fibers and alpha smooth muscle actin and the most increased hepatocyte growth factors (HGF) and matrix metalloprotease (MMP) two in the livers. In conclusion, PS-modified NLCs nanoparticles prolonged the retention time of Cur, and enhanced its bioavailability and delivery efficiency to the livers, resulting in reduced liver fibrosis and up-regulating hepatic expression of HGF and MMP-2.

Accurately diagnosing pleural effusion is a frequent and significant problem in clinical practice. Combining pleural biomarkers with patients' age may be a valuable method for diagnosing TPE. We sought to evaluate the influence of age on diagnostic values of pleural adenosine deaminase (ADA), interferon-gamma (IFN-γ), and interleukin 27 (IL-27) for tuberculous pleural effusion (TPE).

The impact of gut microbiota and its metabolites on fat metabolism have been widely reported in human and animals. However, the critical mediators and the signal transductions are not well demonstrated. As ovipara, chicken represents a specific case in lipid metabolism that liver is the main site of lipid synthesis. The aim of this study is to elucidate the linkage of gut microbiota and fat synthesis in broiler chickens. The broilers were subjected to dietary treatments of combined probiotics (Animal bifidobacterium: 4 × 108 cfu/kg; Lactobacillus plantarum: 2 × 108 cfu/kg; Enterococcus faecalis: 2 × 108 cfu/kg; Clostridium butyrate: 2 × 108 cfu/kg, PB) and guar gum (1 g/kg, GG), respectively. Results showed that dietary supplementation of PB and GG changed the cecal microbiota diversity, altered short chain fatty acids (SCFAs) contents, and suppressed lipogenesis. In intestinal epithelial cells (IECs), SCFAs (acetate, propionate, and butyrate) up-regulated the expression of glucagon-like peptide-1 (GLP-1) via mitogen-activated protein kinase (MAPK) pathways, mainly via the phospho - extracellular regulated protein kinase (ERK) and phospho-p38 mitogen activated protein kinase (p38 MAPK) pathways. GLP-1 suppressed lipid accumulation in primary hepatocytes with the involvement of (AMP)-activated protein kinase/Acetyl CoA carboxylase (AMPK/ACC) signaling. In conclusion, the result suggests that SCFAs-induced GLP-1 secretion via MAPK pathway, which links the regulation of gut microbiota on hepatic lipogenesis in chickens.

Ardisia pusilla A. DC., family Myrsinaceae, is a traditional Chinese medicine named Jiu Jie Long with a variety of pharmacological functions including anti-cancer activities. In this study, we purified a natural triterpenoid saponin, ardipusilloside I, from Ardisia pusilla, and show that it exhibits inhibitory activities in human mucoepidermoid carcinoma Mc3 cells. We also investigated the underlying mechanisms of proliferation inhibition that ardipusilloside I exerts on Mc3 cells.

Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) have been demonstrated to be expressed on pleural mesothelial cells (PMCs), and to mediate leukocyte adhesion and migration; however, little is known about whether adhesion molecule-dependent mechanisms are involved in the regulation of CD4(+) T cells by PMCs in tuberculous pleural effusion (TPE).

RNA binding proteins (RBPs) are a large protein family that plays important roles at almost all levels of gene regulation through interacting with RNAs, and contributes to numerous biological processes. However, the complete list of eukaryotic RBPs including human is still unavailable. Here, we systematically identified RBPs in 162 eukaryotic species based on both computational analysis of RNA binding domains (RBDs) and large-scale RNA binding proteomic data, and established a comprehensive eukaryotic RBP database, EuRBPDB (http://EuRBPDB.syshospital.org). We identified a total of 311 571 RBPs with RBDs (corresponding to 6368 ortholog groups) and 3,651 non-canonical RBPs without known RBDs. EuRBPDB provides detailed annotations for each RBP, including basic information and functional annotation. Moreover, we systematically investigated RBPs in the context of cancer biology based on published literatures, PPI-network and large-scale omics data. To facilitate the exploration of the clinical relevance of RBPs, we additionally designed a cancer web interface to systematically and interactively display the biological features of RBPs in various types of cancers. EuRBPDB has a user-friendly web interface with browse and search functions, as well as data downloading function. We expect that EuRBPDB will be a widely-used resource and platform for both the communities of RNA biology and cancer biology.

Although some parameters of positron emission tomography with 18F-fluorodeoxyglucose (18F-FDG) and computed tomography (PET-CT) are somehow helpful in differentiating malignant pleural effusion (MPE) from benign effusions, no individual parameter offers sufficient evidence for its implementation in the clinical practice. The aim of this study was to establish the diagnostic accuracy of a scoring system based on PET-CT (the PET-CT score) in diagnosing MPE.

Therapeutic goals for rheumatoid arthritis (RA) consist of inhibiting the inflammatory response and repairing the damaged bone/cartilage. Tissue engineering could achieve both goals, however, it was hindered due to the lack of biologically relevant tissue complexity, limitation in covering the entire polyarthritis lesions and requirement of extra surgical implantation. Integrating nanotechnologies into clinically sized implants represents a major opportunity to overcome these problems. Herein, we designed a sialic acid (SA)-modified chitosan oligosaccharide-based biphasic calcium phosphate (BCP), a biomimetic nanoplatform that could load with methotrexate. We found that SA modification could not only improve the accumulation of the designed organic-inorganic nanoplatform in arthritic paws (34.38% higher than those without SA modification at 48 h), but also cooperate with BCP to exert synergetic mineralization of calcium phosphate, allowing more osteoblasts to attach, proliferate and differentiate. The more differentiated osteoblasts produced 4.46-fold type I collagen and 2.60-fold osteoprotegerin compared to the control group. Besides, the disassembled nanorods released chitosan oligosaccharide-based micelles, revealing a cartilage-protective effect by reducing the loss of glycosaminoglycan. All these improvements contributed to the light inflammatory response and reduced destruction on cartilage/bone. The findings provide a novel strategy for RA therapy via nanometer-scale dimension mimicking the natural tissues.

In an attempt to improve therapeutic efficacy of dexamethasone (DXM)-loaded solid lipid nanoparticles (NPs) for renal ischemia-reperfusion injury (IRI)-induced acute renal injury (AKI), sialic acid (SA) is used as a ligand to target the inflamed vascular endothelium. DXM-loaded SA-conjugated polyethylene glycol (PEG)ylated NPs (SA-NPs) are prepared via solvent diffusion method and show the good colloidal stability. SA-NPs reduce apoptotic human umbilical vein endothelial cells (HUVECs) via downregulating oxidative stress-induced Bax, upregulating Bcl-xL, and inhibiting Caspase-3 and Caspase-9 activation. Cellular uptake results suggest SA-NPs can be specifically internalized by the inflamed vascular endothelial cells (H2O2-pretreated HUVECs), and the mechanism is associated with the specific binding between SA and E-selectin receptor expressed on the inflamed vascular endothelial cells. Bio-distribution results further demonstrated the enhanced renal accumulation of DXM is achieved in AKI mice treated with SA-NPs, and its content is 2.70- and 5.88-fold higher than those treated with DXM and NPs at 6 h after intravenous administration, respectively. Pharmacodynamic studies demonstrate SA-NPs effectively ameliorate renal functions in AKI mice, as reflected by improved blood biochemical indexes, histopathological changes, oxidative stress levels and pro-inflammatory cytokines. Moreover, SA-NPs cause little negative effects on lymphocyte count and bone mineral density while DXM leads to severe osteoporosis. It is concluded that SA-NPs provide an efficient and targeted delivery of DXM for ischemia-reperfusion-induced injury-induced AKI, with improved therapeutic outcomes and reduced adverse effects.

Immunocompromised individuals are particularly vulnerable to viral infections and reactivation, especially endogenous herpes viruses such as Epstein-Barr virus (EBV), a member of oncogenic gamma-herpesviruses, which are commonly linked to pneumonia and consequently significant morbidity and mortality. In the study of human and animal oncogenic gammaherpesviruses, the murine gamma-herpesviruses-68 (MHV-68) model has been applied, as it can induce pneumonia in immunocompromised mice. Mesenchymal stem cell (MSC) treatment has demonstrated therapeutic potential for pneumonia, as well as other forms of acute lung injury, in preclinical models. In this study, we aim to investigate the therapeutic efficacy and underlying mechanisms of human bone marrow-derived MSC (hMSC) on MHV-68-induced pneumonia. We found that intravenous administration of hMSCs significantly reduced lung damages, diminished inflammatory mediators and somehow inhibited MHV-68 replication. Furthermore, hMSCs treatment can regulate innate immune response and induce macrophage polarization from M1 to M2 phenotype, could significantly alter leukocyte infiltration and reduce pulmonary fibrosis. Our findings with co-culture system indicated that hMSCs effectively reduced the secretion of of inflammation-related factors and induced a shift in macrophage polarization, consistent with in vivo results. Further investigations revealed that hMSCs treatment suppressed the activation of macrophage ROS/NLRP3 signaling pathway in vivo and in vitro. Moreover, administration of MCC950, a selective NLRP3 inhibitor has been shown to effectively reduce ROS production and subsequently alleviate inflammation induced by MHV-68. Taken together, our work has shown that hMSCs can effectively protect mice from lethal MHV-68 pneumonia, which may throw new light on strategy for combating human EBV-associated pneumonia.

Eutrema salsugineum (= Thellungiella salsuginea Brassicaceae), a species growing in highly saline habitats, is a good model for use in salt-stress research. However, its evolutionary migrations and genetic variations within and between disjunct regions from central Asia to northern China and North America remain largely unknown. We examined genetic variations and phylogeographic patterns of this species by sequencing ITS, 9 chloroplast (cp) DNA fragments (4379 bp) and 10 unlinked nuclear loci (6510 bp) of 24 populations across its distributional range. All markers suggested the high genetic poverty of this species and the limited number of genetic variations recovered was congruently partitioned between central Asia, northern China and North America. Further modelling of nuclear population-genetic data based on approximate bayesian computation (ABC) analyses indicated that the long-distance dispersals after the recent origin of E. salsugineum may have occurred from central Asia to the other two regions respectively within 20000 years. The fast demographic expansions should have occurred in northern China in a more recent past. Our study highlights the importance of using ABC analyses and nuclear population genetic data to trace evolutionary migrations of the disjunct distributions of the plants in the recent past.

Specific delivery of chemotherapy drugs and magnetic resonance imaging (MRI) contrast agent into tumor cells is one of the issues to highly efficient tumor targeting therapy and magnetic resonance imaging. Here, A54 peptide-functionalized poly(lactic-co-glycolic acid)-grafted dextran (A54-Dex-PLGA) was synthesized. The synthesized A54-Dex-PLGA could self-assemble to form micelles with a low critical micelle concentration of 22.51 μg. mL-1 and diameter of about 50 nm. The synthetic A54-Dex-PLGA micelles can encapsulate doxorubicin (DOX) as a model anti-tumor drug and superparamagnetic iron oxide (SPIO) as a contrast agent for MRI. The drug-encapsulation efficiency was about 80% and the in vitro DOX release was prolonged to 72 hours. The DOX/SPIO-loaded micelles could specifically target BEL-7402 cell line. In vitro MRI results also proved the specific binding ability of A54-Dex-PLGA/DOX/SPIO micelles to hepatoma cell BEL-7402. The in vivo MR imaging experiments using a BEL-7402 orthotopic implantation model further validated the targeting effect of DOX/SPIO-loaded micelles. In vitro and in vivo anti-tumor activities results showed that A54-Dex-PLGA/DOX/SPIO micelles revealed better therapeutic effects compared with Dex-PLGA/DOX/SPIO micelles and reduced toxicity compared with commercial adriamycin injection.

Animal manure comprises an important reservoir for antibiotic resistance genes (ARGs), but the variation in ARGs during anaerobic digestion at various temperatures and its underlying mechanism remain unclear. Thus, we performed anaerobic digestion using dairy manure at three temperature levels (moderate: 20 °C, mesophilic: 35 °C, and thermophilic: 55 °C), to analyze the dynamics of ARGs and bacterial communities by quantitative PCR and 16S rRNA gene sequencing. We found that 8/10 detected ARGs declined and 5/10 decreased more than 1.0 log during thermophilic digestion, whereas only four and five ARGs decreased during moderate and mesophilic digestion, respectively. The changes in ARGs and bacterial communities were similar under the moderate and mesophilic treatments, but distinct from those in the thermophilic system. Potential pathogens such as Bacteroidetes, Proteobacteria, and Corynebacterium were removed by thermophilic digestion but not by moderate and mesophilic digestion. The bacterial community succession was the dominant mechanism that influenced the variation in ARGs and integrons during anaerobic digestion. Thermophilic digestion decreased the amount of mesophilic bacteria (Bacteroidetes and Proteobacteria) carrying ARGs. Anaerobic digestion generally decreased the abundance of integrons by eliminating the aerobic hosts of integrons (Actinomycetales and Bacilli). Thermophilic anaerobic digestion is recommended for the treatment and reuse of animal manure.

The numbers of IL-27(+) CD4(+) and IL-27(+) CD8(+) T cells have been found to be increased in tuberculous pleural effusion (TPE) as compared with malignant pleural effusion (MPE). The objective of the present study was to investigate whether pleural IL-27(+) CD4(+) and IL-27(+) CD8(+) T cells can distinguish patients with TPE from those with MPE. Paired specimen of pleural fluid and peripheral blood were collected from 35 patients with TPE and 46 MPE. The numbers of IL-27(+) CD4(+) and IL-27(+) CD8(+) T cells were simultaneously determined by flow cytometry. Receiver operating characteristic curve analysis was used to evaluate the capacity of IL-27(+) CD4(+) and IL-27(+) CD8(+) T cells to differentiate TPE from MPE. The sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), positive predictive value (PPV), and negative predictive value (NPV) of IL-27(+) CD4(+) T cells were 94.3%, 93.5%, 14.46, 0.06, 91.7%, and 95.6%, respectively. The sensitivity, specificity, PLR, NLR, PPV and NPV of IL-27(+) CD8(+) T cells were 80.0%, 93.5%, 12.27, 0.21, 90.3% and 86.0%, respectively. The number of IL-27(+) CD4(+) in pleural fluid is a helpful diagnostic biomarker for the diagnosis of TPE, which performs better than that of IL-27(+) CD8(+) T cells.

In the present study, we demonstrate that Kaempferol inhibited survival and proliferation of established human hepatocellular carcinoma (HCC) cell lines (HepG2, Huh-7, BEL7402, and SMMC) and primary human HCC cells. Kaempferol treatment in HCC cells induced profound AMP-activated protein kinase (AMPK) activation, which led to Ulk1 phosphorylation, mTOR complex 1 inhibition and cell autophagy. Autophagy induction was reflected by Beclin-1/autophagy gene 5 upregulation and p62 degradation as well as light chain 3B (LC3B)-I to LC3B-II conversion and LC3B puncta formation. Inhibition of AMPK, via AMPKα1 shRNA or dominant negative mutation, reversed above signaling changes. AMPK inhibition also largely inhibited Kaempferol-induced cytotoxicity in HCC cells. Autophagy inhibition, by 3-methyaldenine or Beclin-1 shRNA, also protected HCC cells from Kaempferol. Kaempferol downregulated melanoma antigen 6, the AMPK ubiquitin ligase, causing AMPKα1 stabilization and accumulation. We conclude that Kaempferol inhibits human HCC cells via activating AMPK signaling.

The present study was carried out to observe the impact of advanced glycation end products (AGEs) on collagen I derived from vaginal fibroblasts in the context of pelvic organ prolapse (POP), and explore the downstream effects on MAPK and nuclear factor-κB (NF-κB) signaling. After treating primary cultured human vaginal fibroblasts (HVFs) derived from POP and non-POP cases with AGEs, cell counting was carried out by sulforhodamine B. The expression levels of collagen I, receptor of advanced glycation end products (RAGE), matrix metalloproteinase-1 (MMP-1) and tissue inhibitor of metalloproteinase-1 (TIMP-1) were detected by western blot analysis and PCR. RAGE, MAPK and NF-κB were molecularly and pharmacologically-inhibited by siRNA, SB203580 and PDTC, respectively, and downstream changes were detected by western blot analysis and PCR. Inhibition of HVF proliferation by AGEs occurred more readily in POP patients than that noted in the controls. After treatment with AGEs, collagen I levels decreased and MMP-1 levels increased to a greater extent in the HVFs of POP than that noted in the controls. During this same period, RAGE and TIMP-1 levels remained stable. Following treatment with AGEs and RAGE pathway inhibitors by siRNA, SB203580 and PDTC, the impact induced by AGEs was diminished. The inhibition of p-p38 MAPK alone was not able to block the promoting effect of AGEs on the levels of NF-κB, which suggests that AGEs may function through other pathways, as well as p-p38 MAPK. On the whole, this study demonstrated that AGEs inhibited HVF proliferation in POP cases and decreased the expression of collagen I through RAGE and/or p-p38 MAPK and NF-κB-p-p65 pathways. Our results provide important insights into the collagen I metabolism in HVFs in POP.

Imbalance in the cellular redox system is thought to be associated with the induction and progression of breast cancers, and heme proteins may regulate the redox balance. Cytochrome b5 (Cyt b5) is a small mitochondrial heme protein. Its function and regulating mechanism in breast cancer remain unknown. In this study, we elucidated the level of endogenous oxidative stress in breast cancer cells, MCF-7 cells (hormone receptor-positive cells) and MDA-MB-231 cells (triple-negative cells), and investigated the difference in Cyt b5 content. Based on the low content of Cyt b5 in MDA-MB-231 cells, the overexpression of Cyt b5 was found to regulate the oxidative stress and apoptosis cascades, including ERK1/2 and Akt signaling pathways. The overexpressed Cyt b5 MDA-MB-231 cells were shown to exhibit decreased oxidative stress, less phosphorylation of ERK1/2 and Akt, and less cleavage of caspases 3 and 9 upon treatment with H2O2, as compared to those of normal MDA-MB-231 cells. Moreover, the overexpressed Cyt b5 most likely functioned by interacting with its protein partner, Cyt c, as suggested by co-immunoprecipitation studies. These results indicated that Cyt b5 has different effects on breast cancer cells of different phenotypes, which provides useful information for understanding the multiple roles of Cyt b5 and provides clues for clinical treatment.

We aimed to design RGD-anchored liposomes encapsulating an antipyroptosis drug that could efficiently target macrophages and relieve the rate of cytokine release syndrome, providing a new strategy for sepsis treatment, especially sepsis-induced acute renal injury.

Purpose: To develop a model to select appropriate candidates for irradiation stent placement among patients with unresectable pancreatic cancer with malignant biliary obstruction (UPC-MBO). Methods: This retrospective study included 106 patients treated with an irradiation stent for UPC-MBO. These patients were randomly divided into a training group (74 patients) and a validation group (32 patients). A clinical model for predicting restenosis-free survival (RFS) was developed with clinical predictors selected by univariate and multivariate analyses. After integrating the radiomics signature, a combined model was constructed to predict RFS. The predictive performance was evaluated with the concordance index (C-index) in both the training and validation groups. The median risk score of progression in the training group was used to divide patients into high- and low-risk subgroups. Results: Radiomics features were integrated with clinical predictors to develop a combined model. The predictive performance was better in the combined model (C-index, 0.791 and 0.779 in the training and validation groups, respectively) than in the clinical model (C-index, 0.673 and 0.667 in the training and validation groups, respectively). According to the median risk score of 1.264, the RFS was significantly different between the high- and low-risk groups (p < 0.001 for the training group, and p = 0.016 for the validation group). Conclusions: The radiomics-based model had good performance for RFS prediction in patients with UPC-MBO who received an irradiation stent. Patients with slow progression should consider undergoing irradiation stent placement for a longer RFS.

5-Fluorouracil (5-FU) is a common chemotherapy drug for patients with advanced colorectal cancer; however, many patients develop resistance to 5-FU and suffer from treatment failure. Discoidin domain receptor 1 (DDR1) is upregulated in multiple cancers and positively associated with chemoresistance. We explored the effect of DDR1a on the cytotoxicity induced by 5-FU in LoVo cells and the underlying mechanism. Therefore, DDR1a overexpression (DDR1ahigh) and knockdown in LoVo cell lines (shDDR1a) were constructed to detect cell viability and cytotoxicity induced by 5-FU. The results showed that cell viability of DDR1ahigh cells was higher in comparison with that of the control group. When 5-FU (5 µM) was administered, the percentage of apoptotic cells, cytochrome C release and caspase-3 activity was found to be higher in the shDDR1a group than that in the control group. Both of PI3K and MDM2 proteins level decreased in DDR1ahigh and shDDR1a, but the BAX/Bcl-2 level in the shDDR1a group increased compared to that in the control. Therefore, DDR1a might be a potential therapeutic target for 5-FU chemoresistance in colorectal cancer.