IL-4-driven alternative macrophage activation and proliferation are characteristic features of both antihelminthic immune responses and wound healing in contrast to classical macrophage activation, which primarily occurs during inflammatory responses. The signaling pathways defining the genome-wide microRNA expression profile as well as the cellular functions controlled by microRNAs during alternative macrophage activation are largely unknown. Hence, in the current work we examined the regulation and function of IL-4-regulated microRNAs in human and mouse alternative macrophage activation.

Intracellular pH plays an important role in the response to cancer invasion. We have designed and synthesized a series of new fluorescent probes (Superior LysoProbes) with the capacity to label acidic organelles and monitor lysosomal pH. Unlike commercially available fluorescent dyes, Superior LysoProbes are lysosome-specific and are highly stable. The use of Superior LysoProbes facilitates the direct visualization of the lysosomal response to lobaplatin elicited in human chloangiocarcinoma (CCA) RBE cells, using confocal laser scanning microscopy. Additionally, we have characterized the role of lysosomes in autophagy, the correlation between lysosome function and microtubule strength, and the alteration of lysosomal morphology during apoptosis. Our findings indicate that Superior LysoProbes offer numerous advantages over previous reagents to examine the intracellular activities of lysosomes.

The downstream targets of histone deacetylase 1 (HDAC1) mediation of platelet-derived growth factor (PDGF)-induced pulmonary arterial smooth muscle cell (PASMC) proliferation are still unclear, and it is also unknown whether activation of peroxisome proliferator-activated receptor γ (PPARγ) modulates HDAC1 and its down-stream targets in PASMCs. The present study aims to address these issues. Our results showed that PDGF dose- and time-dependently induced PASMC proliferation, and this was accompanied by an increase of HDAC1 and cyclin-dependent kinase 4 (CDK4) protein expression as well as a reduction of microRNA-124 (miR-124). Pre-silencing of HDAC1 with small interfering RNA (siRNA) abolished PDGF-induced miR-124 down-regulation, CDK4 protein up-regulation, and PASMC proliferation. In addition, over-expression of miR-124 reversed CDK4 protein elevation and PASMC proliferation caused by PDGF. We further found that pre-incubation of PASMCs with pioglitazone, an agonist of PPARγ receptors, significantly increased PPARγ expression and activity, and blocked PDGF-stimulated cell proliferation by regulating HDAC1-mediated miR-124 and CDK4 expression. Our study indicates that HDAC1/miR-124/CDK4 axis plays an important role in PDGF-induced PASMC proliferation, and activation of PPARγ inhibits PASMC proliferation by acting on HDAC1 pathway.

The expression of microRNA (miR)-140-5p is known to be reduced in both pulmonary arterial hypertension (PAH) patients and monocrotaline-induced PAH models in rat. Identification of target genes for miR-140-5p with bioinformatics analysis may reveal new pathways and connections in PAH. This study aimed to explore downstream target genes and relevant signaling pathways regulated by miR-140-5p to provide theoretical evidences for further researches on role of miR-140-5p in PAH. Multiple downstream target genes and upstream transcription factors (TFs) of miR-140-5p were predicted in the analysis. Gene ontology (GO) enrichment analysis indicated that downstream target genes of miR-140-5p were enriched in many biological processes, such as biological regulation, signal transduction, response to chemical stimulus, stem cell proliferation, cell surface receptor signaling pathways. Kyoto Encyclopedia of Genes and Genome (KEGG) pathway analysis found that downstream target genes were mainly located in Notch, TGF-beta, PI3K/Akt, and Hippo signaling pathway. According to TF-miRNA-mRNA network, the important downstream target genes of miR-140-5p were PPI, TGF-betaR1, smad4, JAG1, ADAM10, FGF9, PDGFRA, VEGFA, LAMC1, TLR4, and CREB. After thoroughly reviewing published literature, we found that 23 target genes and seven signaling pathways were truly inhibited by miR-140-5p in various tissues or cells; most of these verified targets were in accordance with our present prediction. Other predicted targets still need further verification in vivo and in vitro.

Bushen-Yizhi prescription (BSYZ) has been an effective traditional Chinese medicine (TCM) prescription in treating Alzheimer's disease (AD) for hundreds of years. However, the underlying mechanisms have not been fully elucidated yet. In this work, a systems pharmacology approach was developed to reveal the underlying molecular mechanisms of BSYZ in treating AD. First, we obtained 329 candidate compounds of BSYZ by in silico ADME/T filter analysis and 138 AD-related targets were predicted by our in-house WEGA algorithm via mapping predicted targets into AD-related proteins. In addition, we elucidated the mechanisms of BSYZ action on AD through multiple network analysis, including compound-target network analysis and target-function network analysis. Furthermore, several modules regulated by BSYZ were incorporated into AD-related pathways to uncover the therapeutic mechanisms of this prescription in AD treatment. Finally, further verification experiments also demonstrated the therapeutic effects of BSYZ on cognitive dysfunction in APP/PS1 mice, which was possibly via regulating amyloid-β metabolism and suppressing neuronal apoptosis. In conclusion, we provide an integrative systems pharmacology approach to illustrate the underlying therapeutic mechanisms of BSYZ formula action on AD.

Clozapine (CLO) remains an ultimate option for patients with treatment resistant schizophrenia. However, the atypical antipsychotic is often associated with serious metabolic side effects, such as dyslipidemia. Hepatic sterol regulatory element-binding proteins (SREBPs) are central in the allosteric control of a variety of lipid biosynthetic pathways. There is emerging evidence that CLO can activate SREBP pathway and enhance downstream lipogenesis, whereas curcumin (CUR), a major active compound of Curcuma longa, contains hypolipidemic properties. Therefore, in the present study, we examined the protective effects of CUR against CLO-induced lipid disturbance and analyzed the expression of key components in hepatic lipid metabolism. Our data showed that 4-week treatment of CLO (15 mg/kg/day) markedly elevated serum lipid levels and resulted in hepatic lipid accumulation, whereas co-treatment of CUR (80 mg/kg/day) alleviated the CLO-induced dyslipidemia. We further demonstrated that CUR appears to be a novel AMP-activated protein kinase (AMPK) agonist, which enhanced AMPK phosphorylation and mitigated CLO-induced SREBP overexpression. Additionally, CUR also modulated the downstream SREBP-targeted genes involved in fatty acid synthesis and cholesterol metabolism, including fatty acid synthase (FAS) and HMG-CoA reductase (HMGCR). In summary, our study suggests that the suppressed AMPK activity and thereby enhanced SREBP-dependent lipid synthesis could be associated with the antipsychotic-stimulated dyslipidemia, whereas CUR may maintain lipid homeostasis by directly binding to AMPK, indicating that adjunctive use of CUR could be a promising preventive strategy for the drug-induced lipogenesis.

Studies have shown that peroxisome proliferator-activated receptor γ (PPAR γ) is down-regulated in pulmonary vascular lesions of patients with pulmonary hypertension (PH) and animal models of PH. Yet, the detailed molecular mechanisms underlying this alteration are not fully defined; the aim of this study is to address this issue. 5-HT dose- and time-dependently reduced PPAR γ expression and promoted pulmonary artery smooth muscle cells (PASMCs) proliferation; this was accompanied with the phosphorylation of Akt, inactivation of GSK-3β and up-regulation of β-catenin. Importantly, pre-treatment of cells with PI3K inhibitor (Ly294002) or prior silencing of β-catenin with siRNA blocked 5-HT-induced PPAR γ reduction and PASMCs proliferation. In addition, inactivation or lack of GSK-3β or inhibition of proteasome function up-regulated β-catenin protein without affecting its mRNA level and reduced PPAR γ protein expression. Taken together, our study indicates that 5-HT suppresses PPAR γ expression and stimulates PASMCs proliferation by modulating GSK-3β/β-catenin axis, and suggests that targeting this pathway might have potential value in the management of PH.

This study reports a simple and effective technique for the high-throughput fabrication of flexible all-carbon nanotube (CNT) electronics using a photosensitive dry film instead of traditional liquid photoresists. A 10 in. sized photosensitive dry film is laminated onto a flexible substrate by a roll-to-roll technology, and a 5 µm pattern resolution of the resulting CNT films is achieved for the construction of flexible and transparent all-CNT thin-film transistors (TFTs) and integrated circuits. The fabricated TFTs exhibit a desirable electrical performance including an on-off current ratio of more than 105, a carrier mobility of 33 cm2 V-1 s-1, and a small hysteresis. The standard deviations of on-current and mobility are, respectively, 5% and 2% of the average value, demonstrating the excellent reproducibility and uniformity of the devices, which allows constructing a large noise margin inverter circuit with a voltage gain of 30. This study indicates that a photosensitive dry film is very promising for the low-cost, fast, reliable, and scalable fabrication of flexible and transparent CNT-based integrated circuits, and opens up opportunities for future high-throughput CNT-based printed electronics.

Bladder cancer (BC) is one of the most common malignancies in urinary system with a common malignancy in urinary system with a high mortality and recurrence rate, so we attempt to construct a gene signature to predict the prognosis of BCs. We initially established a co-expression network by performing WGCNA analysis and further identified magenta module as key module (P = 8e-05, R2 = 0.4). Subsequently, we screened 12 genes associated with survival from the key module, which were selected to construct an eight-gene signature by establishing a LASSO Cox model. Moreover, we reckoned the risk score (RS) of each sample, through which we could divide samples into two groups (the high-risk and low-risk groups) and verify the signature, in the training set and 3 validation sets (internal test set, GSE13507and E-MTAB-4321). This signature could distinguish between the high- and low- risk patients well (survival analysis: P = 0.015; AUC: 0.61 at 1 year, 0.61 at 3 years and 0.61 at 5 years). In the validation sets, this signature also showed good performance, which was consistent with the training test. Furthermore, we plotted a nomogram to predict the possibility of the overall survival (OS) and three calibration curves to predict the effectiveness of the nomogram, which suggested good value and clinical utility of the nomogram. In conclusion, we established an eight-gene signature, which was probably effective in the prediction of prognosis of patients with BC.

Existing reports identify the involved roles of ZNF139 and its one circular RNA (circRNA), circZNF139, in the progression of various tumors. However, their relevance and function role in bladder cancer (BC) remain largely unexplored. Herein, we aimed to reconnoiter the role and potential mechanism of ZNF139 and circZNF139 in the progression of BC. Firstly, bioinformatics analyses indicated ZNF139 was upregulated in BC tissues and correlated with disease-free survival of BC patients. The subcellular localization and structural analyses of ZNF139 conveyed the possibility of ZNF139 functioning as a transcription factor. Secondly, circZNF139 was validated by bioinformatics analyses and RNase R tests. ZNF139 and circZNF139 were both significantly upregulated in BC cell lines. Functionally, ZNF139/circZNF139 had facilitated effects on the proliferative, clonal, migratory, and invasive potential of BC cells. Mechanistically, GO, KEGG pathway analyses and western blot assays altogether unveiled ZNF139/circZNF139 activated PI3K/AKT pathway in BC cells, supported by the alteration of AKT at phosphorylation level and PI3K at the protein level. Collectively, this work reveals ZNF139 and circZNF139 cooperate closely with each other to promote cell proliferation, migration and invasion via activation of PI3K/AKT pathway in BC.

Peripheral blood (PB) is a potential source of chondrogenic progenitor cells that can be used for cartilage repair and regeneration. However, the cell types, isolation and implantation methods, seeding dosage, ultimate therapeutic effect, and in vivo safety remain unclear.

Ulcerative colitis (UC) is a main form of inflammatory bowel disease. Due to complicated etiology and a high rate of recurrence, it is quite essential to elucidate the underlying mechanism of and search for effective therapeutic methods for UC.

Background: Despite the acknowledged benefits of immune checkpoint inhibitor (ICI)-based combination therapy (either with other checkpoint inhibitors, chemotherapy, targeted therapy, or radiotherapy), little is known about the impact of age on the efficacy of ICI -based combination therapy in non-small-cell lung cancer (NSCLC) patients. We conducted a systematic review and meta-analysis to investigate the differences in the benefits of ICI-based combination therapy for NSCLC by age (cut-off age, 65 years). Methods: We systematically searched randomized controlled trials (RCTs) of ICI plus other therapies including other ICIs, chemotherapies, targeted therapies, or radiotherapies, in the PubMed, Embase, and Cochrane databases with available hazard ratios (HRs) and 95% confidence intervals (CIs) for death and disease progression according to patient age. The search deadline was May 25, 2020. First, we calculated the pooled HRs of younger and older patients based on the HRs from each trial. Second, we assessed the pooled ratio of HRs reported in older patients to the HRs reported in younger patients for progression or death by the random-effects model. An estimated pooled HR ratio was lower than 1 indicating a better effect in older patients and higher than 1 indicating a better effect in younger patients. Results: A total of 10 eligible RCTs were included in our meta-analysis. The pooled HR for overall survival (OS) comparing ICI combined with other therapies to non-ICI regimens was 0.67 (95%CI 0.58-0.78) for younger patients and 0.79 (95%CI 0.70-0.90) for older patients. The pooled HRs ratio for OS reported in older patients compared to younger patients was 1.16 (95%CI 0.99-1.34), indicating no statistically significant difference between younger and older patients. Consistent with the findings related to OS, the analysis also demonstrated that ICI-based immunotherapy could significantly prolong progression-free survival (PFS) in younger and older patients (HR = 0.55; 95% CI 0.47-0.66, and HR = 0.64; 95% CI 0.57-0.71). The same results could also be observed in the pooled HRs ratio for PFS (HR = 1.15, 95%CI 0.91-1.46) indicating comparable efficacy of ICI-based combination therapy in younger and older patients with NSCLC. Conclusion: ICI-based combination therapy vs. non-ICI treatment had comparable efficacy in younger and older NSCLC patients with a cut-off age of 65 years.

The aims of the present study were to investigate the signaling mechanisms for sphingosine-1-phosphate (S1P)-induced airway smooth muscle cells (ASMCs) proliferation and to explore the effect of activation of adenosine monophosphate-activated protein kinase (AMPK) on S1P-induced ASMCs proliferation and its underlying mechanisms. S1P phosphorylated signal transducer and activator of transcription 3 (STAT3) through binding to S1PR2/3, and this further sequentially up-regulated polo-like kinase 1 (PLK1) and inhibitor of differentiation 2 (ID2) protein expression. Pretreatment of cells with S1PR2 antagonist JTE-013, S1PR3 antagonist CAY-10444, knockdown of STAT3, PLK1 and ID2 attenuated S1P-triggered ASMCs proliferation. In addition, activation of AMPK by metformin inhibited S1P-induced ASMCs proliferation by suppressing STAT3 phosphorylation and therefore suppression of PLK1 and ID2 protein expression. Our study suggests that S1P promotes ASMCs proliferation by stimulating S1PR2/3/STAT3/PLK1/ID2 axis, and activation of AMPK suppresses ASMCs proliferation by targeting on STAT3 signaling pathway. Activation of AMPK might benefit asthma by inhibiting airway remodeling.

Objectives: Prostate cancer (PC) is the second most frequent tumor in men, which has a high recurrence rate and poor prognosis. Therefore, this study aimed to identify novel prognostic biomarkers and therapeutic targets for immunotherapy and small molecule drugs for PC treatment. Materials and Methods: The Estimation of Stromal and Immune cells in Malignant Tumor tissues using Expression data (ESTIMATE) algorithm was applied to calculate immune scores and stromal scores of TCGA-PRAD data. Differentially expressed genes (DEGs) were identified using R package "limma." GO, KEGG, and DO analyses were performed to analyze DEGs. Overall survival and disease-free survival analyses were conducted for hub gene identification. To validate the hub gene at the mRNA and protein expression levels, genetic alterations were measured, and CCLE and Cox regression analyses were performed. Connectivity map (CMap) analysis and GSEA were performed for drug exploration and function analysis, respectively. Results: Immune scores ranged from -1795.98 to 2339.39, and stomal scores ranged from -1877.60 to 1659.96. In total, 45 tumor microenvironment (TME)-related DEGs were identified, of which Complement C7 (C7) was selected and validated as a hub gene. CMap analysis identified six small molecule drugs as potential agents for PC treatment. Further analysis demonstrated that C7 expression was significantly correlated with clinical T, pathological N, and immune infiltration level. Conclusions: In conclusion, of the 45 TME-related DEGs, C7 was shown to correlate with PC prognosis in patients, indicating it as a novel prognostic biomarker and immunotherapy target in PC. Additionally, six small molecule drugs showed strong therapeutic potential for PC treatment.

To explore the activity of Modified Tongyou Decoction (MTD) against Eca109 esophageal cancer (EC) cell invasion and metastasis and to ascertain the mechanism of its anticancer activity during the epithelial-mesenchymal transition (EMT) as mediated by the HIF-1α-Snail axis.

The prevalence of antimicrobial resistance in zoonotic Salmonella is a significant ongoing concern over the world. Several reports have investigated the prevalence of Salmonella infections in the farm animals in China; however, there is only limited knowledge about the Salmonella cross-contamination in the slaughterhouses. Moreover, the application of genomic approaches for understanding the cross-contamination in the food-animal slaughterhouses is still in its infancy in China. In the present study, we have isolated 105 Salmonella strains from pig carcasses and environment samples collected from four independent slaughterhouses in Jiangsu, China. All the Salmonella isolates were subjected to whole genome sequencing, bioinformatics analysis for serovar predictions, multi-locus sequence types, antimicrobial resistance genes, and plasmid types by using the in-house Galaxy platform. The antimicrobial resistance of Salmonella isolates was determined using a minimal inhibitory concentration assay with 14 antimicrobials. We found that the predominant serovar and serogroup was S. Derby and O:4(B), with a prevalence of 41.9 and 55%, respectively. All the isolates were multidrug-resistant and the highest resistance was observed against antimicrobials tetracycline (95.4%) and trimethoprim and sulfamethoxazole (90.9%). Additionally, the colistin-resistant determinant mcr-1 gene was detected in five (4.8%) strains. Our study demonstrated the prevalence of antimicrobial resistance in Salmonella strains isolated from pig slaughterhouses in China and suggested that the genomic platform can serve as routine surveillance along with the food-chain investigation.

Lung cancer is the most frequent cancer worldwide with a poor prognosis. Identification of novel cancer targets and useful therapeutic strategies without toxicity are urgently needed. In this study, we screened natural products for anticancer bioactivity in a library consisting of 429 small molecules. We demonstrated for the first time that daurisoline, a constituent of Rhizoma Menispermi, repressed lung cancer cell proliferation by inducing cell cycle arrest at the G1 phase. Furthermore, daurisoline was found not only to suppress the growth of lung tumor xenografts in animals without obvious side effects, but also to inhibit cell migration and invasion. Mechanistically, quantitative proteomics and bioinformatics analyses, Western blotting and qRT-PCR confirmed that daurisoline exerted its anticancer effects by inhibiting the expression levels of β-catenin and its downstream targets c-myc and cyclin D1. Furthermore, our data from Drug Affinity Responsive Target Stability (DARTS), isothermal titration calorimetry (ITC) and a series of functional assays demonstrated that daurisoline could target HSP90 directly and disrupt its interaction with β-catenin, therefore increasing the ubiquitin-mediated proteasomal degradation of β-catenin. This study reveals that daurisoline could be a promising therapeutic strategy for the treatment of lung cancer.

In recent years, many studies have discovered that cystatin C (Cys C) may play an important role in respiratory diseases, especially in chronic obstructive pulmonary disease (COPD). However, the findings of these studies were inconsistent. This systematic review and meta-analysis aimed to assess the relationship between serum Cys C and COPD.

Word reading has been found to be associated with different neural networks in different languages, with greater involvement of the lexical pathway for opaque languages and greater invovlement of the sub-lexical pathway for transparent langauges. However, we do not know whether this language divergence can be demonstrated in second langauge learners, how learner's metalinguistic ability would modulate the langauge divergence, or whether learning method would interact with the language divergence. In this study, we attempted to answer these questions by comparing brain activations of Chinese and Spanish word reading in native English-speaking adults who learned Chinese and Spanish over a 2 week period under three learning conditions: phonological, handwriting, and passive viewing. We found that mapping orthography to phonology in Chinese had greater activation in the left inferior frontal gyrus (IFG) and left inferior temporal gyrus (ITG) than in Spanish, suggesting greater invovlement of the lexical pathway in opaque langauges. In contrast, Spanish words evoked greater activation in the left superior temporal gyrus (STG) than English, suggesting greater invovlement of the sublexical pathway for transparant languages. Furthermore, brain-behavior correlation analyses found that higher phonological awareness and rapid naming were associated with greater activation in the bilateral IFG for Chinese and in the bilateral STG for Spanish, suggesting greater language divergence in participants with higher meta-linguistic awareness. Finally, a significant interaction between the language and learning condition was found in the left STG and middle frontal gyrus (MFG), with greater activation in handwriting learning than viewing learning in the left STG only for Spanish, and greater activation in handwriting learning than phonological learning in the left MFG only for Chinese. These findings suggest that handwriting facilitates assembled phonology in Spanish and addressed phonology in Chinese. In summary, our study suggests different mechanisms in learning different L2s, providing important insights into neural plasticity and important implications in second language education.