Niemann-Pick type C1 (NPC1) disease is an inherited lysosomal storage disease caused by mutation of the Npc1 gene, resulting in a progressive accumulation of unesterified cholesterol and glycolipids in lysosomes of multiple tissues and leading to neurodegeneration and other disease. In Npc1 mutant mice, retinal degeneration including impaired visual function, lipofuscin accumulation in the pigment epithelium and ganglion cells as well as photoreceptor defects has been found. However, the pathologies of other individual cell types of the retina in Npc1 mutant mice are still not fully clear. We hypothesized that horizontal cells, amacrine cells, bipolar cells and glial cells are also affected in the retina of Npc1 mutant mice.

Insulin-like growth factor 1 receptor (IGF1R) is a transmembrane receptor that is activated by insulin-like growth factor 1 (IGF-1) and by a related hormone called IGF-2. It belongs to the large class of tyrosine kinase receptors and plays an important role in colorectal cancer etiology and progression. In this study, we used bioinformatic analyses to search for miRNAs that potentially target IGF1R. We identified specific target sites for miR-143 and miR-145 (miR-143/145) in the 3'-untranslated region (3'-UTR) of the IGF1R gene. These miRNAs are members of a cluster of miRNAs that have been reported to exhibit tumor suppressor activity. Consistent with the bioinformatic analyses, we identified an inverse correlation between miR-143/145 levels and IGF1R protein levels in colorectal cancer tissues. By overexpressing miR-143/145 in Caco2, HT29 and SW480 colorectal cancer cells, we experimentally validated that miR-143/145 directly recognizes the 3'-UTR of the IGF1R transcript and regulates IGF1R expression. Furthermore, the biological consequences of the targeting of IGF1R by miR-143/145 were examined by cell proliferation assays in vitro. We demonstrated that the repression of IGF1R by miR-143/145 suppressed the proliferation of Caco2 cells. Taken together, our findings provide evidence for a role of the miR-143/145 cluster as a tumor suppressor in colorectal cancer through the inhibition of IGF1R translation.

Niemann-Pick disease, type C1 (Npc1), is an atypical lysosomal storage disorder caused by autosomal recessive inheritance of mutations in Npc1 gene. In the Npc1 mutant mice (Npc1-/- ), the initial manifestation is enlarged spleen, concomitant with free cholesterol accumulation. Telocytes (TCs), a novel type of interstitial cell, exist in a variety of tissues including spleen, presumably thought to be involved in many biological processes such as nursing stem cells and recruiting inflammatory cells. In this study, we found that the spleen is significantly enlarged in Npc1-/- mice, and the results from transmission electron microscopy examination and immunostaining using three different TCs markers, c-Kit, CD34 and Vimentin revealed significantly increased splenic TCs in Npc1-/- mice. Furthermore, hematopoietic stem cells and macrophages were also elevated in Npc1-/- spleen. Taken together, our data indicate that splenic TCs might alleviate the progress of splenic malfunction via recruiting hematopoietic stem cells and macrophages.

Previous studies have demonstrated that mesenchymal stem cell (MSC) transplantation reduces the severity of collagen-induced arthritis (CIA) in mice, which is a model for rheumatoid arthritis (RA) in humans. However, the underlying molecular mechanisms remain ill-defined. Here, we showed that MSC transplantation reduced the activities of NF-κB signaling and decreased microRNA-548e (miR-548e) levels in the joint tissue in CIA-mice, seemingly through activation of transforming growth factor β receptor signaling. Bioinformatics analyses revealed that miR-548e inhibited protein translation of the NF-κB inhibitor, IκB, through binding to the 3'-UTR of the IκB mRNA. MSCs co-transplanted with adeno-associated virus (AAV) carrying miR-548e abolished the therapeutic effects of MSCs on CIA. On the other hand, transplantation of AAV carrying antisense of miR-548e (as-miR-548e) partially mimicked the effects of MSC transplantation on CIA. Together, these data suggest that MSC transplantation may alleviate experimental RA partially through suppressing miR-548e-mediated IκB inhibition.

Berberine (BBR) has been shown to exhibit protective effects against diabetes and dyslipidemia. Previous studies have indicated that BBR modulates lipid metabolism and inhibits hepatic gluconeogensis by decreasing expression of Hepatocyte Nuclear Factor-4α (HNF-4α). However, the mechanism involved in this process was unknown. In the current study, we examined the mechanism of how BBR attenuates hepatic gluconeogenesis and the lipid metabolism alterations observed in type 2 diabetic (T2D) mice and in palmitate (PA)-incubated HepG2 cells. Treatment with BBR for 4 weeks improve all biochemical parameters compared to T2D mice. Treatment of T2D mice for 4 weeks or treatment of PA-incubated HepG2 cells for 24 h with BBR decreased expression of HNF-4α and the microRNA miR122, the key gluconeogenesis enzymes Phosphoenolpyruvate carboxykinase (PEPCK) and Glucose-6-phosphatase (G6Pase) and the key lipid metabolism proteins Sterol response element binding protein-1 (SREBP-1), Fatty acid synthase-1 (FAS-1) and Acetyl-Coenzyme A carboxylase (ACCα) and increased Carnitine palmitoyltransferase-1(CPT-1) compared to T2D mice or PA-incubated HepG2 cells. Expression of HNF-4α in HepG2 cells increased expression of gluconeogenic and lipid metabolism enzymes and BBR treatment or knock down of miR122 attenuated the effect of HNF-4α expression. In contrast, BBR treatment did not alter expression of gluconeogenic and lipid metabolism enzymes in HepG2 cells with knockdown of HNF-4α. In addition, miR122 mimic increased expression of gluconeogenic and lipid metabolism enzymes in HepG2 cells with knockdown of HNF-4α. These data indicate that miR122 is a critical regulator in the downstream pathway of HNF-4α in the regulation of hepatic gluconeogenesis and lipid metabolism in HepG2 cells. The effect of BBR on hepatic gluconeogenesis and lipid metabolism is mediated through HNF-4α and is regulated downstream of miR122. Our data provide new evidence to support HNF-4α and miR122 regulated hepatic gluconeogenesis and lipid metabolism as promising therapeutic targets for the treatment of T2D.

This study aims to explore the molecular mechanisms underlying sphingosine kinase 1 (SphK1) inducing pulmonary vascular remodeling and resveratrol suppressing pulmonary arterial hypertension (PAH).

Biogenic compounds are important materials for drug discovery and chemical biology. In this work, we report a quasi-biogenic molecule generator (QBMG) to compose virtual quasi-biogenic compound libraries by means of gated recurrent unit recurrent neural networks. The library includes stereo-chemical properties, which are crucial features of natural products. QMBG can reproduce the property distribution of the underlying training set, while being able to generate realistic, novel molecules outside of the training set. Furthermore, these compounds are associated with known bioactivities. A focused compound library based on a given chemotype/scaffold can also be generated by this approach combining transfer learning technology. This approach can be used to generate virtual compound libraries for pharmaceutical lead identification and optimization.

Given that most bladder cancers (BCs) are diagnosed in advanced stages with poor prognosis, this study aims to find novel biomarkers associated with the progression and prognosis in patients with BC. 1,779 differentially expressed genes (DEGs) between BC samples and normal bladder tissues were identified in total. Then, 24 DEGs were regarded as candidate hub genes by constructing a protein-protein interaction (PPI) network and a random forest model. Among them, six genes (BUB1B, CCNB1, CDK1, ISG15, KIF15, and RAD54L) were eventually identified by using five analysis methods (one-way Analysis of Variance analysis, spearman correlation analysis, distance correlation analysis, receiver operating characteristic curve, and expression values comparison), which were correlated with the progression and prognosis of BC. Moreover, the validation of hub genes was conducted based on GSE13507, Oncomine, and CBioPortal. Results of univariate Cox regression analysis showed that the expression levels of all the hub genes were influence features of overall survival (OS) and cancer specific survival (CSS) based on GSE13507, and we further established a six-gene signature based on the expression levels of the six genes and their Cox regression coefficients. This signature showed good potential for clinical application suggested by survival analysis (OS: Hazard Ratio = 0.484, 95%CI: 0.298-0.786; P = 0.0034; CSS: Hazard Ratio = 0.244, 95%CI: 0.121-0.493, P < 0.0001) and decision curve analysis. In conclusion, our study indicates that six hub genes have great predictive value for the prognosis and progression of BC and may contribute to the exploration of further basic and clinical research of BC.

Salicylic acid (SA) is synthesized via the phenylalanine lyase (PAL) and isochorismate synthase (ICS) pathways and can influence the stress response in plants by regulating certain secondary metabolites. However, the association between SA and particular secondary metabolites in the Chinese medicinal plant Scutellaria baicalensis Georgi is unclear. To elucidate the association between SA and the secondary metabolites baicalin and baicalein, which constitute the primary effective components of S. baicalensis, we subjected seedlings to drought and salt stress and exogenous SA treatment in a laboratory setting and tested the expression of PAL and ICS, as well as the content of free SA (FSA), total SA (TSA), baicalin, and baicalein. We also assessed the correlation of FSA and TSA with PAL and ICS, and with baicalin and baicalein accumulation, respectively. The results indicated that both FSA and TSA were positively correlated with PAL, ICS, and baicalin, but negatively correlated with baicalein. The findings of this study improve our understanding of the manner in which SA regulates secondary metabolites in S. baicalensis.

Glycine- and proline-rich proteins (GPRPs) comprise a small conserved family that is widely distributed in the plant kingdom. GPRPs are relatively short peptides (<200 amino acids) that contain three typical domains, including an N-terminal XYPP-repeat domain, a middle hydrophobic domain rich in alanine, and a C-terminal HGK-repeat domain. These proteins have been proposed to play fundamental roles in plant growth and environmental adaptation, but their functions remain unknown. In this study, we selected an Arabidopsis GPRP (AtGPRP3) to profile the physiological role of GPRPs. Transcripts of AtGPRP3 could be detected in the whole Arabidopsis plant, but greater amounts were found in the rosette, followed by the cauline. The AtGPRP3::GFP fusion protein was mainly localized in the nucleus. The overexpression and knockout of AtGPRP3, respectively, retarded and accelerated the growth of Arabidopsis seedlings, while the increase in the growth rate of atgprp3 plants was offset by the complementary expression of AtGPRP3. CAT2 and CAT3, but not CAT1, interacted with AtGPRP3 in the nuclei of Arabidopsis protoplasts. The knockout of CAT2 by CRISPR-Cas9 retarded the growth of the Arabidopsis seedlings. Together, our data suggest that AtGPRP3 negatively regulates plant growth, potentially through CAT2 and CAT3.

Doublecortin-like kinase 1 (DCLK1) has been found to be involved in malignant biological behavior of cancers and poor prognosis of cancer patients. The aim of this meta-analysis was to systematically clarify the relationships between expression level of DCLK1 and clinicopathological characteristics in tumors and assess its clinical value in cancer diagnosis and prognosis. 18 eligible studies with a total of 2660 patients were identified by searching the electronic bibliographic databases. Pooled results showed that DCLK1 was highly expressed in tissues from cancer patients compared to normal tissues (OR, 10.00), and overexpression of DCLK1 was significantly correlated with advanced clinical stage (OR, 2.48), positive lymph node metastasis (OR, 2.18), poorly differentiated cancers (OR, 1.83) and poor overall survival (HR, 2.15). The overall combined sensitivity and specificity for DCLK1 in distinguishing malignant tumors were 0.58 and 0.90, respectively. The mean diagnostic odds ratio was 12.70, and the corresponding area under the summary receiver operating characteristic curve was 0.78. In summary, our study indicated that DCLK1 could be a risk factor for development of malignant tumors and may serve as a promising diagnostic and prognostic biomarker for malignant tumors.

We performed a network meta-analysis to compare the efficacy of 12 single-drug regimens (Glibenclamide, Glimepiride, Pioglitazone, Rosiglitazone, Repaglinide, Metformin, Sitaglitin, Exenatide, Liraglutide, Acarbose, Benfluorex, and Glipizide) in the treatment of type 2 diabetes mellitus (T2DM). Fifteen relevant randomized controlled trials (RCTs) were included; direct and indirect evidence from these studies was combined, and weighted mean difference (WMD) and surface under the cumulative ranking curves (SUCRAs) were examined to evaluate the monotherapies. Liraglutide was more effective than Glimepiride, Pioglitazone, Sitaglitin, Exenatide, and Glipizide at reducing glycated hemoglobin (HbA1c) levels. In contrast, Acarbose was less effective than Glibenclamide, Glimepiride, Pioglitazone, Rosiglitazone, Repaglinide, Metformin, and Liraglutide at decreasing HbA1c levels. Reductions in fasting plasma glucose (FPG) levels were similar after all treatments. Rosiglitazone was less effective than Glibenclamide and Repaglinide at reducing total cholesterol (TC) levels. High density lipoprotein (HDL), low density lipoprotein (LDL), and triglyceride levels did not differ after treatment with any of the monotherapies. HbA1c and FPG SUCRA values were highest for Liraglutide, while HbA1c and FPG values were lowest for Acarbose, and TC and LDL values were lowest for Rosiglitazone. These results suggest that Liraglutide may be most effective, and Acarbose least effective, at reducing blood glucose levels, while Glibenclamide, Repaglinide, and Metformin may be most effective, and Rosiglitazone least effective, at reducing lipoidemia, in T2DM patients.

As a novel reactive oxygen species (ROS) scavenger, deuterohemin His peptide‑6 (DhHP‑6) has been demonstrated to prolong the lifespan of Caenorhabditis elegans and has also exhibited protective effects in myocardial ischemia‑reperfusion injury. Whether similar effects occur during cerebral ischemia‑reperfusion (CIR) injury remains to be elucidated. The present study evaluated the function of DhHP‑6 and its underlying mechanisms in a middle cerebral artery occlusion (MCAO) model in rats. The focal transient MCAO model was implemented using the Longa method of ischemia for 2 h followed by reperfusion for 22 h in male Wistar rats. DhHP‑6 was administered at the onset of reperfusion via intraperitoneal injection. The infarct volume, brain edema, brain apoptosis and neurological function were evaluated 24 h following stroke. To further determine the role of DhHP‑6 in CIR injury, the levels of ROS and malondialdehyde (MDA), the activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH‑Px), and the protein expression levels of B‑cell lymphoma 2 (Bcl‑2)‑associated X protein (Bax), cleaved caspase‑3, cytochrome c, Bcl‑2 and phosphorylated‑Akt/Akt were measured in ischemic cortex tissues. The results demonstrated that DhHP‑6 significantly improved infarct volume, brain edema and neurological deficits, and reduced the percentage of TUNEL‑positive cells. The levels of ROS and MDA were decreased, whereas no significant changes in the activities of SOD, CAT and GSH‑Px were observed. The levels of Bax, cleaved caspase‑3, and cytochrome c were downregulated, whereas the levels of Bcl‑2 and p‑Akt/Akt were upregulated. The results of the present study indicated that DhHP‑6 may offer therapeutic potential for cerebral ischemia. The neuroprotective effects of DhHP‑6 maybe mediated by its anti‑oxidative properties, anti‑apoptotic activities, or activation of the phosphoinositide 3‑kinase/Akt survival pathway.

Leukotriene B4 (LTB4) has been found to contribute to pulmonary arterial smooth muscle cells (PASMCs) proliferation and pulmonary arterial remodeling therefore the development of pulmonary arterial hypertension (PAH). Yet, the underlying molecular mechanisms remain poorly understood. The present study aims to address this issue. Our results demonstrate that LTB4 dose- and time-dependently induced proliferation of primary cultured rat PASMCs, this was accompanied with the activation of phosphatidylinositol-3-kinase/Akt (PI3K/Akt) and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathways, and consequent inactivation of glycogen synthase kinase-3β (GSK-3β), up-regulation of β-catenin and induction of cyclin D1 expression. The presence of PI3K inhibitor (LY294002) or MEK inhibitor (U0126) or prior silencing of β-catenin with siRNA suppressed LTB4-induced cyclin D1 up-regulation and PASMCs proliferation. In addition, inactivation or lack of GSK-3β up-regulated β-catenin and cyclin D1 in PASMCs. Taken together, our study indicates that activation of PI3K/Akt and ERK1/2 pathways mediates LTB4-induced PASMCs proliferation by modulating GSK-3β/β-catenin/cyclin D1 axis and suggests that targeting this pathway might have potential value in alleviating vascular remodeling and benefit PAH.

Vitamin D deficiency was associated with CTD-ILD and reduced lung function. We sought to confirm that lower Vitamin D level would be related to shorter survival times.

Background: Accumulating studies have demonstrated that the expression of leucine-rich repeats and immunoglobulin-like domains protein1 (LRIG1) is associated with various types of tumors. However, the conclusions of previous studies are not completely consistent. Thus, we conducted this meta-analysis to further explore the authentic value of LRIG1 in cancer outcome and clinical significance. Methods: We systematically searched electronic databases including PubMed, Web of Science, Embase, Chinese National Knowledge Infrastructure and Wanfang database. The hazard ratios (HRs), odds ratio (OR) and 95 % confidence intervals (CI) were calculated for effect measures. Results: 16 qualified studies involving 2043 patients with cancer were enrolled. High LRIG1 expression was associated with a good prognosis in malignant tumors (HR: 0.49, 95% CI=0.39-0.59). Furthermore, positive expression rate of LRIG1 was distinctly lower in cancer tissues than that in normal tissues (OR: 0.09, 95% CI=0.05-0.17). Positive LRIG1 expression was definitely related with smaller tumor size (OR: 1.64, 95% CI=1.11-2.42), early tumor stage (OR: 3.67, 95% CI=1.87-7.21), well degree of differentiation (OR: 4.35, 95% CI=2.12-8.93) and negative recurrence (OR: 0.29, 95% CI=0.16-0.53). Conclusions: LRIG1 expression was associated with a good prognosis in terms of overall survival (OS) and might act as a predictive factor for characteristics of cancer patients.

The up-regulation of transient receptor potential channel 6 (TRPC6) has been found to contribute to the proliferation of pulmonary artery smooth muscle cells (PASMCs), and inhibition of phosphodiesterase-5 (PDE5) has been shown to suppress TRPC6 expression in PASMCs. However, the molecular mechanisms underlying the up-regulation of TRPC6 expression and PDE5 modulation of TRPC6 expression in PASMCs remain largely unclear. The aim of this study is to address these issues. Endothelin-1 (ET-1) dose and time-dependently up-regulated TRPC6 expression in primary cultured rat PASMCs, and this was accompanied with the activation of calcineurin and subsequent translocation of NFATc4 to the nucleus. Further study indicated that inhibition of calcineurin by cyclosporine A or knockdown of NFATc4 using small interfering RNA suppressed ET-1-induced TRPC6 up-regulation. In addition, luciferase reporter assay showed that NFATc4 directly regulated the expression of TRPC6 in PASMCs. Inhibition of PDE5 by sildenafil suppressed ET-1-induced activation of calcineurin/NFATc4 signaling pathway and consequent TRPC6 up-regulation in PASMCs, while these inhibitory effects of sildenafil were abolished by PKG inhibitor Rp-8Br-cGMPs. Taken together, our study indicates that ET-1 stimulates TRPC6 expression by activation of calcineurin/NFATc4 signaling pathway, and inhibition of PDE5 suppresses calcineurin/NFATc4- mediated TRPC6 expression in PASMCs in a cGMP-PKG-dependent manner.

Multiple hypotheses have been proposed to explain the reading difficulty caused by developmental dyslexia (DD). The current study examined visuo-orthographic processing in children with dyslexia to determine whether orthographic deficits are explainable based solely on visual deficits. To identify orthographic-specific, visual perception-specific, and overlapping deficits, we included two tasks (lexical and perceptual) in three Chinese subject groups: children with DD, age-matched controls (AC), and reading matched controls (RC) using functional magnetic resonance imaging (fMRI). We found that the left precuneus showed decreased activation across both tasks for the DD group compared to the two control groups, thus reflecting visual processing deficits in children with DD, which also affects orthographic processing. Furthermore, we found that the functional connectivity between left middle occipital gyrus (LMOG) and left inferior frontal gyrus (IFG) was decreased in the DD group compared to AC and RC for only the lexical task. This suggests a weaker association between orthography and phonology for children with DD. In addition, the children with DD showed decreased functional connectivity between the LMOG and right parahippocampal gyrus for only the visual perceptual task, thereby indicating a weaker association between visual regions for DD during visual symbol processing. Taken together, our findings suggest that the observed orthographic processing deficit in DD might be driven by both a basic visual deficit, and a linguistic deficit.

Artemisinin is a secondary metabolite extracted from Artemisia annua. As an effective antimalarial component certified by WHO, artemisinin has extensive economical values. Numerous studies about transcription factors positively regulating artemisinin biosynthesis have been published while negative regulators are rarely reported. In the present study, we identified AaMYB15 as the first R2R3-MYB that negatively regulates artemisinin biosynthesis in A. annua. Experimental evidences showed that AaMYB15 is a transcription factor within nucleus and predominantly expressed in glandular secretory trichomes (GSTs) in A. annua where artemisinin is synthesized and accumulated. The expression of AaMYB15 was induced by dark and JA treatment. Overexpression of AaMYB15 led to a significant decline in the expression levels of key enzyme genes ADS, CYP, DBR2, and ALDH1 and a significant decrease in the artemisinin contents of transgenic A. annua. AaMYB15 directly bound to the promoter of AaORA, a reported positive regulator of artemisinin biosynthesis in JA signaling pathway, to repress its transcriptional activity, thus downregulating the expression levels of downstream key enzyme genes and negatively regulating the artemisinin biosynthesis. Our study provides candidate gene for improvement of A. annua germplasm and new insights into the artemisinin biosynthesis regulation network mediated by light and JA.

SCN4 is an autosomal recessive disease caused by mutations in the G6PC3 gene. The clinical, molecular, and immunological features; function of neutrophils; and prognosis of patients with SCN4 have not been fully elucidated.