Photothermal cancer therapy has attracted considerable interest for cancer treatment in recent years, but the effective photothermal agents remain to be explored before this strategy can be applied clinically. In this study, we therefore develop flower-like molybdenum disulfide (MoS2) nanoflakes and investigate their potential for photothermal ablation of cancer cells. MoS2 nanoflakes are synthesized via a facile hydrothermal method and then modified with lipoic acid-terminated polyethylene glycol (LA-PEG), endowing the obtained nanoflakes with high colloidal stability and very low cytotoxicity. Upon irradiation with near infrared (NIR) laser at 808 nm, the nanoflakes showed powerful ability of inducing higher temperature, good photothermal stability and high photothermal conversion efficiency. The in vitro photothermal effects of MoS2-PEG nanoflakes with different concentrations were also evaluated under various power densities of NIR 808-nm laser irradiation, and the results indicated that an effective photothermal killing of cancer cells could be achieved by a low concentration of nanoflakes under a low power NIR 808-nm laser irradiation. Furthermore, cancer cell in vivo could be efficiently destroyed via the photothermal effect of MoS2-PEG nanoflakes under the irradiation. These results thus suggest that the MoS2-PEG nanoflakes would be as promising photothermal agents for future photothermal cancer therapy.

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.

Hepatitis B virus (HBV) X protein (HBx), a trans-regulator, is frequently expressed in truncated form without carboxyl-terminus in hepatocellular carcinoma (HCC), but its functional mechanisms are not fully defined. In this report, we investigated frequency of this natural HBx mutant in HCCs and its functional significance. In 102 HBV-infected patients with HCC, C-terminal truncation of HBx, in contrast to full-length HBx, were more prevalent in tumors (70.6%) rather than adjacent non-tumorous tissues (29.4%) (p = 0.0032). Furthermore, two naturally-occurring HBx variants (HBxΔ31), which have 31 amino acids (aa) deleted (codons 123-125/124-126) at C-terminus were identified in tumors and found that the presence of HBxΔ31 significantly correlated with intrahepatic metastasis. We also show that over-expression of HBxΔ31 enhanced hepatoma cell invasion in vitro and metastasis in vivo compared to full-length HBx. Interestingly, HBxΔ31 exerts this function via down-regulating Maspin, RhoGDIα and CAPZB, a set of putative metastasis-suppressors in HCC, in part, by enhancing the binding of transcriptional repressor, myc-associated zinc finger protein (MAZ) to the promoters through physical association with MAZ. Notably, these HBxΔ31-repressed proteins were also significantly lower expression in a subset of HCC tissues with C-terminal HBx truncation than the adjacent non-tumorous tissues, highlighting the clinical significance of this novel HBxΔ31-driven metastatic molecular cascade. Our data suggest that C-terminal truncation of HBx, particularly breakpoints at 124aa, plays a role in enhancing hepatoma cell invasion and metastasis by deregulating a set of metastasis-suppressors partially through MAZ, thus uncovering a novel mechanism for the progression of HBV-associated hepatocarcinogenesis.

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.

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.

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.

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.

Thyroid cancer is the most common type of endocrine malignancy and the incidence rate is rapidly increasing worldwide. Epigallocatechin-3-gallate (EGCG) could suppress cancer growth and induce apoptosis in many types of cancer cells. However, the mechanism of action of EGCG on the growth of human thyroid carcinoma cells has not been fully illuminated.

Melanoma is a malignant tumor of cutaneous melanocytes that is characterized by high grade malignancy, rapid progression and high mortality. Thus far, its specific etiological mechanism has been unclear. In this study, we discovered that Lyn kinase expression was up-regulated in melanoma tissues and cells. The function of Lyn was determined by knocking down its expression with a lentivirus containing Lyn shRNA and upregulating its expression with pcDNA3.1-Lyn in the melanoma cell lines M14 and A375. The results showed that Lyn knockdown could significantly inhibit the proliferation, migration and invasiveness through its inhibition of apoptosis and autophagy via the PI3K/Akt pathway in melanoma cell lines. This was further confirmed by treatment with PI3K inhibitor BEZ235. Up-regulation of Lyn promoted the expression of p-Akt and Cyclin D1. Additionally, we investigated the effects of Lyn inhibitor Bafetinib on melanoma cells and the results were consistent with Lyn knockdown. Collectively, our results indicated that Lyn plays a carcinogenic role in multiple cellular functions during melanoma development through regulating apoptosis and autophagy via the PI3K/Akt pathway and may be a valuable potential target for the clinical treatment of melanoma.

Background: The present study aimed to explore the changes in the hepatic metabolic profile during the evolution of diabetes mellitus (DM) and verify the key metabolic pathways. Methods: Liver samples were collected from diabetic rats induced by streptozotocin (STZ) and rats in the control group at 1, 5, and 9 weeks after STZ administration. Proton nuclear magnetic resonance spectroscopy (1H NMR)-based metabolomics was used to examine the metabolic changes during the evolution of DM, and partial least squares-discriminate analysis (PLS-DA) was performed to identify the key metabolites. Results: We identified 40 metabolites in the 1H NMR spectra, and 11 metabolites were further selected by PLS-DA model. The levels of α-glucose and β-glucose, which are two energy-related metabolites, gradually increased over time in the DM rats, and were significantly greater than those of the control rats at the three-time points. The levels of choline, betaine, and methionine decreased in the DM livers, indicating that the protective function in response to liver injury may be undermined by hyperglycemia. The levels of the other amino acids (leucine, alanine, glycine, tyrosine, and phenylalanine) were significantly less than those of the control group during DM development. Conclusions: Our results suggested that the hepatic metabolic pathways of glucose, choline-betaine-methionine, and amino acids were disturbed during the evolution of diabetes, and that choline-betaine-methionine metabolism may play a key role.

Gastric cancer (GC), a common gastrointestinal malignancy worldwide, has poor prognosis and frequent recurrence. There is a great need to identify effective therapy for GC. Crizotinib is a multi-targeted, clinically available oral tyrosine kinase inhibitor approved for lung cancer, but its use for the highly heterogeneous disease of GC is unknown. The goal of this study was to investigate the anti-cancer mechanisms of the (S)-crizotinib in inhibiting GC growth. Human GC cell lines (SGC-7901 and BGC-823) and the (S)-crizotinib-resistant BGC-823/R were cultured for determining the effects of (S)-crizotinib on cell viability, apoptosis, oxidant generation, and cell cycle progression. Involvement of ROS, Akt signaling, MTH1, and DNA damage was tested with respective pharmacological blockade. The in vivo anti-tumor effects of (S)-crizotinib were determined using xenograft tumor mice. Results indicated that (S)-crizotinib decreased GC cell viability, induced growth arrest and apoptosis, and increased levels of γH2AX and Ser1981-phosphorylated ATM, which were inhibited by NAC. The anti-cancer mechanism of (S)-crizotinib was independent of MTH1. Moreover, ATM-activated Akt, a pro-survival signal, whose inhibition further enhanced (S)-crizotinib-induced inhibition of GC cell growth and tumor growth in xenograft mice, and re-sensitized resistant GC cells to (S)-crizotinib. (S)-crizotinib reduced GC cell and tumor growth through oxidative DNA damage mechanism and triggered pro-survival Akt signaling. We conclude that inclusion of Akt inhibition (to block the survival signaling) with (S)-crizotinib may provide an effective and novel combination therapy for GC in the clinical setting.

P-selectin, a cell adhesion molecule, is an important member of the selectin family. Recent studies have shown that P-selectin deletion inhibits tumor growth in Rip1-Tag2 mice by suppressing platelet accumulation in tumor tissues. This study aimed to evaluate whether and how P-selectin affects tumor stiffness in Rip1-Tag2 mice. To explore the role of P-selectin in tissue stiffness, we demonstrated that tumor progression in Rip1-Tag2 mice was correlated with tissue stiffness using immunofluorescence and histological staining. Furthermore, we showed that P-selectin deficiency significantly decreased tissue stiffness by inhibiting lysyl oxidase (LOX) expression. Our experiments involving Rip1-Tag2 mice treated with the LOX inhibitor BAPN showed that BAPN significantly abolished collagen deposition to decrease tumor stiffness and thus inhibit tumor growth. These results indicate that P-selectin deletion significantly decreases tumor stiffness in Rip1-Tag2 mice by inhibiting LOX expression. Further study demonstrated that P-selectin-mediated platelet accumulation increases tissue stiffness mainly by increasing LOX expression and thus promotes tumor growth. Therefore, P-selectin may be an effective therapeutic targeting for treating human insulinomas.

The reliability of qRT-PCR results depend on the stability of reference genes used for normalization, suggesting the necessity of identification of reference genes before gene expression analysis. Morels are edible mushrooms well-known across the world and highly prized by many culinary kitchens. Here, several candidate genes were selected and designed according to the Morchella importuna transcriptome data. The stability of the candidate genes was evaluated with geNorm and NormFinder under three different experimental conditions, and several genes with excellent stability were selected. The extensive adaptability of the selected genes was tested in ten Morchella species. Results from the three experimental conditions revealed that ACT1 and INTF7 were the most prominent genes in Morchella, CYC3 was the most stable gene in different development stages, INTF4/AEF3 were the top-ranked genes across carbon sources, while INTF3/CYC3 pair showed the robust stability for temperature stress treatment. We suggest using ACT1, AEF3, CYC3, INTF3, INTF4 and INTF7 as reference genes for gene expression analysis studies for any of the 10 Morchella strains tested in this study. The stability and practicality of the gene, vacuolar protein sorting (INTF3), vacuolar ATP synthase (INTF4) and14-3-3 protein (INTF7) involving the basic biological processes were validated for the first time as the candidate reference genes for quantitative PCR. Furthermore, the stability of the reference genes was found to vary under the three different experimental conditions, indicating the importance of identifying specific reference genes for particular conditions.

Our study aimed to investigate the functional connectivity (FC) between the hippocampus and other brain regions in epilepsy patients with depressive symptoms.

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

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.

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.

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.