Search

Graves' disease (GD) is an autoimmune disease, the incidence of which is increasing yearly. GD requires long-life therapy. Therefore, the potential immune-related biomarkers of GD need to be studied.In our study, differentially expressed genes (DEGs) were derived from the online Gene Expression Omnibus (GEO) microarray expression dataset GSE71956. Protein‒protein interaction (PPI) network analyses were used to identify hub genes, which were validated by qPCR. GSEA was used to screen potential pathways and related immune cells. Next, CIBERSORT analysis was used to further explore the immune subtype distribution pattern among hub genes. ROC curves were used to analyze the specificity and sensitivity of hub genes.44 DEGs were screened from the GEO dataset. Two hub genes, EEF1A1 and EIF4B, were obtained from the PPI network and validated by qPCR (p 0.05). GSEA was conducted to identify potential pathways and immune cells related to these the two hub genes. Immune cell subtype analysis revealed that hub genes had extensive associations with many different types of immune cells, particularly resting memory CD4Our study revealed two hub genes, EEF1A1 and EIF4B, that are associated with resting memory CD4

Background: Graves' disease (GD) is an autoimmune disease, the incidence of which is increasing year by year. And it still needs long life therapy. So, the detailed pathogenesis of GD still needs further study. Method: In our study, differentially expressed genes (DEGs) were derived from online Gene Expression Omnibus (GEO) microarray expression dataset GSE71956. Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes (KEGG) analysis was used to enrichment analysis. Protein-protein interaction (PPI) network analyses were used to identify the hub genes. Then hub gene was validated by qPCR. Next CIBERSORT analysis was used to further explore the immune infiltration among hub genes. ROC curve was used to analysis the specificity and sensitivity of hub genes. Result: 44 DEGs were screened out from GEO dataset. GO and KEGG analysis of DEGs shows that GD involves immunity and metabolism. Two hub genes EEF1A1, EIF4B were recruited from PPI network, and was validated by qPCR ( p < 0.05). Immune cell infiltration analysis revealed that plasma cells, T cells CD4 memory resting, T cells follicular helper, dendritic cells activated, mast cells activated were correlated with GD. We are the first to demonstrate the expression of EEF1A1, EIF4B has significant positive correlations with infiltrating levels of T cells CD4 memory resting. The AUC of EEF1A1 ROC analysis is 0.687 and ROC of EIF4B is 0.733.Conclusion : Our study revels two hub genes, EEF1A1, EIF4B, which were associated with resting memory CD4 + T cells , may be the potential molecular biomarkers and therapeutic targets of GD.

Context Papillary thyroid carcinoma (PTC) is the most common endocrine malignancy. Chaperone-mediated autophagy (CMA), 1 type of autophagy, is thought to promote or suppress cancer development in different cancer types. However, the effect of CMA on PTC development and the underlying mechanisms remain unknown. Objective To determine whether CMA plays implied critical roles in the development of PTC. Design We investigated the association between CMA and PTC development in PTC tissues and normal thyroid tissues by detecting the key protein of CMA, lysosome-associated membrane protein type 2A (LAMP2A), using quantitative polymerase chain reaction (PCR) and immunohistochemistry, which were further validated in the TGCA dataset. The effect of CMA on PTC development was studied by cell proliferation, migration, and apoptosis assays. The underlying mechanisms of peroxisome proliferator-activated receptor γ (PPARγ)-stromal cell-derived factor 1 (SDF1)/ C-X-C motif chemokine receptor 4 (CXCR4) signaling were clarified by western blotting, quantitative PCR, and rescue experiments. Knockdown and tamoxifen were used to analyze the effect of estrogen receptor (ER) α on CMA. Results Our study confirmed that CMA, indicated by LAMP2A expression, was significantly increased in PTC tumor tissues and cell lines, and was associated with tumor size and lymph node metastasis of patients. Higher CMA in PTC promoted tumor cell proliferation and migration, thereby promoting tumor growth and metastasis. These effects of CMA on PTC were exerted by decreasing PPARγ protein expression to enhance SDF1 and CXCR4 expression. Furthermore, CMA was found positively regulated by ERα signaling in PTC. Conclusion Our investigation identified CMA regulated by ERα promoting PTC tumor progression that enhanced tumor cell proliferation and migration by targeting PPARγ-SDF1/CXCR4 signaling, representing a potential target for treatment of PTC.

The relationship between Uric acid (UA) and malignant tumor are still confusing. Gastric cancer(GC) is recognized to be closely related to Helicobacter pylori (H. pylori) infection, early diagnosis rate is very low. In this study, we aimed to investigate the relationship between H. pylori and hyperuricemia (HUA), and evaluate the predictive value of serum uric acid (SUA) in gastric precancerous lesion (GPL) and gastric cancer (GC). This retrospective study included 486 patients who underwent gastroscopy (155 controls, 272 GPL, 59 GC patients). The risk factors for GPL and GC were identified by multiple logistic regression analysis and nomogram was constructed to evaluate the ability of SUA to predict the risk of these diseases based on SUA score. We found that in healthy controls, HUA is positively correlated with H. Pylori (+). SUA was an independent risk factor for GPL and GC. Verification shows that the nomogram was better fitted for GC than for GPL. In conclusion, our study established nomogram based on SUA to predict the risk of GPL and GC, suggested that the incidence of GPL and GC is higher in H. pylori (+) HUA patients, so early intervention and vigilance should be raised.

Objective: The association of the gut microbiome with bone turnover markers (BTMs) in postmenopausal women is poorly understood. Methods: Fecal samples were collected from 97 Chinese postmenopausal women, and the serum CTX and P1NP were determined. Individuals with serum CTX lower or higher than the median value were divided into LCTX and P1NP groups; and individuals with serum P1NP lower or higher than the median value were grouped into LP1NP and HP1NP groups. Microbiota profiles were determined by high-throughput 16S rRNA gene sequencing. Results: In postmenopausal women, only Faecalibacterium showed significant alteration in the HCTX group compared with the LCTX group (P=0.004, q=0.143). Linear discriminant analysis effect size (LEfSe) analysis revealed that Clostridiaceae (P=0.015, LDA=2.89), Faecalibacterium (P=0.017, LDA=4.60), Prevotella (P=0.040, LDA=3.61) and Clostridium (P=0.007, LDA=2.79) were abundant in the LCTX group, and Facklamia (P=0.044, LDA=3.10) was enriched in the HCTX group. Peptostreptococcaceae (P=0.048, LDA=2.83) and the SMB53 (P=0.028, LDA=2.05) genus were enriched in the LPINP group, and Veillonellaceae (P=0.025, LDA=4.43) and the S24_7 (P=0.023, LDA=3.08) family were enriched in the HPINP group. Six taxa correlated with BTMs in all subjects, including Clostridium (Clostridiaceae) that was negatively correlated with serum CTX amounts significantly (r=-0.34, P

Background Lipopolysaccharide (LPS) from Helicobacter pylori (HP) plays an important role in gastric cancer occurrence and development. Toll-like receptor 4 (TLR4) and myeloid differential protein-2 (MD-2) are also reported to be involved in gastric cancer cell proliferation and invasion. CXC chemokine receptor 7 (CXCR7), a second receptor for CXCL12, has been detected in multiple types of tumor tissues. Nevertheless, the biological function and regulation of CXCR7 and its relationship with TLR4 and MD-2 in gastric cancer are not completely understood and therefore warrant further study. Methods CXCR7 expression was examined in 150 gastric cancer tissues using immunohistochemistry (IHC). RT-PCR and western blotting were used to detect CXCR7 expression in several gastric cancer cell lines (SGC7901, AGS, MGC-803, MKN-45 and BGC823). shRNAs were designed using a pGPU6/GFP/Neo vector. A CCK-8 assay was used to assess cell proliferation, and transwell assays were performed to assess cell migration. In addition, a gastric cancer xenograft model was generated. Results The LPS-TLR4-MD-2 pathway elevates CXCR7 expression in SGC7901 cells, and TLR4/MD-2-mediated increases in CXCR7 levels modulate the proliferation and migration of tumor cells. Knockdown of TLR4 and MD-2 demonstrated that both are essential for LPS-induced CXCR7 expression, which in turn is responsible for LPS-induced SGC7901 cell proliferation and migration. Moreover, higher TLR4, MD-2 and CXCR7 expression was detected in gastric cancer tissues than in paracancerous normal control tissues. The expression levels of TLR4, MD-2 and CXCR7 were closely related to gastric cancer TNM stage and lymph node metastasis. In an animal model, significant differences in CXCR7 expression in tumor masses were observed between the control group and experimental group. Conclusions The results of this study indicate that CXCR7 plays an important role in gastric cancer progression via inflammatory mechanisms, suggesting that CXCR7 could provide a basis for the development and clinical application of a targeted drug for gastric cancer.

The prevalence of obesity is increasing rapidly and is closely associated with a variety of metabolic diseases. Recent studies have suggested that autophagy is likely to play an important role in the development of obesity and may be related to insulin sensitivity. Autophagy may be involved in the browning of white adipose tissue and may also affect the metabolic balance of lipids. Autophagy can degrade cytoplasmic lipids by lipophagy in hepatocytes. Furthermore, Autophagy in hepatocytes helps prevent NAFLD. The study of autophagy in glucose metabolism is still in a very preliminary stage. Changes in autophagy activity play an important role in the development of insulin resistance in diabetes and many metabolic diseases. Therefore, it is still worth further exploration on the deeper mechanism of oxidative stress induction of insulin resistance to autophagy and whether there will be corresponding complications to the body.

Autophagy is a dynamic process, regulated by a variety of factors, and may play different roles in different thyroid diseases or in different stages of the same thyroid disease. Autophagy can mediate inflammatory response and immunity, which is closely related to the pathogenesis of thyroid autoimmune diseases. Therefore, it is still necessary to further understand the relationship between autophagy and autoimmune thyroid disease and hypothyroidism. With more and more studies on the relationship between autophagy and thyroid cancer, the relationship between the two is becoming more and more complicated. From the perspective of current studies, it is still worth pondering whether inhibition or activation of autophagy can be a valuable targeted therapy for thyroid cancer, and further research and efforts are still needed.

Polycystic Ovary Syndrome (PCOS) is a common obesity-related reproductive disease in women of child-bearing age,which is usually accompanied with endocrine and metabolic abnormalities such as hyperandrogenemia and hyperinsulinemia. The abnormal reproductive function of PCOS is mainly characterized by the morphological and functional changes of ovary. Autophagy is involved in the maintenance of human ovarian physiological function as well as in the process of luteal degeneration, and affects the survival of granulosa cells. This chapter introduces the latest research progress of the relationship between autophagy and PCOS. How autophagy is involved in the occurrence and development of PCOS remains to be further studied.

Autophagy is a dynamic process, regulated by a variety of factors, and may play different roles in different thyroid diseases or in different stages of the same thyroid disease. Autophagy can mediate inflammatory response and immunity, which is closely related to the pathogenesis of thyroid autoimmune diseases. Therefore, it is still necessary to further understand the relationship between autophagy and autoimmune thyroid disease and hypothyroidism. With more and more studies on the relationship between autophagy and thyroid cancer, the relationship between the two is becoming more and more complicated. From the perspective of current studies, it is still worth pondering whether inhibition or activation of autophagy can be a valuable targeted therapy for thyroid cancer, and further research and efforts are still needed.

The prevalence of obesity is increasing rapidly and is closely associated with a variety of metabolic diseases. Recent studies have suggested that autophagy is likely to play an important role in the development of obesity and may be related to insulin sensitivity. Autophagy may be involved in the browning of white adipose tissue and may also affect the metabolic balance of lipids. Autophagy can degrade cytoplasmic lipids by lipophagy in hepatocytes. Furthermore, Autophagy in hepatocytes helps prevent NAFLD. The study of autophagy in glucose metabolism is still in a very preliminary stage. Changes in autophagy activity play an important role in the development of insulin resistance in diabetes and many metabolic diseases. Therefore, it is still worth further exploration on the deeper mechanism of oxidative stress induction of insulin resistance to autophagy and whether there will be corresponding complications to the body.

Polycystic Ovary Syndrome (PCOS) is a common obesity-related reproductive disease in women of child-bearing age,which is usually accompanied with endocrine and metabolic abnormalities such as hyperandrogenemia and hyperinsulinemia. The abnormal reproductive function of PCOS is mainly characterized by the morphological and functional changes of ovary. Autophagy is involved in the maintenance of human ovarian physiological function as well as in the process of luteal degeneration, and affects the survival of granulosa cells. This chapter introduces the latest research progress of the relationship between autophagy and PCOS. How autophagy is involved in the occurrence and development of PCOS remains to be further studied.

Background Gastric cancer is a common malignant tumor with high morbidity and mortality worldwide, which seriously affects human health. Gramicidin is a short peptide antibiotic which could be used for treating infection induced by bacteria or fungi. However, the anti-cancer effect of gramicidin on gastric cancer cells and its underlying mechanism remains largely unknown. Results Gastric cancer cells SGC-7901, BGC-823 and normal gastric mucosal cells GES-1 were treated with different concentrations of gramicidin respectively. The results of CCK-8 experiment revealed cellular toxicity of gramicidin to cancer cells while cell colony formation assay showed that gramicidin significantly inhibited the proliferation of gastric cancer cells, but had little effect on normal gastric mucosal cells. In addition, the wound healing assay showed that gramicidin inhibited the migration of SGC-7901 cell. Meanwhile, apoptosis and cell cycle analysis revealed that gramicidin induced cell apoptosis with G2/M cell cycle inhibition. Furthermore, western blot analysis demonstrated that gramicidin down-regulated the expression of cyclinD1 and Bcl-2 as well as the FoxO1 phosphorylation. Conclusions The current study illustrated the anti-tumor activity of gramicidin on gastric cancer cells, providing a possibility for gramicidin to be applied in clinical practice for the treatment of gastric cancer.

Background Fully understanding the developmental process of hepatic stem cells (HSCs) and the mechanisms of their committed differentiation is essential for optimizing the generation of functional hepatocytes for cell therapy in liver disease. Delta-like 1 homolog (Dlk1), primarily the membrane-bound form (Dlk1M), is generally used as a surface marker for fetal hepatic stem cell isolation, while its soluble form (Dlk1S) and the functional roles of different Dlk1 isoforms in HSC differentiation remain to be investigated. Methods Hepatic spheroid-derived cells (HSDCs) were isolated from E12.5 mouse livers to obtain Dlk1+ and Dlk1−subpopulations. Colony formation, BrdU staining, and CCK8 assays were used to evaluate the cell proliferation capacity, and hepatic/cholangiocytic differentiation and osteogenesis/adipogenesis were used to assess the multipotency of the two subpopulations. Transformation of Dlk1+ cells into Dlk1− cells was detected by FACS, and the expression of Dlk1 isoforms were measured by western blot. The distinct roles and regulatory mechanisms of Dlk1 isoforms in HSC differentiation were investigated by overexpressing Dlk1M. Results HSDCs were capable of differentiating into liver and mesenchymal lineages, comprising Dlk1+ and Dlk1− subpopulations. Dlk1+ cells expressed both Dlk1M and Dlk1S and lost expression of Dlk1M during passaging, thus transforming into Dlk1− cells, which still contained Dlk1S. Dlk1− cells maintained a self-renewal ability similar to that of Dlk1+ cells, but their capacity to differentiate into cholangiocytes was obviously enhanced. Forced expression of Dlk1M in Dlk1− cells restored their ability to differentiate into hepatocytes, with an attenuated ability to differentiate into cholangiocytes, suggesting a functional role of Dlk1 in regulating HSC differentiation in addition to acting as a biomarker. Further experiments illustrated that the regulation of committed HSC differentiation by Dlk1 was mediated by the AKT and MAPK signaling pathways. In addition, bFGF was found to serve as an important inducement for the loss of Dlk1M from Dlk1+ cells, and autophagy might be involved. Conclusions Overall, our study uncovered the differential expression and regulatory roles of Dlk1 isoforms in the commitment of HSC differentiation and suggested that Dlk1 functions as a key regulator that instructs cell differentiation rather than only as a marker of HSCs. Thus, our findings expand the current understanding of the differential regulation of bi-potential HSC differentiation and provide a fine-tuning target for cell therapy in liver disease. Electronic supplementary material The online version of this article (10.1186/s13287-019-1131-2) contains supplementary material, which is available to authorized users.

Table S1. Primers used in PCR (DOCX 33 kb)

The LIM protein AJUBA is a scaffold protein participating in the regulation of cell adhesion, mitosis, DNA damage, cell differentiation, proliferation, migration and gene transcription. However, its roles in tumorigenesis and progression are poorly defined. Here, we report that AJUBA is highly expressed in colorectal cancer (CRC) and promotes CRC cell growth in culture and in xenografted mice via an inhibition of apoptosis. AJUBA represses the expression of IFIT2 gene, an interferon-stimulated gene and a known apoptosis inducer and tumour suppressor to mediate its resistance to apoptosis. Mechanistic investigations reveal that AJUBA specifically binds the FERM domain of JAK1 to dissociate JAK1 from the IFNγ recepter, resulting in an inhibition of STAT1 phosporylation and concomitantly its nuclear translocation. Clinically, the level of AJUBA in CRC specimens is negatively correlated with the levels of IFIT2 and pSTAT1. Collectively, these studies demonstrate that AJUBA can promote CRC growth via inhibiting apoptosis and serve as a target for the therapeutics and a marker for diagnosis of CRC.

A specialized culture medium termed ciliary neurotrophic factor-treated astrocyte-conditioned medium (CNTF-ACM) allows investigators to assess the peripheral effects of CNTF-induced activated astrocytes upon cultured neurons. CNTF-ACM has been shown to upregulate neuronal L-type calcium channel current activity, which has been previously linked to changes in mitochondrial respiration and oxidative stress. Therefore, the aim of this study was to evaluate CNTF-ACM’s effects upon mitochondrial respiration and oxidative stress in rat cortical neurons. Cortical neurons, CNTF-ACM, and untreated control astrocyte-conditioned medium (UC-ACM) were prepared from neonatal Sprague–Dawley rat cortical tissue. Neurons were cultured in either CNTF-ACM or UC-ACM for a 48-h period. Changes in the following parameters before and after treatment with the L-type calcium channel blocker isradipine were assessed: (i) intracellular calcium levels, (ii) mitochondrial membrane potential (ΔΨm), (iii) oxygen consumption rate (OCR) and adenosine triphosphate (ATP) formation, (iv) intracellular nitric oxide (NO) levels, (v) mitochondrial reactive oxygen species (ROS) production, and (vi) susceptibility to the mitochondrial complex I toxin rotenone. CNTF-ACM neurons displayed the following significant changes relative to UC-ACM neurons: (i) increased intracellular calcium levels (p < 0.05), (ii) elevation in ΔΨm (p < 0.05), (iii) increased OCR and ATP formation (p < 0.05), (iv) increased intracellular NO levels (p < 0.05), (v) increased mitochondrial ROS production (p < 0.05), and (vi) increased susceptibility to rotenone (p < 0.05). Treatment with isradipine was able to partially rescue these negative effects of CNTF-ACM (p < 0.05). CNTF-ACM promotes mitochondrial respiration and oxidative stress in cortical neurons through elevating L-type calcium channel activity.

Seizure activity is linked to astrocyte activation as well as dysfunctional cortical neuron excitability produced from changes in calcium-activated potassium (KCa) channel function. Ciliary neurotrophic factor-treated astrocyte conditioned medium (CNTF-ACM) can be used to investigate the peripheral effects of activated astrocytes upon cortical neurons. However, CNTF-ACM's effect upon KCa channel activity in cultured cortical neurons has not yet been investigated. Whole-cell patch clamp recordings were performed in rat cortical neurons to evaluate CNTF-ACM's effects upon charybdotoxin-sensitive large-conductance KCa (BK) channel currents and apamin-sensitive small-conductance KCa (SK) channel current. Biotinylation and RT-PCR were applied to assess CNTF-ACM's effects upon the protein and mRNA expression, respectively, of the SK channel subunits SK2 and SK3 and the BK channel subunits BKα1 and BKβ3. An anti-fibroblast growth factor-2 (FGF-2) monoclonal neutralizing antibody was used to assess the effects of the FGF-2 component of CNTF-ACM. CNTF-ACM significantly increased KCa channel current density, which was predominantly attributable to gains in BK channel activity (p 0.05). CNTF-ACM produced a significant increase in BKα1 and BKβ3 expression (p 0.05) but had no significant effect upon SK2 or SK3 expression (p 0.05). Blocking FGF-2 produced significant reductions in KCa channel current density (p 0.05) as well as BKα1 and BKβ3 expression in CNTF-ACM-treated neurons (p 0.05). CNTF-ACM significantly enhances BK channel activity in rat cortical neurons and that FGF-2 is partially responsible for these effects. CNTF-induced astrocyte activation results in secretion of neuroactive factors which may affect neuronal excitability and resultant seizure activity in mammalian cortical neurons.

Idiopathic pulmonary fibrosis (IPF) is a chronic and irreversible lung disease with limited therapeutic strategies. Lycorine (LYC), an alkaloid isolated from Amaryllidaceae family plants, exhibits effective anti-inflammatory, antiviral, and anti-tumor activities. In this study, we attempted to determine the effect of LYC on bleomycin (BLM)-induced IPF and NLRP3 inflammasome activation. Our results demonstrated that the LYC treatment ameliorated BLM-induced pulmonary fibrosis and inflammation in mice. LYC inhibited active Caspase-1 expression and lactate dehydrogenase (LDH) release during BLM-induced acute lung injury (ALI) in mice. Furthermore, our in vitro assay showed that LYC inhibited LPS/Nigericin- or LPS/ATP-induced NACHT, LRP and PYD domains-containing protein 3 (NLRP3) inflammasome activation, and pyroptosis in bone marrow-derived macrophages (BMDMs). Mechanically, LYC could disturb the interaction of NLRP3 with apoptosis-associated speck-like protein containing a CARD (ASC) by targeting the pyrin domain (PYD) on Leu9, Leu50, and Thr53. Our findings indicate that LYC ameliorated BLM-induced pulmonary fibrosis by inhibiting NLRP3 inflammasome activation and pyroptosis through targeting the PYD domain of ASC. Thus, LYC might be a potential therapeutic agent for pulmonary inflammation and fibrosis.

L1 cell adhesion molecule (L1CAM) promotes invasiveness and metastasis in non-small cell lung cancer (NSCLC) cells and is upregulated by the p53-regulated transcription factor Slug. p21-activated kinase 4 (PAK4) directly phosphorylates Slug, resulting in pro-malignant Slug stabilization. We hypothesized that microRNA-based negative regulation of PAK4 would reduce L1CAM-induced NSCLC aggressiveness via destabilizing Slug. We found that elevated L1CAM expression was tightly correlated with p53 loss-of-function and reduced NSCLC patient survival. L1CAM suppression reduced NSCLC cell migration and invasiveness in vitro as well as tumor formation and distal metastasis in vivo. Mechanistically, p53 restricts L1CAM expression through the β-catenin/Slug pathway, with levels of β-catenin and Slug positively correlating with L1CAM expression in NSCLC tumors. The microRNA miR-193a-3p directly targets PAK4 and suppresses downstream p-Slug and L1CAM expression. Silencing PAK4, Slug, and L1CAM mirrored miR-193a-3p's effects upon the migration and invasiveness of NSCLC cells in vitro. Decreased miR-193a-3p levels correlated with elevated PAK4, p-Slug, and L1CAM levels in NSCLC tumors. Our findings support a model of miR-193a-3p as a suppressor of metastatic disease progression in NSCLC via modulation of the p53/Slug/L1CAM pathway.

Objective Obesity is associated with an increased risk of many metabolic disorders, including non-alcoholic fatty liver disease (NAFLD). However, the underlying mechanisms remain poorly understood. Recent studies have demonstrated that MicroRNA-mediated gene silencing plays an important role in hepatic triglyceride (TG) metabolism. In the present study, we aimed to investigate the pathological function of miR-361-5p in the development of NAFLD. Methods Expression levels of miR-361-5p was determined by quantitative real-time PCR in livers of obese mice and NAFLD patients. Liver tissues from mice with miR-361-5p overexpression or inhibition were collected and analyzed by TG contents, gene expression profile. Results Expression of miR-361-5p was increased in the livers of two obese mouse models and NAFLD subjects. Overexpression of miR-361-5p in C57BL/6 mice led to hepatosteatosis, whereas inhibition of miR-361-5p expression in db/db mice improved TG accumulation and insulin sensitivity. Mechanistically, we identified Sirt1 as a direct target gene of miR-361-5p and re-introduction of Sirt1 largely abolished the metabolic action of miR-361-5p. Conclusions Our results demonstrated the role of miR-361-5p in the regulation of hepatic TG homeostasis, which may provide potential therapeutic target for hepatosteatosis.

Papillary thyroid carcinoma (PTC) is the most common endocrine malignancy. It has been demonstrated that micro-RNAs (miRNAs) are involved in the development of PTC. The miRNA-chromatin immunoprecipitation microarray assay revealed down-regulation of miR-219-5p; however, the effect of miR-219-5p on PTC cell growth remains unknown. This result implied the critical role of miR-219-5p in the development of PTC.We investigated the association between miR-219-5p and PTC development. Expression of miR-219-5p was monitored in 30 PTC tissue specimens and compared with that in 30 normal thyroid tissue specimens. The effect of miR-219-5p on PTC development was studied by cell proliferation, migration, and apoptosis assays. The underlying mechanism was clarified by a reporter assay and rescue experiment.The current study confirmed that miR-219-5p expression was inhibited in PTC tissue samples. There were statistically significant differences in the expression of miR-219-5p with regard to sex, tumor size, and lymph node metastasis in patients with PTC. Forced expression of miR-219-5p suppressed PTC cell proliferation and migration and promoted apoptosis. Further study showed that estrogen receptor (ER) α was the direct target of miR-219-5p and mediated the effect of miR-219-5p on PTC occurrence. Expression of miR-219-5p was inversely correlated with that of ERα. Importantly, ERα overexpression in PTC cells rescued the inhibitory effect of miR-219-5p on PTC cell proliferation and migration. Thus, our results indicated that miR-219-5p played a critical role in PTC growth by inhibiting ERα.Our investigation identified miR-219-5p as a negative regulator of PTC development through targeting of ERα.

G-protein-coupled receptor 120 (GPR120) functions as a receptor for unsaturated long-chain free fatty acids and has an important role in regulating lipid and glucose metabolism. However, a role for GPR120 in the development of tumors has not yet been clarified. Here, we show that GPR120 signaling promotes angiogenic switching and motility of human colorectal carcinoma (CRC) cells. We show that the expression of GPR120 is significantly induced in CRC tissues and cell lines, which is associated with tumor progression. Activation of GPR120 signaling in human CRC promotes angiogenesis in vitro and in vivo, largely by inducing the expression and secretion of proangiogenic mediators such as vascular endothelial growth factor (VEGF), interleukin-8 and cyclooxygenase-2-derived prostaglandin E2. The PI3K/Akt-NF-κB pathway is activated by GPR120 signaling and is required for GPR120 signaling-induced angiogenic switching in CRC cells. And, GPR120 activation enhances the motility of CRC cells and induces epithelial-mesenchymal transition. Furthermore, in vivo study shows that activation of GPR120 promotes angiogenesis and tumor growth. Finally, we find that GPR120 expression is positively correlated with VEGF expression and inversely correlated with the epithelial marker E-cadherin in CRC tissues. Collectively, our results demonstrate that GPR120 functions as a tumor-promoting receptor in CRC and, therefore, shows promise as a new potential target for cancer therapeutics.

The genetic regulation of cell cycle progression and cell proliferation plays a role in the growth of non-small cell lung cancer (NSCLC), one of the most common causes of cancer-related mortality. Although DEAD-box RNA helicases are known to play a role in cancer development, including lung cancer, the potential involvement of the novel family member DDX51 has not yet been investigated. In the current study we assessed the role of DDX51 in NSCLC using a siRNA-based approach. DDX51 siRNA-expressing cells exhibited a slower cell proliferation rate and underwent arrest in S-phase of the cell cycle compared with control cells. Microarray analyses revealed that DDX51siRNA expression resulted in the dysregulation of a number of cell signalling pathways. Moreover, injection of DDX51 siRNA into an animal model resulted in the formation of smaller tumours compared with the control group. We also assessed the expression of DDX51 in patients with NSCLC, and the data revealed that the expression was correlated with patient age but no other risk factors. Overall, our data suggest for the first time that DDX51 aids cell cancer proliferation by regulating multiple signalling pathways, and that this protein might be a therapeutic target for NSCLC.

Mesenchymal stem cell (MSC)-based therapy is a promising approach to treat various inflammatory disorders including multiple sclerosis. However, the fate of MSCs in the inflammatory microenvironment is largely unknown. Experimental autoimmune encephalomyelitis (EAE) is a well-studied animal model of multiple sclerosis. We demonstrated that autophagy occurred in MSCs during their application for EAE treatment. Inflammatory cytokines, e.g., interferon gamma and tumor necrosis factor, induced autophagy in MSCs synergistically by inducing expression of BECN1/Beclin 1. Inhibition of autophagy by knockdown of Becn1 significantly improved the therapeutic effects of MSCs on EAE, which was mainly attributable to enhanced suppression upon activation and expansion of CD4(+) T cells. Mechanistically, inhibition of autophagy increased reactive oxygen species generation and mitogen-activated protein kinase 1/3 activation in MSCs, which were essential for PTGS2 (prostaglandin-endoperoxide synthase 2 [prostaglandin G/H synthase and cyclooxygenase]) and downstream prostaglandin E2 expression to exert immunoregulatory function. Furthermore, pharmacological treatment of MSCs to inhibit autophagy increased their immunosuppressive effects on T cell-mediated EAE. Our findings indicate that inflammatory microenvironment-induced autophagy downregulates the immunosuppressive function of MSCs. Therefore, modulation of autophagy in MSCs would provide a novel strategy to improve MSC-based immunotherapy.

In inflammatory sites, high molecular weight hyaluronan fragments are degraded into lower molecular weight hyaluronan fragments (LMW-HA) to regulate immune responses. However, the function of LMW-HA in PTC progression remains to be elucidated. In this study, we found that receptor of LMW-HA, TLR4, was aberrantly overexpressed in PTC tissues and cell line W3. Exposure of W3 cells to LMW-HA promoted cell proliferation and migration via TLR4. Knockdown of TLR4 has provided evidence that TLR4 is essential for LMW-HA-induced CXCR7 expression, which is responsible for LMW-HA-induced proliferation and migration of W3 cells. In tumor-bearing adult nude mice, stimulation of LMW-HA on W3 cells promotes CXCR7 expression in tumor masses (P=0.002) and tumor growth (P<0.001). To further confirm our findings, we investigated the clinicopathologic significance of TLR4 and CXCR7 expression using immumohistochemistry in 135 human PTC tissues and 56 normal thyroid tissue samples. Higher rates of TLR4 (53%) and CXCR7 (24%) expression were found in PTC tissues than in normal tissues. Expression of TLR4 or CXCR7 is associated with tumor size and lymph node metastasis. Therefore, LMW-HA may contribute to the development of PTC via TLR4/CXCR7 pathway, which may be a novel target for PTC immunomodulatory therapy.

The link between inflammation and colorectal carcinoma has been acknowledged. However, the impact of bacterial lipopolysaccharide (LPS) binding to Toll-like receptor 4 (TLR4) on chemokine receptors in human colorectal carcinoma cells still remains to be elucidated. The present study shows that exposure to LPS elevated CXC chemokine receptor 7 (CXCR7) expression in colorectal carcinoma SW480 and Colo 205 cell lines expressing TLR4/myeloid differential protein (MD-2). CXCR7 is associated with SW480 cell proliferation and migration. However, exposure of SW480 and Colo 205 cells to LPS had no effect on CXCR4 expression. To further support the above results, the expression of TLR4, MD-2, and CXCR7 was analyzed in human colorectal carcinoma tissues. Higher rates of TLR4 (53%), MD-2 (70%), and CXCR7 (29%) expression were found in colorectal carcinoma tissues than in normal tissues. We demonstrated that the recombination of TLR4, MD-2 and CXCR7 strongly correlated with tumor size, lymph node metastasis and distant metastasis in colorectal carcinoma tissue samples (p = 0.037, p = 0.002, p = 0.042, resp.). Accordingly, simultaneous examination of the expression of TLR4, MD-2 and CXCR7 in cancer tissues of colorectal carcinoma may provide valuable prognostic diagnosis of carcinoma growth and metastasis. Interplay of TLR4, MD-2 and CXCR7 may be of interest in the context of novel immunomodulatory therapies for colorectal carcinoma.

We investigated the clinicopathologic significance of HIF-1, CXCR4, and VEGF expression using immumohistochemistry in human colon cancer. HIF-1, CXCR4, and VEGF high expression levels were correlated positively with TNM stage, lymph node involvement, and distant metastasis Furthermore, we found that combined high expression of any two of the three molecules (P=.028for HIF-1/CXCR4,P=.007for HIF-1/VEGF, andP=.004for CXCR4/VEGF) had stronger correlation with lymph node metastasis than did each alone. However, a relationship with distant metastasis is seen only with the combinations CXCR4/VEGF (P=.069for HIF-1/CXCR4,P=.062for HIF-1/VEGF, andP=.035for CXCR4/VEGF) as compared with those of single molecule high expression alone. Combined expression of all three molecules strongly correlates with lymph node metastasis and distant metastasis. The mRNA expression of HIF-1, CXCR4, and VEGF were quantified by real-time PCR in different colon cancer tissue samples, the experiment results shown that fresh colon tissue samples significantly overexpressed CXCR4 and VEGF mRNA compared with negative control. Therefore, the disease-free survival of all patients after curative resection can be considered in association with all three markers expression.

BackgroundChildhood trauma is known to predispose to a variety of psychiatric disorders, including anxiety, mood, and substance use. However, the relationship between childhood trauma and obsessive-compulsive disorder (OCD) has not been well studied. The aim of the present study is to compare childhood trauma experience between OCD and controls, and explore its impact on symptoms of OCD.MethodsOne hundred eighty-five outpatients who met DSM-IV diagnosis of OCD and 132 gender- age- matched controls were included in this study. The Early Trauma Inventory Self Report-Short Form (ETISR-SF) was administered to all participants to evaluate 4 types (general, physical, emotional and sexual) of trauma and its severity. The Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) was used to measure the severity of symptoms of OCD patients.ResultsOCD patients showed a significantly greater severity in all four types of trauma when compare with controls. 77% of OCD patients reported at least one type of childhood trauma experience, and 18% reported sexual trauma. Sexual trauma experience is significantly associated with obsessive but not compulsive symptoms of OCD patients. When compared to female OCD patients, male patients reported significantly higher scores on general trauma, physical abuse and emotional abuse; but lower of sexual abuse.ConclusionThe present study revealed the high prevalence of childhood trauma among OCD patients, which is consistent with evidence from previous studies suggesting that childhood trauma may play a role in the development of mental disorders. It may be important to consider the impact of childhood trauma in OCD clinical management.