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Viral corneal infection is a common cause of visual impairment and blindness. Polyinosinic‑polycytidylic acid, or poly(I:C), is similar to viral double‑stranded RNA in structure and has been implicated in the release of a variety of cytokines, chemokines and matrix metalloproteinases (MMPs) by corneal fibroblasts. Sulforaphane (SFN) is an isothiocyanate compound found in cruciferous vegetables. The present study investigated the potential effect of SFN on the poly(I:C)‑stimulated release of cytokines, chemokines and MMPs in human corneal fibroblasts (HCFs). ELISA showed that SFN was associated with a time‑ and dose‑dependent reduction in poly(I:C)‑stimulated production of interleukin (IL)‑8, chemoattractant protein‑1, IL‑6, MMP‑1 and MMP‑3 by HCFs. Western blot analysis indicated that SFN suppressed the function of poly(I:C) by modulating mitogen‑activated protein kinases (MAPKs), including p38 and extracellular signal‑regulated kinase (ERK), activator protein‑1 (AP‑1) component c‑Jun and the kinase, Akt, and the phosphorylation and degradation of the nuclear factor (NF)‑κB inhibitor IκB‑α. Immunofluorescence analysis revealed that SFN attenuated the production of poly(I:C)‑induced nuclear translocation of the NF‑κB p65 subunit. Reverse transcription‑quantitative PCR analysis revealed that SFN prevented the poly(I:C)‑induced upregulation of Toll‑like receptor 3 (TLR3) mRNA expression in HCFs. No significant cytotoxic effect of SFN on HCFs was observed. In summary, SFN attenuated the poly(I:C)‑induced production of proinflammatory chemokines, cytokines and MMPs by HCFs, by inhibiting TLR3, MAPK (p38 and ERK), AP‑1, Akt and NF‑κB signaling. SFN may therefore be a potential novel treatment for viral corneal infection by limiting immune cell infiltration. [ABSTRACT FROM AUTHOR]

Epithelial‑mesenchymal transition (EMT) serves an important regulatory role in obstructive nephropathy and renal fibrosis. As an intracellular energy sensor, AMP‑activated protein kinase (AMPK) is essential in the process of EMT. The aim of the present study was to elucidate changes in the expression levels of AMPKα2 and which AMPKα2 genes play a role during EMT. TGF‑β1 was used to induce EMT in normal rat renal tubular epithelial (NRK‑52E) cells. The short hairpin AMPKα2 lentivirus was used to interfere with AMPKα2 expression levels in EMT‑derived NRK‑52E cells and AMPKα2 expression levels and EMT were detected. Differential gene expression levels following AMPKα2 knockdown in EMT‑derived NRK‑52E cells were assessed via gene microarray. Potential regulatory pathways were analyzed using ingenuity pathway analysis (IPA) and differentially expressed genes were partially verified by reverse transcription‑quantitative PCR (RT‑qPCR) and western blotting. AMPKα2 was upregulated in TGF‑β1‑induced EMT‑derived NRK‑52E cells. EMT progression was significantly inhibited following downregulation of expression levels of AMPKα2 by shAMPKα2 lentivirus. A total of 1,588 differentially expressed genes were detected following AMPKα2 knockdown in NRK‑52E cells in which EMT occurred. The ERK/MAPK pathway was significantly impaired following AMPKα2 knockdown, as indicated by IPA analysis. Furthermore, RT‑qPCR and western blot results demonstrated that the expression levels of AMPKα2, v‑ets erythroblastosis virus E26 oncogene homolog‑1 (ETS1) and ribosomal protein S6 kinase A1 (RPS6KA1) were upregulated following EMT in NRK‑52E cells, whereas the expression levels of ETS1 and RPS6KA1 were downregulated following AMPKα2 knockdown. It was concluded that AMPKα2 plays a key role in the regulation of rat renal tubular EMT, which may be achieved by modulating ETS1 and RPS6KA1 in the ERK/MAPK pathway. [ABSTRACT FROM AUTHOR]

Mitogen-activated protein kinase (MAPK) signal transduction pathways may be involved in the destruction of pancreatic islet β cells induced by inflammatory cytokines. The present study aimed to investigate the role of different MAPK signal transduction pathways in the interleukin-1β (IL-1β)-induced inhibition of glucose-stimulated insulin secretion (GSIS) in Min6 mouse pancreatic cells. Min6 cells were stimulated with different concentrations of glucose (0.0, 5.5, 11.1 and 22.2 mmol/l), or different concentrations of IL-1β (0.00, 0.25 and 2.50 ng/ml) in combination with high glucose (22.2 mmol/l) and the culture supernatant was collected. The concentration of insulin was measured by enzyme-linked immunosorbent assay and the activation of different MAPK pathways was assessed by measuring the phosphorylation levels of extracellular signal-regulated kinase 1/2 (ERK1/2), p38 and c-jun N-terminal kinase (JNK) via western blotting. The production of reactive oxygen species (ROS) was determined via flow cytometry, and cell viability was detected by Cell Counting Kit-8 assay. Reverse transcription-quantitative PCR was used to detect the insulin 1 gene. The results revealed that glucose activated ERK1/2 phosphorylation, but inhibited JNK and p38 phosphorylation in a concentration-dependent manner. Furthermore, IL-1β inhibited glucose-stimulated insulin secretion in a dose-dependent manner. Western blotting revealed that IL-1β inhibited the activation of ERK1/2 phosphorylation and attenuated the inhibition of p38 phosphorylation induced by glucose stimulation. JNK was neither activated nor inhibited by IL-1β. These results suggest that MAPK signal transduction pathways participated in the IL-1β-induced GSIS inhibition in Min6 cells, with the ERK1/2, JNK and p38 signaling pathways playing different roles. [ABSTRACT FROM AUTHOR]

Previous studies have shown that caspase-1 plays an important role in the acute inflammatory response of spinal cord injury (SCI). VX-765, a novel and irreversible caspase-1 inhibitor, has been reported to effectively intervene in inflammation. However, the effect of VX-765 on genome-wide transcription in acutely injured spinal cords remains unknown. Therefore, in the present study, RNA-sequencing (RNA-Seq) was used to analyze the effect of VX-765 on the local expression of gene transcription 8 h following injury. The differentially expressed genes (DEGs) underwent enrichment analysis of functions and pathways by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses, respectively. Parallel analysis of western blot confirmed that VX-765 can effectively inhibit the expression and activation of caspase-1. RNA-Seq showed that VX-765 treatment resulted in 1,137 upregulated and 1,762 downregulated DEGs. These downregulated DEGs and their associated signaling pathways, such as focal adhesion, cytokine-cytokine receptor interaction, leukocyte transendothelial migration, extracellular matrix-receptor interaction, phosphatidylinositol 3-kinase-protein kinase B, Rap1 and hypoxia inducible factor-1 signaling pathway, are mainly associated with inflammatory response, local hypoxia, macrophage differentiation, adhesion migration and apoptosis of local cells. This suggests that the application of VX-765 in the acute phase can improve the local microenvironment of SCI by inhibiting caspase-1. However, whether VX-765 can be used as a therapeutic drug for SCI requires further exploration. The sequence data have been deposited into the Sequence Read Archive (https://www.ncbi.nlm.nih.gov/sra/PRJNA548970). [ABSTRACT FROM AUTHOR]

The present study examined whether lipoxin A4 (LXA4) increases the expression of HO-1, and inhibits the production of interleukin 6 (IL-6) and monocyte chemotactic protein 1 (MCP-1) in LXA4-induced protection during hyperoxia-induced injury in murine lung epithelial cells (MLE-12) and what signal pathway may participate in the actions of LXA4 inhibiting IL-6 and MCP-1. MLE-12 cells were exposed to air or hyperoxia with or without pretreatment with LXA4, Zinc protoporphyrin IX (ZnPP-IX), IL-6, anti-IL-6, MCP-1, anti-MCP-1, inhibitors of p38 mitogen-activated protein kinase (p38 MAPK), protein kinase B (Akt) and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathways. The cell survival rates, cell viability, apoptosis rates, expression of superoxide dismutase (SOD), heme oxygenase-1 (HO-1), IL-6 and MCP-1, and the activations of p38 MAPK, ERK1/2 and Akt were measured. LXA4 significantly increased the cell survival rates, cell viability, SOD levels and HO-1 expression, reduced the apoptosis rates, and inhibited the MCP-1 and IL-6 levels induced by hyperoxia in cells. ZnPP-IX, an inhibitor of HO-1, blocked LXA4-induced protection on cell viability in cells exposed to hyperoxia. Anti-IL-6 and anti-MCP-1 improved the cell viability of cells exposed to hyperoxia. Inhibition of p38 MAPK and ERK1/2 blocked the expression of MCP-1 and IL-6 induced by hyperoxia. LXA4 inhibited the activation of p38 MAPK and ERK1/2 induced by hyperoxia, and increased the activation of the Akt signaling pathway, which was inhibited by hyperoxia. Therefore, LXA4 attenuated hyperoxia-induced injury in MLE-12 cells via the upregulation of HO-1 expression. The protection of LXA4 in hyperoxia-induced cell injury may be associated with the downregulation IL-6 and MCP-1 levels via the inhibition of the p38 MAPK and ERK1/2 signaling pathways. [ABSTRACT FROM AUTHOR]

Propofol is a general anesthetic used in surgical operations. Phosphoprotein enriched in astrocytes 15(PEA15) was initially identified in astrocytes. The present study examined the role of PEA15 in the damage induced by propofol in hippocampal neurons. A model of hippocampal neuron damage was established using 50 µmol/l propofol. Cell viability, proliferation and apoptosis of hippocampal neurons were tested by Cell Counting Kit-8 and flow cytometry. Western blotting and reverse transcription-quantitative polymerase chain reaction analysis were performed to measure the expression levels of PEA15, and additional factors involved in apoptosis or in the signaling pathway downstream of PEA15. The present results suggested that propofol significantly decreased PEA15 expression levels in hippocampal neurons. Furthermore, overexpression of PEA15 significantly increased the cell viability and cell proliferation of cells treated with propofol. Additionally, PEA15 overexpression decreased apoptosis, which was promoted by propofol. Treatment with propofol significantly decreased the protein expression levels of pro-caspase-3, B-cell lymphoma-2, phosphorylated extracellular signal-regulated kinases (ERK)1/2, ribosomal S6 kinase 2 (RSK2) and phosphorylated cAMP responsive element binding protein 1 (CREB1). However, propofol upregulated active caspase-3 and Bax expression levels. Notably, PEA15 overexpression was able to reverse the effects of propofol. Collectively, overexpression of PEA15 was able to attenuate the neurotoxicity of propofol in rat hippocampal neurons by increasing proliferation and repressing apoptosis via upregulation of the ERK-CREB-RSK2 signaling pathway. [ABSTRACT FROM AUTHOR]

Electroacupuncture (EA), a traditional Chinese therapeutic technique, is considered an effective method for treating certain painful neuropathies induced by various neuropathological damage. The current study investigated the effect of EA on intrathecal (IT) morphine-induced hyperalgesia (MIH) and examined the hypothesis that activation of cannabinoid receptor 1 (CB1) could enhance the antinociceptive effect of EA on MIH via regulation of the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway. Using a rat model of IT MIH, mechanical and thermal hyperalgesia were evaluated by an electronic von Frey filament and hotplate at baseline (1 day before IT administration) and at days 1, 3, 5 and 7 after IT administration. Rats received IT normal saline, IT morphine or IT morphine + EA at ST36-GB34. The protein levels of ERK1/2, phosphorylated (p)-ERK1/2 and CB1 in the spinal cord were assayed by western blotting. Furthermore, the effect of IT injection of the CB1 agonist WIN 55,212-2 and the CB1 antagonist SR141716 on the antinociceptive effect of EA in rats with MIH was investigated. Nociceptive behavior and ERK1/2, phosphorylated (p)-ERK1/2 and CB1 protein levels were evaluated as mentioned above. The results revealed that chronic IT injections of morphine induced a significant decrease in mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) accompanied with remarkable upregulation of p-ERK1/2 in the spinal cord, which could be attenuated by EA at the ST36-GB34 acupoints. In the rat model of MIH, IT injection of WIN 55,212-2 combined with EA induced a significant increase in MWT and TWL accompanied with a significant decrease in p-ERK1/2 and a significant increase in CB1 protein level compared with EA alone, while SR141716 induced the opposite results. The present study suggests that EA alleviates hyperalgesia induced by IT injection of morphine partially through the inhibition of ERK1/2 activation. Activation of the CB1 receptor enhances the antinociceptive effect of EA in rats with MIH partly through the regulation of the spinal CB1-ERK1/2 signaling pathway. [ABSTRACT FROM AUTHOR]

Advances in the treatment of nasopharyngeal carcinoma (NPC) have significantly improved the local control rate; however, distant metastasis remains a principal cause of mortality. Previous studies have demonstrated that the expression levels of amyloid β precursor protein (APP) are increased in NPC. The present study aimed to investigate the association between APP and the development of NPC. In order to knockdown APP expression, an APP-small interfering RNA vector was synthesized and transfected into SUNE-1 cells. Cell Counting Kit-8 assay was performed to assess cell viability. The migratory and invasive abilities of SUNE-1 cells were examined by wound healing and Transwell assays, respectively. Reverse transcription-quantitative polymerase chain reaction and western blotting were performed to measure the mRNA and protein expression levels of APP, and additional factors involved in epithelial-mesenchymal transition (EMT) and in the mitogen-activated protein kinase (MAPK) signaling pathway. APP silencing significantly suppressed cell viability, migration and invasion. In addition, APP interference downregulated the expression levels of metastasis-associated 1, matrix metalloproteinase (MMP)-2 and MMP-9; however, knockdown of APP led to upregulation of tissue inhibitor of metalloproteinases 2 and inhibited EMT. The phosphorylation levels of p38, extracellular signal-regulated kinases 1/2 and c-Jun N-terminal kinases 1/2 were decreased following downregulation of APP. The present results suggested that APP knockdown may significantly inhibit the development of NPC by suppressing cell viability, migration and invasion, and by inhibiting the EMT process via downregulation of the MAPK signaling pathway. Therefore, APP may facilitate the development of a novel gene therapy for the treatment of NPC. [ABSTRACT FROM AUTHOR]

Wound healing is a dynamic process that involves highly coordinated cellular events, including proliferation and migration. Oral gingival fibroblasts serve a central role in maintaining oral mucosa homeostasis, and their functions include the coordination of physiological tissue repair. Recently, surface pre-reacted glass-ionomer (S-PRG) fillers have been widely applied in the field of dental materials for the prevention of dental caries, due to an excellent ability to release fluoride (F). In addition to F, S-PRG fillers are known to release several types of ions, including aluminum (Al), boron (B), sodium (Na), silicon (Si) and strontium (Sr). However, the influence of these ions on gingival fibroblasts remains unknown. The aim of the present study was to examine the effect of various concentrations of an S-PRG filler eluate on the growth and migration of gingival fibroblasts. The human gingival fibroblast cell line HGF-1 was treated with various dilutions of an eluent solution of S-PRG, which contained 32.0 ppm Al, 1,488.6 ppm B, 505.0 ppm Na, 12.9 ppm Si, 156.5 ppm Sr and 136.5 ppm F. Treatment with eluate at a dilution of 1:10,000 was observed to significantly promote the migration of HGF-1 cells. In addition, the current study evaluated the mechanism underlying the mediated cell migration by the S-PRG solution and revealed that it activated the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), but not of p38. Furthermore, treatment with a MEK inhibitor blocked the cell migration induced by the solution. Taken together, these results suggest that S-PRG fillers can stimulate HGF-1 cell migration via the ERK1/2 signaling pathway, indicating that a dental material containing this type of filler is useful for oral mucosa homeostasis and wound healing. [ABSTRACT FROM AUTHOR]

Periodontal ligament stem cells (PDLSCs) are promising stem cells sources for regenerative medicine, particularly clinical periodontal ligament repair. It is critical to maintain high quality and a large quantity of PDLSCs for clinical usage. However, how PDLSCs respond to environmental stimuli, including reactive oxygen species (ROS), is poorly understood. The aim of the present study was to investigate how PDLSCs react to oxidative stress and the underlying mechanisms. Hydrogen peroxide-induced oxidative stress was used to mimic a ROS increase in rat PDLSCs. The expression levels of Creb were detected under oxidative stress to examine the role that Creb serves in PDLSCs under oxidative stress. The present results demonstrated that the expression of Creb was reduced in a dose-dependent manner in response to the H2O2 stimulus. Overexpressing Creb significantly reduced the ROS levels and protein expression levels of apoptotic genes in PDLSCs. The phosphorylation of the ERK pathway is indispensable in the activation of Creb-induced protection. Our results revealed a protective role of Creb in ROS-induced apoptosis, and validated the ERK/Creb/apoptosis regulator Bcl-2 pathway works as an anti-apoptotic signaling in PDLSCs. These findings will facilitate the in vitro culturing of PDLSCs for clinical usage and promote stem cell based therapy for periodontal tissue regeneration. [ABSTRACT FROM AUTHOR]

Senescence is a result of cellular stress and is a potential mechanism for regulating cancer. As a member of the mitogen-activated protein kinase family, ERK1/2 (extracellular signal-regulated protein kinase) has an important role in delivering extracellular signals to the nucleus, and these signals regulate the cell cycle, cell proliferation and cell development. Previous studies demonstrated that ERK1/2 is closely associated with cell aging; however other previous studies suggested that ERK1/2 exerts an opposite effect on aging models and target proteins, even within the same cell model. Recent studies demonstrated that the effect of ERK1/2 on aging is likely associated with its target proteins and regulators, negative feedback loops, phosphorylated ERK1/2 factors and ERK1/2 translocation from the cytoplasm to the nucleus. The present review aims to examine the mechanism of ERK1/2 and discuss its role in cellular outcomes and novel drug development. [ABSTRACT FROM AUTHOR]

The (pro)renin receptor [(P)RR] serves an important role in cardiovascular complications. However, the precise mechanisms of (P)RR in the heart remain obscure. The authors hypothesized that overexpression of (P)RR would be associated with activation of the relevant signal pathway which could lead to organ injury. The aim of the present study was to test the role of cardiac (P)RR and its potential signaling pathway components including phospholipase C (PLC), protein kinase C (PKC), extracellular signal-regulated kinase (ERK)1/2 and Raf-1 proto-oncogene, serine/threonine kinase (Raf-1). Hypertension and cardiac hypertrophy were induced by partial abdominal aortic ligation in Sprague-Dawley rats. The expression levels of cardiac (P)RR, PLC-β3, PKC, ERK1/2 and Raf-1 were measured following administration of the handle region peptide (HRP) and PLC-β3 inhibitor U73122. The expression of (P)RR and PLC-β3 significantly increased in the left ventricle (P<0.05). Levels of PKC-α, ERK1/2 and Raf-1 in the heart rose significantly (P<0.05). HRP and U73122 significantly decreased the levels of cardiac (P)RR and PLC-β3. Furthermore, levels of PKC-α, ERK1/2 and Raf-1 were also decreased (P<0.05). Cardiac parameters, blood pressure and plasma Angiotensin (Ang) I and Ang II levels were altered significantly (P<0.05). The results demonstrated that hypertension induced by aortic restriction activated the (P)RR in the heart. This action led to hypertension and cardiac hypertrophy via the (P)RR-PLC-β3-PKC-ERK1/2-Raf-1 signaling pathway. These results provide a mechanism by which elevated (P)RR levels in hypertension may contribute to the development of cardiac remodeling. [ABSTRACT FROM AUTHOR]

Vein graft remains the most broadly applied vascular material in coronary artery bypass surgery. However, the restenosis rate of the vein bridge following angioplasty is high. The present study investigated the effect of medical adhesive on vascular intimal hyperplasia, in addition to the signal transduction mechanism. A total of 36 New Zealand white rabbits were divided into three groups at random, including the normal group, the surgery group and the medical adhesive spray group. Following surgery for transplantation of the left external jugular vein to the ipsilateral common carotid artery for 4 weeks, the thickness and area of the intima and media of the vessel were measured on formalin-fixed, paraffin wax-embedded pathological sections using hematoxylin-eosin staining, and alterations in the expression of proliferating cell nuclear antigen (PCNA), platelet endothelial cell adhesion molecule 1 (PECAM-1), vascular cell adhesion protein 1 (VCAM-1), extracellular signal-regulated kinase (ERK)1/2, and endothelial nitric oxide synthase (eNOS) were detected by immunohistochemical staining, reverse transcription-quantitative polymerase chain reaction analysis and western blotting. The levels of intimal hyperplasia in the medical adhesive spray group were markedly decreased compared with the surgery group. Consistently, PCNA, PECAM-1 and VCAM-1 were underexpressed in the medical adhesive spray group compared with the surgery group. ERK1/2 and eNOS were underexpressed in the medical adhesive spray group compared with the surgery group. Therefore, the application of medical adhesive may inhibit intimal hyperplasia, which may be associated with the restriction of the over-distension of the vein graft by downregulating the ERK1/2 and eNOS levels, reducing injury to the vascular intima and inhibiting the signaling pathway involved in intimal hyperplasia. [ABSTRACT FROM AUTHOR]

Demyelination is a nervous system disease in which the myelin sheaths of neurons are damaged due to inflammatory reactions, inherited abnormalities or trauma. This damage impairs the conduction of signals in the affected nerves, which in turn causes deficiencies in sensation, movement and cognition. Oligodendrocyte precursor cells (OPCs) are able to induce remyelination. However, the remyelination is suboptimal due to the limited migration of OPCs. In the present study, neonatal OPCs were isolated from rats for the investigation of the role of C-X-C motif chemokine ligand 12 (CXCL12), an important chemokine, in mediating the migration ability of OPCs. The present results demonstrated that CXCL12 stimulation markedly promoted the migration of OPCs and activated the dual specificity mitogen-activated protein kinase kinase 1 (MEK)/extracellular signal-regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K)/RAC-α serine/threonine-protein kinase (AKT) pathways. Knockdown of C-X-C motif chemokine receptor 4 (CXCR4; a receptor of CXCL12) reversed the CXCL12-induced migration of OPCs and blocked the MEK/ERK and PI3K/AKT pathways. In addition, specific inhibitors of the MEK/ERK and PI3K/AKT pathways significantly reduced the migration of OPCs. Based on these findings, it was concluded that CXCL12 may induce the migration of OPCs through the CXCR4-activated MEK/ERK and PI3K/AKT pathways. The results of the present study support the manipulation of CXCL12-mediated OPC migration to improve remyelination. [ABSTRACT FROM AUTHOR]

Atrial fibrillation (AF) is a common cardiac arrhythmia, which is associated with increased cardiovascular morbidity and mortality. microRNA (miRNA/miR)‑122 has been reported to be related with heart diseases, however, the functional role of miR‑122 in atrial fibrillation is unclear. Therefore, the aim of the present study was to investigate the roles of miR‑122 in atrial fibrillation. Male C57BL/6 mice were divided into the following three groups: Control, sham‑operation and AF. Mice in the AF group received transesophageal rapid atrial stimulation for the induction of AF. Cardiomyocytes isolated from mice in the AF group and were transfected with miR‑122 inhibitors. Reverse transcription‑quantitative polymerase chain reaction was used to assess the expression of miR‑122 in cardiomyocytes isolated from mice in the AF, sham‑operation and control groups, and in cells transfected with miR‑122 inhibitors. MTT and TUNEL assays were used to evaluate cardiomyocyte viability and apoptosis, respectively. Western blot analysis was used to assess the expression levels of extracellular signal‑regulated kinase (ERK) and phosphorylated (p)‑ERK, as well as the apoptosis‑associated proteins caspase‑3 and B‑cell lymphoma 2‑like 1 (Bcl‑x). The present results demonstrated that miR‑122 expression in the AF group was significantly increased compared with the sham‑operation and control groups, whereas it was significantly decreased following transfection with the miR‑122 inhibitor. Cardiomyocyte viability was increased and their apoptosis rate was significantly decreased following miR‑122 transfection. In addition, the expression of the anti‑apoptotic protein Bcl‑x was significantly upregulated, whereas the expression of the pro‑apoptotic caspase‑3 was significantly downregulated following miR‑122 inhibition. Furthermore, the p‑ERK/total ERK ratio was significantly increased in the miR‑122 inhibitor group compared with the AF and control groups. The present results suggested that miR‑122 may be implicated in the molecular mechanisms underlying the proliferation and apoptosis of cardiomyocytes in AF. [ABSTRACT FROM AUTHOR]

Physical exercise is beneficial for the functional recovery of neurons after stroke. It has been suggested that exercise regulates proliferation and differentiation of endogenous neural stem cells (NSCs); however, the underlying molecular mechanisms are still largely unknown. In the present study, the aim was to investigate whether physical exercise activates the extracellular signal‑regulated kinase (ERK) signaling pathway to promote proliferation and differentiation of NSCs in rats with cerebral infarction, thereby improving neurological function. Following middle cerebral artery occlusion, rats underwent physical exercise and neurological behavior was analyzed at various time points. Immunofluorescence staining was performed to detect proliferation and differentiation of NSCs, and western blotting was used to analyze cyclin‑dependent kinase 4 (CDK4), Cyclin D1, retinoblastoma protein (p‑Rb), P‑16, phosphorylated (p)‑ERK1/2 and c‑Fos expression. The results indicated that physical exercise promoted proliferation and differentiation of NSCs, and led to improved neural function. In addition, the expression levels of CDK4, Cyclin D1, p‑Rb, p‑ERK1/2 and c‑Fos were upregulated, whereas the expression of P‑16 was downregulated following exercise. U0126, an inhibitor of ERK signaling, reversed the beneficial effects of exercise. Therefore, it may be hypothesized that physical exercise enhances proliferation and differentiation of endogenous NSCs in the hippocampus of rats with cerebral infarction via the ERK signaling pathway. [ABSTRACT FROM AUTHOR]

Pulmonary fibrosis is a severe respiratory disease characterized by the aggregation of extracellular matrix components and inflammation‑associated injury. Studies have suggested that long non‑coding RNAs (lncRNA) may serve a role in the pathophysiological processes of pulmonary fibrosis. However, the potential molecular mechanisms involving the lncRNA, prostate cancer‑associated transcript 29 (lncRNAPCAT29) in the progression of pulmonary fibrosis are yet to be determined. In the present study, the role of lncRNAPCAT29 and the potential signaling mechanism in pulmonary fibrosis progression was investigated. Reverse transcription‑quantitative polymerase chain reaction and immunohistochemistry revealed that the expression levels of lncRNAPCAT29 were downregulated within interstitial lung cells from mice with silica‑induced pulmonary fibrosis. Transfection with lncRNAPCAT29 was associated with upregulated expression of microRNA (miRNA)‑221 and downregulated expression of transforming growth factor‑β1 (TGF‑β1); reduced inflammation and fibrotic progression was also associated with lncRNAPCAT29 transfection. TGF‑β1 expression levels were inhibited within pulmonary fibroblasts due to lncRNAPCAT29 expression; NEDD4 binding protein 2 and Plexin‑A4 expression levels were also suppressed. Analysis of the potential mechanism underlying silica‑induced pulmonary fibrosis revealed that the expression levels of RAS protein activator like 1 (RASAL1) and extracellular signal‑regulated kinases 1/2 (ERK1/2) were suppressed due to lncRNAPCAT29 expression. The results of the present study demonstrated that lncRNAPCAT29 induced miRNA‑221 upregulation and TGF‑β1 downregulation. These observations were associated with reduced inflammation and progression of silica‑induced pulmonary fibrosis via the TGF‑β1‑regulated RASAL1/ERK1/2 signaling pathway, which may serve as a potential target for the treatment of pulmonary fibrosis. [ABSTRACT FROM AUTHOR]

Diabetes mellitus is a complicated metabolic disease with symptoms of hyperglycemia, insulin resistance, chronic damage and dysfunction of tissues, and metabolic syndrome for insufficient insulin production. Evidence has indicated that exercise treatments are essential in the progression of type‑ІІ diabetes mellitus, and affect insulin resistance and activity of islet β‑cells. In the present study, the efficacy and signaling mechanism of aerobic exercise on blood lipids and insulin resistance were investigated in the progression of type‑ІІ diabetes mellitus. Body weight, glucose metabolism and insulin serum levels were investigated in mouse models of type‑ІІ diabetes mellitus following experienced aerobic exercise. Expression levels of inflammatory factors, interleukin (IL)‑6, high‑sensitivity C‑reactive protein, tumor necrosis factor‑α and leucocyte differentiation antigens, soluble CD40 ligand in the serum were analyzed in the experimental mice. In addition, expression levels of toll‑like receptor 4 (TLR‑4) were analyzed in the liver cells of experimental mice. Changes of oxidative stress indicators, including reactive oxygen species, superoxide dismutase, glutathione and catalase were examined in the liver cells of experimental mice treated by aerobic exercise. Expression levels and activity of extracellular signal‑regulated kinases (ERK) and AMP‑activated protein kinase (AMPK) signaling pathways were investigated in the liver cells of mouse models of type‑ІІ diabetes mellitus after undergoing aerobic exercise. Aerobic exercise decreased the expression levels of inflammatory factors in the serum of mouse models of type‑ІІ diabetes mellitus. The results indicated that aerobic exercise downregulated oxidative stress indicators in liver cells from mouse models of type‑ІІ diabetes mellitus. In addition, the ERK and AMPK signaling pathways were inactivated by aerobic exercise in liver cells in mouse models of type‑ІІ diabetes mellitus. The activity of ERK and AMPK, and the function of islet β‑cells were observed to be improved in experimental mice treated with aerobic exercise. Furthermore, blood lipid metabolism and insulin resistance were improved by treatment with aerobic exercise. Body weight and glucose concentration of serology was markedly improved in mouse models of type‑ІІ diabetes mellitus. Furthermore, TLR‑4 inhibition markedly promoted ERK and AMPK expression levels and activity. Thus, these results indicate that aerobic exercise may improve blood lipid metabolism, insulin resistance and glucose plasma concentration in mouse models of type‑ІІ diabetes mellitus. Thus indicating aerobic exercise is beneficial for improvement of blood lipid and insulin resistance via the TLR‑4‑mediated ERK/AMPK signaling pathway in the progression of type‑ІІ diabetes mellitus. [ABSTRACT FROM AUTHOR]

Maintenance of the chondrocyte phenotype is crucial for cartilage repair during tissue engineering. Intraflagellar transport protein 88 (IFT88) is an essential component of primary cilia, shuttling signals along the axoneme. The hypothesis of the present study was that IFT88 could exert an important role in icariin‑regulated maintenance of the chondrocyte phenotype. To this end, the effects of icariin on proliferation and differentiation of the chondrogenic cell line, ATDC5, were explored. Icariin‑treated ATDC5 cells and primary chondrocytes expressed IFT88. Icariin has been demonstrated to aid in the maintenance of the articular cartilage phenotype in a rat model of post‑traumatic osteoarthritis (PTOA). Icariin promoted chondrocyte proliferation and expression of the chondrogenesis marker genes, COL II and SOX9, increased ciliary assembly, and upregulated IFT88 expression in a concentration‑ and time‑dependent manner. Icariin‑treated PTOA rats secreted more cartilage matrix compared with the controls. Knockdown of IFT88 expression with siRNA reduced extracellular signal‑regulated kinase (ERK) phosphorylation, and icariin upregulated IFT88 expression by promoting ERK phosphorylation. Thus, IFT88 serves a major role in icariin‑mediated maintenance of the chondrocyte phenotype, promoting ciliogenesis and IFT88 expression by increasing ERK phosphorylation. Icariin may therefore be useful for maintenance of the cartilage phenotype during tissue engineering. [ABSTRACT FROM AUTHOR]

Lactoferrin (Lf) is a multifunctional glycoprotein, which promotes the proliferation of murine C2C12 myoblasts. In the present study, it was investigated how Lf promotes myoblast proliferation and whether Lf promotes myoblast differentiation or induces myotube hypertrophy. Lf promoted the proliferation of myoblasts in a dose‑dependent manner. Myoblast proliferation increased on day 3 when myoblasts were cultured in the presence of Lf for three days and also when myoblasts were cultured in the presence of Lf for the first day and in the absence of Lf for the subsequent two days. In addition, Lf induced the phosphorylation of extracellular signal‑regulated kinase (ERK)1/2 in myoblasts. The mitogen‑activated protein kinase kinase 1/2 inhibitor U0126 inhibited Lf‑induced ERK1/2 phosphorylation and repressed Lf‑promoted myoblast proliferation. C2C12 myoblasts, myotubes and skeletal muscle expressed low‑density lipoprotein receptor‑related protein (LRP)1 mRNA and Lf‑promoted myoblast proliferation was attenuated by an LRP1 antagonist or LRP1 gene silencing. The knockdown of LRP1 repressed Lf‑induced phosphorylation of ERK1/2. Furthermore, when myoblasts were induced to differentiate, Lf increased the expression of the myotube‑specific structural protein, myosin heavy chain (MyHC) and promoted myotube formation. Knockdown of LRP1 repressed Lf‑induced MyHC expression. Lf also increased myotube size following differentiation. These results indicate that Lf promotes myoblast proliferation and differentiation, at least partially through LRP1 and also stimulates myotube hypertrophy. [ABSTRACT FROM AUTHOR]

Non-small cell lung carcinoma (NSCLC) is the most common cause of cancer‑associated mortality in the world and accounts for ~85% of human lung cancers. Metastasis‑associated protein 2 (MTA2) is a component of the histone deacetylase complex and serves a role in tumor progression; however, the mechanism through which MTA2 is involved in the progression of NSCLC remains unclear. The aim of the present study was to investigate the expression and function of MTA2 and the MTA2‑mediated signaling pathway in NSCLC cells. Expression of MTA2 and its target genes was analyzed in MTA2‑overexpressing and anti‑MTA2 antibody (AbMTA2)‑treated NSCLC cells, as well as growth, migration, invasion and apoptotic‑resistance. The inhibitory effects on tumor formation were analyzed using AbMTA2‑treated NSCLC cells and in a mouse model. Histological assessment was conducted to analyze the expressions levels of extracellular signal‑regulated kinase (ERK), RAC‑α serine/threonine protein kinase (AKT) and vascular endothelial growth factor (VEGF) in experimental tumors. Results of the present study demonstrated that MTA2 was overexpressed in NSCLC cells. The growth, migration and invasion of NSCLC cells were markedly inhibited by AbMTA2. In addition, it was observed that the ERK/AKT and VEGF signaling pathways were both upregulated in MTA2‑overexpressing NSCLC cells, and downregulated following silencing of MTA2 activation. ERK and AKT phosphorylation levels were downregulated in NSCLC cells and tumors following MTA2 silencing. The in vivo study demonstrated that tumor growth was markedly inhibited following siRNA‑MTA2 treatment. In conclusion, the results of the present study suggested that MTA2 silencing may significantly inhibit the growth and aggressiveness of NSCLC cells. Results from the present study indicated that the mechanism underlying the MTA2‑mediated invasive potential of NSCLC cells involved the ERK/AKT and VEGF signaling pathways, which may be a potential therapeutic target for the treatment of NSCLC. [ABSTRACT FROM AUTHOR]

Arsenic is a toxic metal, which ultimately leads to cell apoptosis. ERK is considered a key transcriptional regulator of arsenic‑induced apoptosis. Due to a few controversial issues about arsenic‑mediated extracellular signal‑regulated MAP kinases (ERK) signaling, a meta‑analysis was performed. Subgroup analyses demonstrated that high doses (≥2 μmol/l) of arsenic increased the expression of Ras, ERK, ERK1, ERK2, phosphorylated (p)‑ERK, p‑ERK1, and p‑ERK2, while low doses (<2 μmol/l) decreased the expression of Ras, ERK1, p‑ERK, and p‑ERK2 when compared to control groups. Long term exposure (>24 h) to arsenic led to inhibition of expression of ERK1, p‑ERK1, and p‑ERK2, whereas short‑term exposure (≤24 h) triggered the expression of ERK1, ERK2, p‑ERK, p‑ERK1, and p‑ERK2. Furthermore, normal cells exposed to arsenic exhibited higher production levels of Ras and p‑ERK. Conversely, exposure of cancer cells to arsenic showed a lower level of production of Ras and p‑ERK as well as higher level of p‑ERK1 and p‑ERK2 as compared to control group. Short‑term exposure of normal cells to high doses of arsenic may promote ERK signaling pathway. In contrast, long‑term exposure of cancer cells to low doses of arsenic may inhibit ERK signaling pathway. This study may be helpful in providing a theoretical basis for the diverging result of arsenic adverse effects on one hand and therapeutic mechanisms on the other concerning arsenic‑induced apoptosis. [ABSTRACT FROM AUTHOR]

The present study aimed to determine the protective effects of arctigenin against myocardial infarction (MI), and its effects on oxidative stress and inflammation in rats. Left anterior coronary arteries of Sprague‑Dawley rats were ligated, in order to generate an acute MI (AMI) model. Arctigenin was administered to AMI rats at 0, 50, 100 or 200 μmol/kg. Western blotting and ELISAs were performed to analyze protein expression and enzyme activity. Arctigenin was demonstrated to effectively inhibit the levels of alanine transaminase, creatine kinase‑MB and lactate dehydrogenase, and to reduce infarct size in AMI rats. In addition, the activity levels of malondialdehyde, interleukin (IL)‑1β and IL‑6 were significantly suppressed, and the levels of glutathione peroxidase, catalase and superoxide dismutase were significantly increased by arctigenin treatment. Arctigenin treatment also suppressed the protein expression levels of inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX‑2) and heme oxygenase 1 (HO‑1), and increased the protein expression levels of phosphorylated‑extracellular signal‑regulated kinase 1/2 (p‑ERK1/2) in AMI rats. Overall, the results of the present study suggest that arctigenin may inhibit MI, and exhibits antioxidative and anti‑inflammatory effects through regulation of the iNOS, COX‑2, ERK1/2 and HO‑1 pathways in a rat model of AMI. [ABSTRACT FROM AUTHOR]

Tubeimoside‑1 (TBMS1), a triterpenoid saponin isolated from the tuber of Bolbostemma paniculatum (Maxim) Franquet, serves an universal suppressive role in multiple cancer types, including lung cancer. However, the mechanism involved in non‑small cell lung cancer (NSCLC) cells by which TBMS1 elicits its antitumor effects is not yet completely understood. The present study indicated that 10 μmol/l TBMS1 significantly enhanced apoptosis and notably blocked the migration and invasion of NCI‑H1299 cells. These effects were reversed following transfection with miR‑126‑5p inhibitor into TBMS1‑treated NCI‑H1299 cells. Vascular endothelial growth factor-A (VEGF‑A) is a target gene for miR‑126‑5p. Notably, results suggested that the downregulated VEGF‑A and VEGFR‑2 in TBMS1‑treated NCI‑H1299 cells were upregulated after inhibiting miR‑126‑5p, and overexpression of VEGF‑A or VEGFR‑2 could significantly reduce apoptosis and promote the migration and invasion of TBMS1‑treated NCI‑H1299 cells. Furthermore, TBMS1 combined with TBHQ (an ERK activator) dramatically suppressed TBMS1‑induced apoptosis and stimulated TBMS1‑reduced migration and invasion in NCI‑H1299 cells, suggesting that TBMS1 inhibits the ERK signaling pathway and represses the growth and metastasis of NCI‑H1299 cells. Further study demonstrated that either inhibiting miR‑126‑5p or overexpressing VEGF‑A and VEGFR‑2 in TBMS1‑treated NCI‑H1299 cells elevated the mRNA expression levels and phosphorylation levels of MEK1, as well as ERK. To conclude, TBMS1 increases miR‑126‑5p expression, whereas overexpressing miR‑126‑5p inactivates VEGF‑A/VEGFR‑2/ERK signaling pathway, which ultimately actuates the pro‑apoptotic and anti‑metastatic effects in NCI‑H1299 cells. Therefore, the present findings provide a theoretical foundation for TBMS1 as a potential candidate in NSCLC treatment. [ABSTRACT FROM AUTHOR]

Autotaxin (ATX) is a key enzyme that converts lysophosphatidylcholine to lysophosphatidic acid (LPA). ATX is a crucial factor that facilitates cancer progression; however, the effect of ATX on endometrial cancer has not been explored. The aim of the present study was to investigate the role of ATX in the progression of endometrial cancer. The immunohistochemical results revealed higher protein expression levels of ATX and LPA receptors (LPA 1, 2 and 3) in human endometrial cancer tissue than in non‑carcinoma tissue. In addition, reverse transcription‑quantitative polymerase chain reaction and western blotting analysis demonstrated that ATX and LPA receptor mRNA and protein expression was greater in Ishikawa cells, which are positive for estrogen receptor (ER), than in Hec‑1A cells that exhibit low ER expression. Short interfering RNA knockdown of ATX in Ishikawa cells led to decreased cell proliferation and cell colony number, as determined by Cell Counting kit‑8 and colony formation assays. Estrogen stimulated ATX mRNA expression. Inhibition of ATX decreased estrogen and LPA‑induced cell proliferation. High LPA levels markedly elevated the phosphorylation levels of extracellular signal‑regulated kinase (ERK). ATX downregulation moderately decreased estrogen‑ and LPA‑induced phosphorylation of ERK. In addition, the ERK inhibitor, PD98059, reduced cell proliferation with estrogen, ATX and LPA treatment. The present study suggested that the ATX‑LPA axis may facilitate estrogen‑induced cell proliferation in endometrial cancer via the mitogen‑activated protein kinase/ERK signaling pathway. The present study may provide ideas and an experimental basis for clinicians to identify new molecular targeted drugs for the treatment of endometrial cancer. [ABSTRACT FROM AUTHOR]

Depressive disorder is a mental health disorder caused by the dysfunction of nerve regeneration, neuroendocrine and neurobiochemistry, which frequently results in cognitive impairments and disorder. Evidence has shown that resveratrol offers benefits for the treatment of depressive disorder. In the present study, the therapeutic effects of resveratrol were investigated and the potential mechanisms mediated by resveratrol were analyzed in hippocampal neuron cells. The anti‑oxidative stress and anti‑inflammatory properties of resveratrol were also examined in vitro and in vivo. The results revealed that resveratrol administration inhibited the inflammation in hippocampal neuron cells induced by ouabain. Oxidative stress in the hippocampal neuron cells was ameliorated by resveratrol treatment in vitro and in vivo. In addition, the apoptosis of hippocampal neuron cells was inhibited by the upregulation of anti‑apoptotic genes, including P53, B‑cell lymphoma‑2 (Bcl‑2) and Bcl‑2‑associated death promoter, and the downregulation of the cleaved caspase‑3 and caspase‑9. The analysis of the mechanism revealed that that resveratrol treatment suppressed the apoptosis of hippocampal neuron cells through the NETRIN1‑mediated extracellular signal‑regulated kinase/cAMP signal transduction pathway. The results of the in vivo assay showed that resveratrol treatment led to improvements in cognitive competence, learning memory ability and anxiety in a mouse model of depressive disorder induced by ouabain. In conclusion, these results indicated that resveratrol treatment had protective effects against oxidative stress and neuroinflammatory pathogenesis through the NETRIN1‑mediated extracellular signal‑regulated kinase/cAMP signal transduction pathway, suggesting that resveratrol treatment may be a potential antidepressant agent for the treatment of depressive disorder. [ABSTRACT FROM AUTHOR]

Astilbin has anti‑inflammatory and immunoregulatory effects, and is frequently used in prescriptions treating psoriasis; however, the mechanism remains to be fully elucidated. In the present study, the effect of an astilbin microemulsion on a psoriasis‑like model in guinea pigs was examined, and the underlying mechanism was investigated. The levels of interkeukin (IL)‑6, IL‑17A and IL‑22 were determined using fluorescent reverse transcription‑quantitative polymerase chain reaction analysis and enzyme‑linked immunosorbent assays. The phosphorylation of p38 and extracellular signal‑regulated kinase (ERK)1/2 was detected using western blot analysis. Compared with the untreated control, astilbin significantly ameliorated the lesions induced by propranolol hydrochloride. The effect of astilbin on cytokine levels were cytokine‑ and drug‑concentration‑dependent. At a concentration of 2.22 μM, astilbin decreased the mRNA expression levels of IL‑6, IL‑17A and IL‑22 in lipopolysaccharide (LPS)‑induced HaCaT cells by 89, 69.1 and 69.3%, respectively. However, 2.22 μM astilbin had no effect on the protein expression of IL‑17A, and decreased the protein expression levels of IL‑6 and IL‑22 by 79.2 and 49.5%, respectively (P<0.05). At a concentration of 11.10 μM, astilbin decreased the mRNA expression of IL‑6, which was significantly induced by LPS, and significantly (P<0.05) decreased the protein expression levels of IL‑6 and IL‑22. Additionally, astilbin inhibited the LPS‑induced activation of phosphorylated p38. These results suggested that astilbin has the potential to be developed into a topical drug for the treatment of psoriasis via the inhibition of inflammatory cytokines. [ABSTRACT FROM AUTHOR]

The aim of the present study was to investigate the expression and function mechanism of bone morphogenetic protein 9 (BMP9) in cerebral ischemia-reperfusion (I/R) injuries in vivo and in vitro. A total of 40 Sprague-Dawley rats were randomly divided into four groups (n=10): i) Normal control; ii) sham surgery group, the procedure without occlusion; iii) I/R group, right middle cerebral artery occlusion (MCAO) followed by reperfusion; and iv) adenoviral vector (Ad)-BMP9 + I/R group, Ad-BMP9 intracerebroventricular injection was performed 2 days prior to MCAO. Neurological deficit score and infarct volume were measured at 24 h following reperfusion. To further test the mechanism of BMP9, astrocytes were isolated and treated with Ad-BMP9, Ad-BMP9 + extracellular signal-regulated kinase (ERK) inhibitor PD098059, Ad-BMP9 + c-Jun N-terminal kinase inhibitor SP600125 and Ad-BMP9 + p38 inhibitor SB203580 for 24 h, followed by undergoing oxygen-glucose deprivation and reoxygenation (OGD/R) treatment. Cell viability and death were assessed by 3-(4,5-dimethylthiazol-2yl)-5-(3-carboxymethoxyphenyl)- (4-sulfophenyl)-2H-tetrazolium and lactate dehydrogenase release, respectively. Gene expression was determined by quantitative polymerase chain reaction and western blotting. BMP9 was identified to be upregulated at mRNA and protein levels in cerebral I/R animal and cell models. BMP9 pretreatment significantly reduced the neurological score and infarct volume compared with I/R rats. In astrocytes, overexpression of BMP9 significantly decreased cell death and improved cell viability, an effect which may be mediated by the ERK signaling pathway, as ERK was activated by BMP9 and the use of PD098059 partially reversed the protective effect of BMP9. Pretreatment with BMP-9 may be a promising treatment option for prevention of cerebral I/R injuries. [ABSTRACT FROM AUTHOR]

Hepatic oval cells (HOCs) are thought to possess self-renewal ability and a bipotential capacity for differentiation, which allows them to differentiate into hepatocytes and cholangiocytes. Autophagy serves an important role in self-renewal and differentiation of stem cells; however, how autophagy contributes to proliferation and differentiation of hepatic progenitor cells has yet to be elucidated. In the present study, autophagy was regulated by rapamycin (Rapa) and chloroquine (Chlo) administration. The results demonstrated that Chlo-treated HOCs exhibited decreased autophagic activity alongside a decreased tendency to proliferate, as determined by Cell Counting Kit-8. In addition, activation of autophagy by Rapa enhanced the biliary differentiation of HOCs. Furthermore, increased phosphorylated (p)-extracellular signal-regulated kinase (ERK)/p-p38 expression was observed following the induction of autophagy, thus indicating that the mitogen-activated protein kinase (MAPK)/ERK signaling pathway was activated by autophagy to exert effects on the stimulation of HOC proliferation and differentiation. In conclusion, the present study demonstrated that autophagy regulates proliferation and biliary differentiation of HOCs via the MAPK/ERK signaling pathway. These results suggest a role for autophagy in stimulating the proliferation and differentiation of HOCs. [ABSTRACT FROM AUTHOR]

Sulforaphane (SFN) has been revealed to inhibit the growth and induce apoptosis of cancer cells. However, the detailed anticancer effects of SFN on p53‑deficient colon cancer cells has yet to be clearly elucidated. The present study employed p53‑deficient SW480 cells to establish an SFN‑induced in vitro model of apoptosis. The critical events leading to apoptosis were then evaluated in SFN‑treated p53‑deficient SW480 cells, by performing an MTT assay, flow cytometry, western blotting and ELISA. The results demonstrated that SFN at concentrations of 5, 10, 15 and 20 μM induced mitochondria‑associated cell apoptosis, which was further confirmed by disruption of the mitochondrial membrane potential, an increase in the Bax/Bcl‑2 ratio, as well as activation of caspase‑3, ‑7 and ‑9. In addition, SFN‑induced apoptosis was associated with an increase in the generation of reactive oxygen species (ROS), and the activation of extracellular signal‑regulated kinases (Erk) and p38 mitogen‑activated protein kinases. However, SFN did not induce expression of the p53 family member, p73. SFN‑induced apoptosis was subsequently confirmed to be ROS‑dependent and associated with Erk/p38, as the specific inhibitors for ROS, phosphorylated (p)‑Erk and p‑p38, completely or partially attenuated the SFN‑induced reduction in SW480 cell viability. In addition, the results demonstrated that even at the lowest concentrations (5 μM), SFN increased the sensitivity of p53‑proficient HCT‑116 cells to cisplatin. In conclusion, the results suggest that SFN may induce apoptosis in p53‑deficient SW480 cells via p53/p73‑independent and ROS‑Erk/p38‑dependent signaling pathways. [ABSTRACT FROM AUTHOR]

Infections by pathogens may lead to cardiovascular diseases, including acute/chronic myocarditis. (Coxsackieviruses B3) CVB3 is considered to be the most common causative agent in m‑yocarditis, which can lead to dilated cardiomyopathy. The present study aimed to investigate the mechanism of CVB3‑infected myocardial microvascular endothelial cells. The CVB3 infection was detected by 50% tissue culture infective dose (TCID50). The role of fractalkine (FKN) in the infection was detected using western blotting and RNA interference. To assess mitogen‑activated protein kinase signaling activity, levels of total and phosphorylated extracellular signal‑regulated kinase (ERK)1/2, c‑Jun N‑terminal kinase, and p38 were measured at 0, 20, 40, and 60 min after CVB3 infection by western blot analysis. The results showed that infection activated FKN via the ERK1/2 signaling pathway. Furthermore, the TCID50 of CVB3 in infected cells was lower compared with that in myocardial microvascular endothelial cells following ERK1/2 inhibition and FKN silencing. CVB3 infection of myocardial microvascular endothelial cells activates FKN via the ERK1/2 signaling pathway. These findings represent a foundation for the development of novel methods of treating CVB3‑induced myocarditis. [ABSTRACT FROM AUTHOR]

Heme oxygenase‑1 (HO‑1), as an inducible and cytoprotective enzyme, has a protective effect against cellular oxidative stress. In the present study, cholesterol was used to induce lipid overload and increase reactive oxygen species (ROS), leading to oxidative stress in EA.hy926 cells. In the present study, western blotting and immunofluorescence analysis were used to detect the expression level of important molecules in the metabolism process of cholesterol. It was confirmed that cholesterol stimulation upregulated the expression of HO‑1 in a time‑dependent manner via the activation and translocation of nuclear factor erythroid 2‑related factor 2 (Nrf2), activation of the mitogen‑activated protein kinase (MAPK)/extracellular signal‑regulated kinase (ERK) signaling pathway and increasing intercellular Ca2+ ([Ca2+]i) concentration. The results showed that increasing the expression of HO‑1 decreased activation of the phosphoinositide 3‑kinase (PI3K)/AKT signaling pathway and inhibited the expression of c‑Myc. It was confirmed that cholesterol‑mediated oxidative damage in vascular endothelial cells induced an increase in the expression of HO‑1 via the activation of Nrf2 and the MAPK/ERK signaling pathway, and increasing the [Ca2+]i concentration. The overexpression of HO‑1 alleviated oxidative damage through inhibition of the PI3K/AKT signaling pathway and downregulation of the expression of c‑Myc. [ABSTRACT FROM AUTHOR]

Nifedipine is widely used to treat high blood pressure and angina. Were nifedipine able to promote the proliferation and migration of breast cancer, it would pose a significant threat for patients. Thus, it is important to determine the effects of nifedipine on breast cancer and the mechanism involved. The present study identified that nifedipine significantly promoted the proliferation and migration of breast cancer cells in vitro. The mechanism of nifedipine on different breast cancer cells was investigated and it was identified that the effects of nifedipine on MCF-7 cells were via the protein kinase B-endothelial constitutive nitric oxide synthase-nitric oxide axis, and on MDA-MB-231 cells via activation of the extracellular signal-regulated kinase pathway. These results identified the distinct pathways in the activation of cell proliferation and migration presented in different cell lines by nifedipine. The present study advises that nifedipine can promote breast cancer and should be avoided for women who suffer from breast cancer and hypertension. [ABSTRACT FROM AUTHOR]

Previous studies have suggested that estradiol can reduce the ischemia/reperfusion (I/R) injury in skin flaps. However, the mechanism, particularly the signal pathways involved in this protective effect are not well established. In the current study, an I/R injury model was established in rats to explore the connection between estradiol protection during I/R injury and extracellular signal-regulated kinase (ERK) signaling. Healthy male Wistar rats were divided into five groups (n=10): Control group (group I), I/R group (group II), saline group (group III), estradiol group (group IV) and inhibitor (PD-98059) group (group V). The survival rate of the flap was compared between groups, morphological changes were observed by hematoxylin and eosin staining of sections, and terminal deoxynucleotidyl transferase dUTP nick end labeling was performed to identify apoptotic cells and determine the apoptotic index. To further investigate the mechanism, western blot analysis was performed to assess the protein level of ERK1/2, phospho-ERK1/2, and mitogen-activated protein kinase phosphatase 1 (MKP-1). The results of the present study demonstrated that estradiol therapy can reduce I/R injury and decrease the apoptosis index in an axial skin flap model. The inhibitor of the ERK pathway (PD-98059) partially abolished the effects of estradiol, which involve the phosphatase enzyme MKP-1. Taken together, the findings of the present study indicate that estradiol may act by reducing the expression of MKP-1, mediating the expression/activation changes of the ERK pathway and subsequently reduce the level of apoptosis and the I/R injury the axial flap. Estrogen may be used to mitigate the adverse reaction caused by ischemia-reperfusion injury and effectively improve the survival rate and survival quality of free skin flap and improve patient prognosis. [ABSTRACT FROM AUTHOR]

Saikosaponin D (SSd) is a type of Saponin derivative, which is a component extracted from Bupleurum falactum. SSd has been reported to exert anticancer activities. However, the effects of SSd on gliomas have not been elucidated. The aim of the present study was to investigate the pharmacological functions and potential molecular mechanisms of SSd in human U87 glioblastoma cells. The cells were treated with SSd at various concentrations for 48 h, the cell viability was assessed with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium assay, and the activation of Akt, extracellular signal-regulated kinases (ERK), c-Jun N-terminal kinases (JNK) and caspase-3 was assessed by western blotting. In addition, apoptosis levels were analyzed with Hoechst 33258 and Annexin V staining. The results demonstrated that treatment of the U87 glioma cells with SSd markedly suppressed cell proliferation in a dose-dependent manner. Meanwhile, SSd treatment enhanced apoptosis in the U87 cells. Furthermore, SSd significantly inhibited the phosphorylation of Akt and ERK, and promoted phosphorylated-JNK and cleaved caspase-3 expression. The present study revealed the potential therapeutic effects of SSd in the treatment of gliomas, and the cytotoxic effects of SSd in U87 cells were at least partly attributed to the depression of phosphatidylinositol 3-kinase/Akt and ERK protein expression levels, and activation of JNK and caspase-3 expression. [ABSTRACT FROM AUTHOR]

Insulin-like growth factor binding protein-related protein 1 (IGFBP-rP1) is a potential tumor-suppressor gene in various cancers. However, its biological role and underlying mechanism has not been well investigated in endometrial cancer yet. The aim of the present study aimed to investigate the role and underlying molecular mechanisms of IGFBP-rP1 in endometrial cancer cells in vitro. The authors used transfection of IGFBP-rP1 or small interfering (si)RNA in endometrial cancer HEC-1A or Ishikawa cells, respectively. Biological functional alterations, such as cell growth and cell cycle were analyzed in endometrial cancer cells, combined with the use of PD98059. A panel of proteins including phospho-retinoblastoma (p-RB) and p-extracellular signal-regulated kinase (ERK)/ERK were detected by western blot analysis. It was observed that IGFBP-rP1 transfection inhibited cell growth, and induced G1 phase arrest and cellular senescence in HEC-1A cells while gene silencing presented the adverse functional changes. Moreover, p-RB and p-ERK were significantly downregulated or upregulated in HEC-1A-IGFBP-rP1 cells or Ishikawa-siRNA (IGFBP-rP1) compared with control cells, respectively. These observations were reinforced in endometrial cancer cells by PD98059 treatment. The authors conclude that IGFBP-rP1 acts as a potential tumor suppressor via the suppression of the ERK signaling pathway in endometrial cancer cells. These findings suggested that IGFBP-rP1 may serve as a potential therapeutic target for cancer intervention in the future. [ABSTRACT FROM AUTHOR]

5-aza-2'-deoxycytidine (5-Aza) has been approved for clinical use in the treatment of myelodysplastic syndrome and acute myeloid leukemia (AML). It inhibits cell proliferation and induces cell differentiation by demethylating various genes, including tumor suppressor genes, transcription factors, and genes encoding cell cycle inhibitors. Although it has demonstrated efficacy in the clinic, drug resistance following 5-Aza treatment occurs. Cell migration and invasion following 5-Aza treatment are considered to be the key factors underlying drug resistance; however, there is currently limited information regarding the detailed mechanisms involved. In the present study, the THP-1 monocytic leukemia cell line was employed. The anti-leukemic functions of 5-Aza in THP-1 cells were first investigated. The results demonstrated that 5-Aza induced differentiation and inhibited THP-1 cell growth. Notably, 5-Aza significantly promoted THP-1 cell migration. Using reverse transcription-polymerase chain reaction, Western blot and enzyme-linked immunosorbent assay analyses, 5-Aza treatment was observed to upregulate the expression of chemokine (C-C motif) ligand 2 (CCL2) and C-C chemokine receptor type 2 (CCR2) in THP-1 cells. In addition, the results demonstrated that CCL2 induced extracellular signal-regulated kinase (ERK) phosphorylation by CCR2 in 5-Aza-treated THP-1 cells. Treatment with a CCR2 or ERK inhibitor inhibited the 5-Aza-induced increase in THP-1 cell migration. In conclusion, the results of the present study provide an insight into the molecular mechanism underlying the 5-Aza-induced increase in THP-1 cell migration, as well as a potential strategy to overcome drug resistance in AML therapy. [ABSTRACT FROM AUTHOR]

Apelin is hypothesized to serve a dual function in pain processing. Spinal administration of apelin induces hyperalgesia, while opioid receptors are implicated in the antinociceptive effects of apelin in acute nociceptive models. However, whether the apelin-apelin receptor (APJ) system is involved in neuropathic pain remains to be elucidated. The present study aimed to evaluate the impact and mechanism of the spinal apelin-APJ system in neuropathic pain. Chronic constriction injury (CCI) of the sciatic nerve produced sustained spinal apelin and APJ upregulation, which was associated with mechanical allodynia and heat hyperalgesia development in the hind-paw plantar surface. Immunofluorescence demonstrated that apelin and APJ were localized to the superficial dorsal horns. In order to further clarify the function of the apelin-APJ system, a single intrathecal administration of ML221, an APJ antagonist, was used; this transiently reduced CCI-induced pain hypersensitivity. However, apelin-13 (the isoform which binds most strongly to APJ) exhibited no effect on the nociceptive response, suggesting an essential role for the spinal apelin-APJ system in neuropathic pain sensitization. The present study demonstrated that a single application of ML221 alleviated mechanical allodynia and heat hyperalgesia 7 days following CCI, in a dose-dependent manner. Intraspinal delivery of ML221, at the onset of and in fully-established neuropathic pain, persistently attenuated CCI-induced pain hypersensitivity, indicating that the apelin-APJ system was involved in initiating and maintaining pain. It was demonstrated, using immunoblotting, that intrathecal ML221 downregulated phosphorylated extracellular signal-related kinase (ERK) in the rat spinal cord dorsal horn, suggesting that the effect of apelin on neuropathic pain may be mediated via ERK signaling. The results of the present study suggested that the spinal apelin-APJ system may drive neuropathic pain. Inhibition of APJ may provide novel pharmacological interventions for neuropathic pain. [ABSTRACT FROM AUTHOR]

Stichopus japonicus has been used as a folk medicine and as an ingredient in traditional food in East Asian countries. In recent years, the bioactive compounds found in S. japonicus have been reported to possess efficacy in wound healing and may be of potential use in the cosmeceutical, pharmaceutical and biomedical industries. Although the components and their functions require further investigation, S. japonicus extracts exhibit anti-inflammatory properties, and may be used for cancer prevention and treatment. Although several reports have examined different aspects of S. japonicus, the effects of S. japonicus extract on melanogenesis in the skin has not been reported to date. Therefore the present study aimed to investigate the effects of S. japonicus extract on melanogenesis. Treatment with a mixture of S. japonicus extracts (MSCE) reduced melanin synthesis and tyrosinase (TYR) activity in mouse melanocyte cells lines, B16F10 and Melan-A. In addition, MSCE treatment reduced the protein expression levels of TYR, tyrosinase-related protein-1 and tyrosinase-related protein-2. The reduced protein levels may be the result of decreased microphthalmia-associated transcription factor (MITF) expression, which is an important regulator of melanogenesis. The reduced expression level of MITF was associated with delayed phosphorylation of extracellular signal-regulated kinase (ERK) induced by MSCE treatment. A specific MEK inhibitor, PD98059, significantly blocked MSCE-mediated inhibition of melanin synthesis. In conclusion, these results indicate that MSCE may be useful as a potential skin-whitening compound in the skin medical industry. [ABSTRACT FROM AUTHOR]

Tobacco smoke (TS) is an important risk factor of bladder cancer. Epithelial‑mesenchymal transition (EMT) is involved in the initiation and development of cancer. The role of extracellular signal‑regulated kinase (ERK) 5 in regulating TS‑induced EMT remains to be elucidated. The aim of the present study was to investigate the regulatory role of ERK5 in TS‑triggered EMT in the bladder of mice. BALB/c mice were used for an in vivo TS exposure model. Mice were treated for 6 h a day for 12 weeks. The results demonstrated that mice exposed to TS had decreased mRNA and protein expression levels of the epithelial markers E‑cadherin and zonula occludens‑1, whereas expression levels of the mesenchymal markers Vimentin and N‑cadherin were increased. Treatment with XMD8‑92, a highly specific ERK5 inhibitor, effectively abrogated TS‑triggered activation of ERK5, activator protein‑1 and EMT alterations in the bladder of BALB/c mice. The data suggested that ERK5 regulates TS‑mediated urocystic EMT. These findings provide insight into the molecular mechanisms of TS‑associated bladder tumorigenesis. [ABSTRACT FROM AUTHOR]

Long non‑coding RNA (lncRNA), transcripts of >200 bp in length that do not appear to exhibit any coding capacity, are important in the occurrence and development of cancer, cardiovascular and neurological diseases. However, effects of lncRNAs on photo‑aging remain to be elucidated. To explore the potential effects of the lncRNA metastasis‑associated lung adenocarcinoma transcript 1 (MALAT1) on photo‑aging in fibroblasts, MALAT1 expression was silenced in fibroblasts using small interference RNA. Reverse transcription‑quantitative polymerase chain reaction (RT-qPCR) was used to examine MALAT1 expression in normal and silenced fibroblasts following irradiation with 60 mJ/cm² ultraviolet B (UVB) and an ELISA assay was used to identify matrix metalloproteinase-1 (MMP-1) content in the cellular supernatant. A β‑galactosidase kit was applied to measure the number of senescent cells and a western blot assay was used to detect extracellular signal‑regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 phosphorylation levels. RT-qPCR was additionally used to detect changes in MALAT1 expression following suppression of UVB-induced reactive oxygen species (ROS) generation with N-acetyl-L-cysteine (NAC). Fibroblasts irradiated with 60 mJ/cm² UVB demonstrated increased MALAT1 expression, MMP-1 secretory volume and number of senescent cells, and greater levels of ERK, p38 and JNK phosphorylation. Following silencing of MALAT1 expression in photo‑aged fibroblasts, decreases were observed in MMP-1 secretory volume, number of senescent cells and phosphorylation levels of ERK. NAC reduced ROS content, however, it did not affect MALAT1 expression. Therefore, it was concluded that MALAT1 may participate in UVB‑induced photo‑aging via regulation of the ERK/mitogen‑activated protein kinase signaling pathway and UVB‑induced MALAT1 expression is independent of ROS generation. [ABSTRACT FROM AUTHOR]

Acute myocarditis is a non-ischemic inflammatory disease of the myocardium, and there is currently no standard treatment. Mesenchymal stem cells (MSCs) can alleviate myosin‑induced myocarditis; however, the mechanism has not been clearly elucidated. In the present study, the authors investigated the ability of human umbilical cordMSCs (HuMSCs) to attenuate myocardial injury and dysfunction during the acute phase of experimental myocarditis. Male Lewis rats (aged 8 weeks) were injected with porcine myosin to induce myocarditis. Cultured HuMSCs (1x106 cells/rat) were intravenously injected 10 days following myosin injection. A total of 3 weeks following injection, this resulted in severe inflammation and significant deterioration of cardiac function. HuMSC transplantation attenuated infiltration of inflammatory cells and adverse cardiac remodeling, as well as reduced cardiomyocyte apoptosis. Furthermore, it was identified that HuMSC transplantation suppressed endoplasmic reticulum stress and extracellular signal‑regulated kinase (ERK)1/2 signaling in experimental autoimmune myocarditis (EAM). The reduced number of TUNEL‑positive apoptotic cells in myocardial sections from HuMSC‑treated EAM rats compared with control demonstrates HuMSCs' anti‑apoptotic function. Based on these data, the author suggested that treatment with HuMSCs inhibits myocardial apoptosis in EAM rats, ultimately protecting them from myocardial damage. The conclusion demonstrated that HuMSC transplantation attenuates myocardial injury and dysfunction in a rat model of acute myocarditis, potentially via regulation of ER stress, ERK1/2 signaling and induction of cardiomyocyte apoptosis. [ABSTRACT FROM AUTHOR]

B23, a multifunctional nucleolar protein, is overexpressed in numerous cancers and is associated with tumorigenesis. However, the clinical significance and potential role of B23 in bladder urothelial carcinoma remains to be elucidated. The present study observed that the mRNA and protein expression levels of B23 were increased in bladder cancer cells and tissues. The overexpression of B23 contributed to tumorigenesis and was associated with poor prognosis in bladder cancer patients. Silencing of B23 by short hairpin RNA inhibited tumor cell growth and colony formation. In addition, knockdown of B23 suppressed the phosphorylation of extracellular signal-regulated kinase (ERK), resulting in the inactivation of the ERK signaling pathway. Therefore, the present study indicated that B23 promotes bladder cancer cell growth via activation of the ERK signaling pathway and is a novel potential biomarker for the diagnosis and prognosis of bladder cancer. [ABSTRACT FROM AUTHOR]

Temozolomide (TMZ) is an alkylating agent used for the treatment of aggressive forms of brain tumor based on its antitumor actions. However, the exact effect on cancer and the underlying anticancer molecular mechanism of TMZ remain to be elucidated. In the present study, the effects of TMZ on the growth and motility of glioma C6 cells were investigated. MTT and Transwell assays were used to detect cellular growth and motility. The results showed that TMZ inhibited the proliferation, migration and invasion of the glioma C6 cells in vitro, western blot analysis determined that the phosphorylation of extracellular signal-regulated protein kinase (ERK)1/2 was decreased in the TMZ-treated cells, compared with the untreated control cells. The ERK1/2 specific inhibitor, U0126, augmented the inhibitory effects of TMZ on the proliferation, migration and invasion of the glioma C6 cells, and the mitogen-activated protein kinase kinase/ERK pathway activator, curcumin, attenuated the inhibitory effects of TMZ on the proliferation and motility of the glioma C6 cells. Additionally, the western blotting in the present study demonstrated that TMZ and U0126 decreased the expression of vascular endothelial growth factor-C (VEGF-C), and the expression level was restored by curcumin, suggesting that VEGF-C may be the downstream effector of ERK1/2. Furthermore, the overexpression of VEGF-C enhanced the growth, migration and invasion of the TMZ-treated cells. These results suggested that TMZ suppressed glioma C6 cell development, at least in part, and downregulated the expression of VEGF-C by inhibiting the ERK signaling pathway. The results of the present study provides the foundation for a combinational therapeutic strategy to improve the efficacy of TMZ. [ABSTRACT FROM AUTHOR]

Mammalian stanniocalcin 2 (STC2) is a glycoprotein hormone with multiple functions. The present study determined the importance of STC2 in osteoblast differentiation. It was revealed that the expression of STC2 was increased during the differentiation of MC3T3-E1 cells to osteoblasts and that knockdown of STC2 reduced osteoblast differentiation and mineralization, whereas STC2 overexpression increased differentiation and mineralization. Knockdown of STC2 downregulated the expression of osteoblast-associated genes, including runt-related transcription factor 2, collagen type I α 1 chain, osterix and osteocalcin. Overexpression of STC2 upregulated the expression of these osteoblastic genes. In addition, overexpression of STC2 enhanced the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), whereas inhibition of ERK phosphorylation reduced osteoblast differentiation of MC3T3-E1 cells overexpressing STC2. These findings indicated that STC2 may promote osteoblast differentiation and mineralization by regulating ERK activation. [ABSTRACT FROM AUTHOR]

The present study aimed to determine the protective and anti-angiopathy effects of ginsenoside (GSS) on Wistar rats with diabetes mellitus (DM). Diabetic angiopathy occurs during the early stage of diabetes, and in type 1 DM (T1DM) and type 2 DM (T2DM). In the present study, early DM, T1DM and T2DM were induced by treatment with a high-sucrose-high-fat diet, alloxan monohydrate or streptozocin, respectively. The levels of blood glucose, insulin, lipid metabolism markers [total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL) and lipoprotein(a) (Lp-a)], and endothelial cell function markers [endothelin, nitric oxide, vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6)] were determined following treatment with GSS. In addition, oral glucose tolerance test and insulin tolerance test were performed. The phosphorylation levels of p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK) were detected in aorta samples harvested from T2DM rats by western blot analysis. The present study determined that GSS treatment effectively decreased the levels of blood glucose, TC, TG, Lp-a, VEGF, IL-6, phosphorylated (p)-p38, p-ERK1/2 and p-JNK; however, treatment with GSS increased insulin and HDL levels. Therefore, it is possible that GSS exerts protective and anti-angiopathy effects against the early stage of diabetes, T1DM and T2DM in vivo via the activation of p38 MAPK, ERK1/2 and JNK signaling. [ABSTRACT FROM AUTHOR]

S100 calcium -binding protein B (S100B) is expressed and released by adipocytes, and is positively correlated with body mass index, however, the direct effects of S100B on adipocytes remain unclear. Bone marrow-derived mesenchymal stem cells have the capacity to differentiate into osteoblasts and adipocytes, which is important for bone metabolism. The current study aimed to determine the effect of S100B on adipogenesis and osteogenesis. The mouse embryo cell line C3H/10T1/2 was used to build cell models with varying levels of S100B protein expression. Western blot analysis was performed to assess the expression of various marker proteins. Oil red O staining and alizarin red S staining were used to detect adipogenesis and osteogenesis, respectively. S100B overexpression was associated with a significant increase in oil red O staining and a significant reduction in alizarin red S staining. Runt-related transcription factor-2 and bone morphogenetic protein 2 expression levels were significantly increased in the S100B underexpression group, however not in the S100B overexpression group. By contrast, the expression levels of the adipogenesis markers peroxisome proliferator-activated receptor γ and CCAAT-enhancer-binding protein α was significantly increased in the S100B overexpression group, however not in the S100B underexpression group. Osteogenesis stimulation increased extracellular signal-regulated kinase (ERK) phosphorylation, and adipogenesis stimulation increased c-Jun N-terminal kinase (JNK) phosphorylation. The results suggest that S100B inhibits osteogenesis, however stimulates adipogenesis. The ERK pathway is involved in the regulation of osteogenesis, whereas the JNK pathway is involved in the regulation of adipogenesis. [ABSTRACT FROM AUTHOR]

Neuregulin 1 (Nrg1) is involved in multiple biological processes in the nervous system. The present study investigated changes in Nrg1 signaling in the major brain regions of mice subjected to lipopolysaccharide (LPS)-induced neuroinflammation. At 24 h post-intraperitoneal injection of LPS, mouse brain tissues, including tissues from the cortex, striatum, hippocampus and hypothalamus, were collected. Reverse transcription-polymerase chain reaction was used to determine the expression of Nrg1 and its receptors, Neu and ErbB4, at the mRNA level. Western blotting was performed to determine the levels of these proteins and the protein levels of phosphorylated extracellular signal-regulated kinases (Erk)1/2 and Akt1. Immunohistochemical staining was utilized to detect the levels of pNeu and pErbB4 in these regions. LPS successfully induced sites of neuroinflammation in these regions, in which changes in Nrg1, Neu and ErbB4 at the mRNA and protein levels were identified compared with controls. LPS induced a reduction in pNeu and pErbB4 in the striatum and hypothalamus, although marginally increased pErbB4 levels were found in the hippocampus. LPS increased the overall phosphorylation of Src but this effect was reduced in the hypothalamus. Moreover, increased phosphorylation of Akt1 was found in the striatum and hippocampus. These data suggest diverse roles for Nrg1 signaling in these regions during the process of neuroinflammation. [ABSTRACT FROM AUTHOR]

The migration of circulating mesenchymal stem cells (MSCs) to injured tissue is an important step in tissue regeneration and requires adhesion to the microvascular endothelium. The current study investigated the underlying mechanism of MSC adhesion to endothelial cells during inflammation. In in vitro MSC culture, tumor necrosis factor-α (TNF-α) increased the level of vascular cell adhesion molecule-1 (VCAM-1) expression in a dose-dependent manner. The nuclear factor-κB (NF-κB), extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) signaling pathway inhibitors, pyrrolidine dithiocarbamate (PDTC), U0126 and SP600125, respectively, suppressed VCAM-1 expression induced by TNF-α at the mRNA and protein levels (P<0.05). TNF-α augmented the activation of NF-κB, ERK and JNK, and promoted MSC adhesion to human umbilical vein endothelial cells; however, the inhibitors of NF-κB, ERK and JNK did not affect this process in these cells. The results of the current study indicate that adhesion of circulating MSCs to the endothelium is regulated by TNF-α-induced VCAM-1 expression, which is potentially mediated by the NF-κB, ERK and JNK signaling pathways. [ABSTRACT FROM AUTHOR]

β-arrestins, including β-arrestin1 and β-arrestin2, two ubiquitously expressed members of the arrestin family in various types of tissue, are adaptor proteins that modulate the desensitization and trafficking of seven membrane-spanning receptors. Recently, β-arrestins have been shown to bind to numerous signaling molecules, including c-Src and mitogen-activated protein kinase family members. In addition, accumulating evidence has suggested that β-arrestins are involved in the anti-apoptosis signaling pathway by associating with kinases, such as Akt and ERK, and altering their activities. However, the role of β-arrestins in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis remains unclear. In the present study, β-arrestin2, but not β-arrestin1, was observed to modulate TRAIL-triggered HepG2 cell apoptosis by regulating activation of the Src-extracellular signal-regulated kinase (ERK) signaling pathway. Using overexpression and RNA interference experiments, β-arrestin2 was demonstrated to prevent TRAIL-induced HepG2 cell apoptosis. Additionally, β-arrestin2 exerted an additive effect on TRAIL-induced activation of Src and ERK. Furthermore, downregulating β-arrestin2 expression attenuated the TRAIL-induced activation of Src and ERK survival signaling and enhanced TRAIL-induced apoptosis. PP2, a pharmacological inhibitor of Src, reduced activation of the Src-ERK signaling pathway and enhanced TRAIL-induced HepG2 cell apoptosis. Co-immunoprecipitation experiments demonstrated a physical association between β-arrestin2 and Src, and TRAIL stimulation resulted in enhanced quantities of the β-arrestin2/Src complex. A notable interaction was identified between β-arrestin2 and death receptors (DR)4 and 5, but only in the presence of TRAIL stimulation. To the best of our knowledge, these findings are the first to demonstrate that β-arrestin2 mediates TRAIL-induced apoptosis by combing with DRs and Src, and regulates the activation of Src-ERK signaling in HepG2 cells. It is hypothesized that the formation of a signaling complex comprising DR, β-arrestin2 and Src is required for the action of TRAIL on HepG2 cell apoptosis, which provides a novel insight into analyzing the effects of β-arrestin2 on protecting cells from TRAIL-induced apoptosis. [ABSTRACT FROM AUTHOR]