Lysophospholipids in retinal axon guidance: roles and cell signaling

Nerve regeneration in the central nervous system（CNS）has become a holy grail of biomedical research.To understand nerve growth that would be required for efficient regeneration,many scientists have turned to developing systems where nerve growth is abundant and normal neural connections are established.One aspect of this neural development,which would also be important in nerve regeneration,

Regulation of microRNAs in cell signaling pathways-mediated vascular remodeling

Vascular remodeling,which can be found in atherosclerosis,restenosis after angioplasty,hypertension,and some other frequent and serious chronic diseases.Smooth muscle cell(SMC)phenotype change,which has been described as converting from a contractile state into a synthetic phenotype,is a crucial event during vascular remodeling.Recently,micro RNAs(mi RNAs)a kind of small non-coding RNA molecules,has been proven to target critical genes of cell signaling pathways to regulate SMC phenotypic change.By searching the Pub Med,Embase,reviews,and reference listsof relevant papers,we systematically carried out a review of the literature to provide an overview of the mi RNAs and their target genes in cell signaling pathways,focus inthe pathways involving in SMC phenotype change.To be specific,mi RNAs that regulate genes involved in the MAPK signaling pathways(such as:mi R-155,mi R-92a,mi R-424/503,mi R-133,mi R-181b,mi R-31,mi R-1298,mi R-132,mi R-200c and mi R-483-3p),mi RNAs target genes involved in the TGF-βsignaling pathways(including mi R-24,mi R-17/92 cluster,mi R-599,mi R-21 and mi R-143/145),mi RNAs target the genes involved in the AMPK signaling pathways including mi R-144/451 and mi R-195,mi RNAs target the genes involved in the PI3K-Akt signaling pathways(including mi R-138,mi R-34c,mi R-223,mi R-761,mi R-10a,mi R-146a),mi R-199a-5ptargets the genes involved in the Wnt signaling pathways mi RNAs(mi R-221/222,mi R-15b,mi R-24/29a,mi R-224)involved in the PDGF signaling pathways and some mi RNAs(mi R-638,mi R-328,mi R-365,mi R-663,mi R-29b,mi R-130,mi R-142-5p,mi R-424/322)which regulate SMC phenotype change by other corresponding targets were in detailed discussed in our review.Exploring the regulation of miR NAs in key cellsignaling pathways-mediatedvascular remodeling wil have momentous impact on identifying novel therapeutic targets for its associated disease.

Research Progress of miRNA Regulating Cell Signaling Pathways Related to Hepatocarcinogenesis

Hepatocellular carcinoma(HCC)is one of the most common malignant tumors in clinical practice.The pathogenesis of HCC is still unclear.Currently,the clinical treatment of HCC is poorly targeted and the therapeutic effect is poor.MicroRNAs(miRNAs)are closely related to the occurrence of HCC,and they are mainly involved in the occurrence and development of HCC through binding to target genes or acting on related signaling pathways.In recent years,studies have shown that miRNA can be used as a potential biomarker for diagnosis and prognosis of HCC.In addition,studies have also shown that miRNA plays a tumorsuppressing or tumor-promoting role in the process of HCC by regulating the biological processes of tumor cell proliferation,migration,invasion and metastasis.In this paper,the recent studies on miRNA signaling pathways related to the occurrence and development of HCC were reviewed,with a view to providing ideas for the clinical diagnosis and treatment of HCC.

Early monitoring values of oncogenic signalling molecules for hepatocellular carcinoma

The prevention and early diagnosis of liver cancer remains a global medical challenge.During the malignant transformation of hepatocytes,a variety of oncogenic cellular signalling molecules,such as novel high mobility group-Box 3,angiopoietin-2,Golgi protein 73,glypican-3,Wnt3a(a signalling molecule in the Wnt/β-catenin pathway),and secretory clusterin,can be expressed and secreted into the blood.These signalling molecules are derived from different signalling pathways and may not only participate in the malignant transformation of hepatocytes but also become early diagnostic indicators of hepatocarcinogenesis or specific targeted molecules for hepatocellular carcinoma therapy.This article reviews recent progress in the study of several signalling molecules as sensitive biomarkers for monitoring hepatocarcinogenesis.

Osteogenesis stimulation by copper-containing 316L stainless steel via activation of akt cell signaling pathway and Runx2 upregulation

As a metallic orthopedic implant,316L stainless steel(316L SS)is used extensively for its good resistance to corrosion and mechanical properties.However,it takes a long time to achieve osseointegration between 316L SS and adjacent tissues due to its bio-inert characteristic.Hence,the aim is to improve the bio-adaption of 316L SS.A good approach is to add elements to materials to improve their osteogenic capabilities by the appropriate release of ions.Hence copper-containing 316L stainless steel(316L-Cu SS)was investigated in this work,where Cu is an essential trace element that can stimulates osteogenesis.It was found that 316L-Cu SS was bio-safe and did not affect the proliferation of co-cultured osteoblasts in comparison with 316L SS.It increased cell apoptosis on day 1 but inhibited it on day 3,which cooperates with new bone formation processes.Osteoblasts extend themselves more quickly and in a better manner on the surface of 316L-Cu SS,wheneven more pseudopodia are present.Furthermore,the gene expression of alkaline phosphatase,collagen I and runt-related transcription factor 2(Runx2)in osteoblasts cultured with 316L-Cu SS was significantly enhanced.Runx2 protein expression increased,and osteogenesis was stimulated by 316L-Cu SS via an Akt cell signaling pathway.In conclusion,316L-Cu SS stimulates osteogenesis through activation of the Akt cell signaling pathway and the upregulation of Runx2.Thus,316L-Cu SS is a promising material that may be used in surgical implants to stimulate osteogenesis.

Cell signaling leads the way

Cells in plants, like in animals, constantly communicate with one another to coordinate their cellular activities in response to surrounding environmental conditions. Higher plants are multicellular organisms. A plant is originated from a single fertilized egg, which eventually develops into an intact individual with all necessary tissues and organs. Cell-to-cell communication is therefore especially critical throughout its life span, from embryo development, to tissue and organ formation, and finally to flowering and senescence, in addition.

B cell receptor signaling pathway involved in benign lymphoepithelial lesions of the lacrimal gland

AIM：To detect the expression of B cell receptor signaling pathway（BCRSP） in lacrimal gland benign lymphoepithelial lesions（LGBLEL）.METHODS：Gene microarray was used to compare whole-genome expression in lacrimal gland tissues from LGBLEL patients to tissues from orbital cavernous hemangioma（control tissues）. Expression of BCRSP was confirmed by polymerase chain reaction（PCR） and immunohistochemistry. RESULTS：The expression of 22 genes of the BCRSP increased significantly in LGBLEL patients. PCR analysis showed that CD22, CR2, and BTK were all highly expressed in LGBLEL tissues. Immunohistochemical analysis showed that CR2 protein was present in LGBLEL, but CD22 and BTK proteins were negative. CR2, CD22, and BTK were not observed in the orbital cavernous hemangiomas with either PCR or immunohistochemistry. CONCLUSION：BCRSP might be involved in the pathogenesis of LGBLEL.

Mitogen activated protein kinase signaling pathways participate in the active principle region of Buyang Huanwu decoction-induced differentiation of bone marrow mesenchymal stem cells

Our preliminary studies confirmed that an active principle region of Buyang Huanwu decoction, comprising alkaloid, polysaccharide, aglycon, glucoside and volatile oil, can induce bone marrow mesenchymal stem cell differentiation into neurons. Mitogen-activated protein kinase signaling was identified as one of the key pathways underlying this differentiation process. The present study shows phosphorylated extracellular signal-regulated protein kinase and phosphorylated p38 protein expression was increased after differentiation. Cellular signaling pathway blocking agents, PD98059 and SB203580, inhibited extracellular signal-regulated protein kinase and p38 in mitogen-activated protein kinase signaling pathways respectively, mRNA and protein expression of the neuronal marker, neuron specific enolase, and neural stem cell marker, nestin, were decreased in bone marrow mesenchymal stem cells after treatment with the active principle region of Buyang Huanwu decoction. Experimental findings indicate that, extracellular signal-regulated protein kinase and p38 in mitogen-activated protein kinase signaling pathways participate in bone marrow mesenchymal stem cell differentiation into neuron-like cells, induced by the active principle region of Buyang Huanwu decoction.

RANKL signaling in bone marrow mesenchymal stem cells negatively regulates osteoblastic bone formation

RANKL signaling is essential for osteoclastogenesis. Its role in osteoblastic differentiation and bone formation is unknown. Here we demonstrate that RANK is expressed at an early stage of bone marrow mesenchymal stem cells(BMSCs) during osteogenic differentiation in both mice and human and decreased rapidly. RANKL signaling inhibits osteogenesis by promoting β-catenin degradation and inhibiting its synthesis. In contrast, RANKL signaling has no significant effects on adipogenesis of BMSCs.Interestingly, conditional knockout of rank in BMSCs with Prx1-Cre mice leads to a higher bone mass and increased trabecular bone formation independent of osteoclasts. In addition, rank: Prx1-Cre mice show resistance to ovariectomy-(OVX) induced bone loss. Thus, our results reveal that RANKL signaling regulates both osteoclasts and osteoblasts by inhibition of osteogenic differentiation of BMSCs and promotion of osteoclastogenesis.

Angiogenesis in a 3D model containing adipose tissue stem cells and endothelial cells is mediated by canonical Wnt signaling

Adipose-derived stromal cells （ASCs） have gained great attention in regenerative medicine. Progress in our understanding of adult neovascularization further suggests the potential of ASCs in promoting vascular regeneration, although the specific cues that stimulate their angiogenic behavior remain controversial In this study, we established a three-dimensional （3D） angiogenesis model by co-culturing ASCs and endothelial cells （ECs） in collagen gel and found that ASC-EC-instructed angiogenesis was regulated by the canonical Wnt pathway. Furthermore, the angiogenesis that occurred in implants collected after injections of our collagen gel- based 3D angiogenesis model into nude mice was confirmed to be functional and also regulated by the canonical Wnt pathway. Wnt regulation of angiogenesis involving changes in vessel length, vessel density, vessel sprout, and connection numbers occurred in our system. Wnt signaling was then shown to regulate ASC- mediated paracrine signaling during angiogenesis through the nuclear translocation of β-catenin after its cytoplasmic accumulation in both ASCs and ECs. This translocation enhanced the expression of nuclear cofactor Lef-1 and cyclin D1 and activated the angiogenic transcription of vascular endothelial growth factor A （VEGFA）, basic fibroblast growth factor （bFGF）, and insulin-like growth factor 1 （IGF-1）. The angiogenesis process in the 3D collagen model appeared to follow canonical Wnt signaling, and this model can help us understand the importance of the canonical Wnt pathway in the use of ASCs in vascular regeneration.

Role of JAK-STAT3 signaling pathway during neuronal differentiation of rat bone marrow mesenchymal stem cells

Recent studies regarding neuronal differentiation of mesenchymal stem cells （MSCs） have primarily focused on induction methods and transplantation in vivo. However, knowledge about the intrinsic regulatory mechanisms underlying neuronal induction of MSCs remains limited and unclear. OBJECTIVE： To elucidate the role of JAK-STAT3 signaling pathway during neuronal differentiation of MSCs using a combination of the JAK-STAT3 signaling inhibitor AG490 and growth factors. DESIGN, TIME AND SETTING： Neural, molecular, biomedical, in vitro experiment was performed at the Laboratory of Pharmacology, School of Pharmacy, Nanjing Medical University between March and December 2008 MATERIALS： An inhibitor of the JAK-STAT3 signaling pathway was purchased from Calbiochem, USA. Antibody kit for total and phosphorylated STAT3 was purchased from Cell Signaling, USA. METHODS： MSCs from passage 3 were assigned to non-induced, growth factor, and AG490 groups. MAIN OUTCOME MEASURE： The number of cells expressing neuron-specific enolase, microtubule-associated protein, and glial fibrillary acidic protein were determined by immunocytochemistry. Total and phosphorylated （Tyr705） expression levels of STAT3 protein were measured by Western blot analysis. RESULTS： MSCs were transdifferentiated into neuronal- and astrocyte-like phenotypes through the induction of epidermal growth factor, basic fibroblast growth factor, and brain-derived neurotrophic factor. In addition, the JAK-STAT3 signaling pathway was significantly activated during neural differentiation. Expression of phosphorylated （Tyr705） STAT3 was inhibited with AG490 （5 pmol/L） prior to neural induction with epidermal growth factor, basic fibroblast growth factor, and brain-derived neurotrophic factor; proportion of astrocyte-like cells was significantly reduced （P 〈 0.01）, and the proportion of neuronal-like phenotypes was significantly increased （P〈 0.01）. CONCLUSION： JAK-STAT3 signaling pathway was shown to regulate neuronal induction of bone marrow MSCs. The proportion of MSC-induced neuronal-like cells was increased following treatment with the JAK-STAT3 signaling inhibitor AG490.

Effect of the Notch signaling pathway on retinal ganglion cells and its neuroprotection in rats with acute ocular hypertension

AIM： To explore the effect of the Notch signaling pathway on retinal ganglion cells（RGCs） and optic nerve in rats with acute ocular hypertension（OH）.METHODS： Totally 48 Sprague-Dawley（SD） rats were included, among which 36 rats were selected to establish acute OH models. OH rats received a single intravitreal injection of 2 μL phosphate buffered solution（PBS） and another group of OH rats received a single intravitreal injection of 10 μmol/L γ-secretase inhibitor（DAPT）. Quantitative real-time polymerase chain reaction（qPCR） and Western blot assay were adopted to determine the mRNA level of Notch and the protein levels of Notch, Bcl-2, Bax, caspase-3, and growth-associated protein 43（GAP-43）. The RGC apoptosis conditions were assessed by TUNEL staining.RESULTS： The OH rats and PBS-injected rats had increased expression levels of Notch1, Bax, caspase-3, and GAP-43, decreased expression levels of Bcl-2, and increased RGC apoptosis, with severer macular edema and RGCs more loosely aligned, when compared with the normal rats. The DAPT-treated rats displayed increased expression levels of Notch1, Bax, caspase-3, and GAP-43, decreased expression levels of Bcl-2, and increased RGC apoptosis, in comparison with the OH rats and PBSinjected rats. RGCs were hardly observed and macular edema became severe in the DAPT-treated rat.CONCLUSION： The Notch signaling pathway may suppress the apoptosis of retinal ganglion cells and enhances the regeneration of the damaged optic nerves in rats with acute OH.

Gas6-Tyro3 signaling is required for Schwann cell myelination and possible remyelination

Myelin plays important roles in vertebrates,ensuring the rapid propagation of action potentials and the long-term integrity of axons,but the molecular mechanisms of myelin formation remain poorly understood.Recent studies have demonstrated that myelination is regulated by the TYRO3,AXL（also known as UFO）and MERTK.

Inhibition of epidermal growth factor receptor signaling protects human malignant glioma cells from hypoxia - induced cell death

Epidermal growth factor receptor(EGFR)signaling has become an importanttarget for drug development becauseEGFR signaling enhances tumor cell proliferation,migration,and invasion and inhibits apoptosis.However,theresults of clinical trials using EGFR inhibitors in patients with solid tumors have been disappointing.Here,wereport a protective effect of the EGFR inhibitors AG1478 and PD153035 against cell death induced by acute hy-poxia,which contrasts with their proapoptotic effects under normoxia.Under hypoxic conditions,both agents re-

Cellular signaling pathways of T cells in giant cell arteritis

Giant cell arteritis(GCA)is a commonly occurring large vacuities characterized by angiopathy of medium and large-sized vessels.GCA granulomatous formation plays an important role in the pathogenesis of GCA.Analysis of T cell lineages and signaling pathways in GCA have revealed the essential role of T cells in the pathology of GCA.T cells are the dominant population present in GCA lesions.CD4+T cell subtypes that are present include Th1,Th2,Th9,Th17,follicular helper T(Tfh)cells,and regulatory T(Treg)cells.CD8 T cells can primarily differentiate into cytotoxic CD8+T lymphocytes and Treg cells.The instrumental part of GCA is the interplay between dendritic cells,macrophages and endothelial cells,which can result in the vascular injury and the characteristics granulomatous infiltrates formation.During the inflammatory loop of GCA,several signaling pathways have been reported to play an essential role in recruiting,activating and differentiating T cells,including T-cell receptor(TCR)signaling,vascular endothelial growth factor(VEGF)-Jagged-Notch signaling and the Janus kinase and signal transducer and activator of transcription(STAT)pathway(JAK-STAT)pathway.In this review,we have focused on the role of T cells and their potential signaling mechanism(s)that are involved in the pathogenesis of GCA.A better understanding of the role of T cells mediated complicated orchestration during the homeostasis and the changes could possibly favor developments of novel treatment strategies against immunological disorders associated with GCA.

Link between dysregulated hypoxia signaling and aberrant methylation in clear cell renal cell carcinoma？

Dysregulated pseudo-hypoxia （through its effects on cell survival, angiogenesis, metabolism, invasion） and epigenetic dysregulation [through widespread suppression of tumor suppressor genes involved in cell cycle, apoptosis, adhesion, immune evasion, etc. （1）] are considered to be the two central driving pathogenic features in the progression of clear cell Renal Cell Carcinoma （ccRCC） （2,3）.

Rosiglitazone uppresses lipopolysaccharide-induced matrix metalloproteinase-2 activity in rat aortic endothelial cells via rasMEK1/2 signaling

ix metalloproteinase(MMPs) plays a key role in the pathogenesis of chronic inflammatory disease,such as atherosclerosis.Among MMPs,MMP-2 is regarded as a major proteinase in atherosclerotic plaque lesions.Peroxisome proliferator activated receptor-gamma(PPARg) ameliorates oxidative stress and the inflammatory response.The aim of the present study was to evaluate the effect of Rosiglitazone on Lipopolysaccharide(LPS)-induced MMP-2 activation as well as its possible mechanism.LPS-induced MMP-2 activity was inhibited by Rosiglitazone(PPARg agonist) in the rat aortic endothelial cells(RAEC).LPS-induced MMP-2 activation was diminished no matter exposure to NF-kB Activation Inhibitor II(JSH-23)or Ras inhibitor,farnesylthiosalicylic acid(FTS). Further study shows that LPS-induced activation of Phospho-Rho A and Phospho-MEKl/2 were significantly inhibited by Rosiglitazone.The activation of NF-kB p65 in the nuclear extract of cells was also significantly suppressed by Rosiglitazone, moreover,the expression of NF-κB p65 was partly activated by GW9662(PPARg antagonist).NF-kB DNA binding activity was also demolished by Rosiglitazone.In summary,our data showed that PPARg agonist,Rosiglitazone suppresses LPS-activated MMP-2 secretion via Ras-MEK1/2 signaling pathways and NF-kB activation.PPARg agonist and Ras-MEK1/2 pathway may be another potential therapeutic target for the disease induced by chronic inflammation.

Potential Mechanisms Involved in Ceramide-induced Apoptosis in Human Colon Cancer HT29 Cells

Objective To investigate the potential mechanisms of cell death after the treatment with ceramide. Methods MTT assay, DNA ladder, reporter assay, FACS and Western blot assay were employed to investigate the potential mechanisms of cell death after the treatment with C2-ceramide. Results A short-time treatment with C2-ceramide induced cell death, which was associated with p38 MAP kinase activation, but had no links with typical caspase activation or PARP degradation. Rather than caspase inhibitor, Inhibitor of p38 MAP kinase blocked cell death induced by a short-time treatment with ceramide （〈12 h）. However, inhibition of p38 MAP kinase could not block cell death induced by a prolonged treatment with ceramide （〉12 h）. Moreover, incubation of cells with ceramide for a long time （〉12 h） increased subG1, but reduced S phase accompanied by caspase-dependent and caspase-independent changes including NFr, B activation. Conclusion Ceramide-induced cell apoptosis involves both caspase-dependent and -independent signaling pathway. Caspase-independent cell death occurring in a relatively early stage, which is mediated via p38 MAP kinase, can progress into a stage involving both caspase-dependent and -independent mechanisms accompanied by cell signaling of MAPKs and NFκB.