Role of Toll-like receptor 4 and Janus kinase and signal transducer and activator of transcription signal transduction pathway in sepsis-induced brain damage

The Janus kinase and signal transducer and activator of transcription （JAK/STAT） signal transduction pathway is involved in sepsis-induced functional damage to the heart, liver, kidney, and other organs. However, the cellular and molecular mechanisms underlying sepsis-induced brain damage remain elusive. In the present study, we found severe loss of neurons in the hippocampal CA1 region in rats with sepsis-induced brain damage following intraperitoneal injection of endotoxin, The expression of toll-like receptor 4, tumor necrosis factor a, and interleukin-6 was significantly increased in brain tissues following lipopolysaccharide exposure. AG490 （JAK2 antagonist） and rapamycin （STAT3 antagonist） significantly reduced neuronal loss and suppressed the increased expression of toll-like receptor 4, tumor necrosis factor a, and interleukin-6 in the hippocampal CA1 region in sepsis-induced brain damaged rats. Overall, these data suggest that blockade of the JAK/STAT signal transduction pathway is neuroprotective in sepsis-induced brain damage via the inhibition of toll-like receptor 4, tumor necrosis factor a, and interleukin-6 exoression.

Involvement of M3 Cholinergic Receptor Signal Transduction Pathway in Regulation of the Expression of Chemokine MOB-1, MCP-1 Genes in Pancreatic Acinar Cells

Whether M3 cholinergic receptor signal transduction pathway is involved in regulation of the activation of NF-κB and the expression of chemokine MOB-1, MCP-1genes in pancreatic acinar cells was investigated. Rat pancreatic acinar cells were isolated, cultured and treated with carbachol, atropine and PDTC in vitro. The MOB-1 and MCP-1 mRNA expression was detected by using RT-PCR. The activation of NF-κB was monitored by using electrophoretic mobility shift assay. The results showed that as compared with control group, M3 cholinergic receptor agonist (10 -3 mol/L, 10 -4 mol/L carbachol) could induce a concentration-dependent and time-dependent increase in the expression of MOB-1, MCP-1 mRNA in pancreatic acinar cells. After treatment with 10 -3 mol/L carbachol for 2 h, the expression of MOB-1, MCP-1 mRNA was strongest. The activity of NF-κB in pancreatic acinar cells was significantly increased (P<0.01) after treated with M3 cholinergic receptor agonist (10 -3 mol/L carbachol) in vitro for 30 min. Either M3 cholinergic receptor antagonist (10 -5 mol/L atropine) or NF-κB inhibitor (10 -2 mol/L PDTC) could obviously inhibit the activation of NF-κB and the chemokine MOB-1, MCP-1 mRNA expression induced by carbachol (P<0.05). This inhibitory effect was significantly increased by atropine plus PDTC (P<0.01). The results of these studies indicated that M3 cholinergic receptor signal transduction pathway was likely involved in regulation of the expression of chemokine MOB-1 and MCP-1genes in pancreatic acinar cells in vitro through the activation of NF-κB.

The Erythropoietin Receptor: Dimerization and Intracellular Signal Transduction

Erythropoietin (EPO), a 34 kD glycopro-tein, is the principal growth factor regulating theproduction of circulating erythrocytes; EPO isessential for committed CFU - E erythroid pro-genitors to divide several times and then to dif-ferentiate into erythrocytes. Like most receptorsfor hematopoietic growth factors, the erythro-poietin receptor (EPO - R) is a type I trans-membrane protein and a member of the cytokinereceptor superfamily. These receptors containfour conserved cysteines and a Trp - Ser - X -

Glucocorticoid receptor signaling in the brain and its involvement in cognitive function

The hypothalamic-pituitary-adrenal axis regulates the secretion of glucoco rticoids in response to environmental challenges.In the brain,a nuclear receptor transcription fa ctor,the glucocorticoid recepto r,is an important component of the hypothalamicpituitary-a d renal axis's negative feedback loop and plays a key role in regulating cognitive equilibrium and neuroplasticity.The glucoco rticoid receptor influences cognitive processes,including glutamate neurotransmission,calcium signaling,and the activation of brain-derived neurotrophic factor-mediated pathways,through a combination of genomic and non-genomic mechanisms.Protein interactions within the central nervous system can alter the expression and activity of the glucocorticoid receptor,there by affecting the hypothalamic-pituitary-a d renal axis and stress-related cognitive functions.An appropriate level of glucocorticoid receptor expression can improve cognitive function,while excessive glucocorticoid receptors or long-term exposure to glucoco rticoids may lead to cognitive impairment.Patients with cognitive impairment-associated diseases,such as Alzheimer's disease,aging,depression,Parkinson's disease,Huntington's disease,stroke,and addiction,often present with dysregulation of the hypothalamic-pituitary-adrenal axis and glucocorticoid receptor expression.This review provides a comprehensive overview of the functions of the glucoco rticoid receptor in the hypothalamic-pituitary-a d renal axis and cognitive activities.It emphasizes that appropriate glucocorticoid receptor signaling fa cilitates learning and memory,while its dysregulation can lead to cognitive impairment.This provides clues about how glucocorticoid receptor signaling can be targeted to ove rcome cognitive disability-related disorders.

Metabotropic glutamate receptors(mGluRs)in epileptogenesis:an update on abnormal mGluRs signaling and its therapeutic implications

Epilepsy is a neurological disorder characterized by high morbidity,high recurrence,and drug resistance.Enhanced signaling through the excitatory neurotransmitter glutamate is intricately associated with epilepsy.Metabotropic glutamate receptors(mGluRs)are G protein-coupled receptors activated by glutamate and are key regulators of neuronal and synaptic plasticity.Dysregulated mGluR signaling has been associated with various neurological disorders,and numerous studies have shown a close relationship between mGluRs expression/activity and the development of epilepsy.In this review,we first introduce the three groups of mGluRs and their associated signaling pathways.Then,we detail how these receptors influence epilepsy by describing the signaling cascades triggered by their activation and their neuroprotective or detrimental roles in epileptogenesis.In addition,strategies for pharmacological manipulation of these receptors during the treatment of epilepsy in experimental studies is also summarized.We hope that this review will provide a foundation for future studies on the development of mGluR-targeted antiepileptic drugs.

STAT3-Dependent Effects of Polymeric Immunoglobulin Receptor in Regulating Interleukin-17 Signaling and Preventing Autoimmune Hepatitis

One-third of patients with autoimmune hepatitis(AIH)have cirrhosis at the time of diagnosis.The relevance of these variables,although unknown,is believed to be critical in AIH because of suspected interactions between the gut microbiome and genetic factors.Dysbiosis of the gut flora and elevated polymeric immunoglobulin receptor(pIgR)levels have been observed in both patients and mouse models.Moreover,there is a direct relationship between pIgR expression and transaminase levels in patients with AIH.In this study,we aimed to explore how pIgR influences the secretion of regenerating islet-derived 3 beta(Reg3b)and the flora composition in AIH using in vivo experiments involving patients with AIH and a concanavalin A-induced mouse model of AIH.Reg3b expression was reduced in pIgR gene(Pigr)-knockout mice compared to that in wild-type mice,leading to increased microbiota disruption.Conversely,exogenous pIgR supplementation increased Reg3b expression and maintained microbiota homeostasis.RNA sequencing revealed the participation of the interleukin(IL)-17 signaling pathway in the regulation of Reg3b through pIgR.Furthermore,the introduction of external pIgR could not restore the imbalance in gut microbiota in AIH,and the decrease in Reg3b expression was not apparent following the inhibition of signal transducer and activator of transcription 3(STAT3).In this study,pIgR facilitated the upregulation of Reg3b via the STAT3 pathway,which plays a crucial role in preserving the balance of the intestinal microbiota in AIH.Through this research,we discovered new molecular targets that can be used for the diagnosis and treatment of AIH.

Chronic Hyperinsulinism Induced Down-regulation of Insulin Post-Receptor Signaling Transduction in Hep G2 Cells

To study the regulatory effect of acute and chronic insulin treatmenton insulin post- re- ceptor signaling transduction pathway in a human hepatom a cell line (Hep G2 ) ,Hep G2 cells were incubated in the presence or absence of insulin with different concentrations in serum free m edia for16 h and then stim ulated with10 0 nmol/ L insulin for1m in.Protein levels of insulin receptor β- subunit(IRβ) ,insulin receptor substrate- 1(IRS- 1) and p85 subunit of phosphatidylinositol3- kinase(PI3- kinase) were determined in total cell lysates by Western- im munoblot.Phosphorylat- ed proteins IRβ,IRS- 1and interaction of PI3- kinase with IRS- 1were determ ined by im munopre- cipitation.Results showed that 1- min insulin stimulation rapidly induced tyrosine phosphorylation of IRβ and IRS- 1,which in turn,resulting in association of PI 3- kinase with IRS- 1.1- 10 0 nm ol/ L chronic insulin treatment induced a dose- dependent decrease in the protein level of IRβ and a slight decrease in the protein level of IRS- 1.There was a m ore marked reduction in the phospho- rylation of IRβ,IRS- 1,reaching a nadir of2 2 % (P<0 .0 1) and15 % (P<0 .0 1) of control lev- els,respectively,after16 h treatment with 10 0 nm ol/ L insulin.The association between IRS- 1 and PI3- kinase was decreased by6 6 % (P<0 .0 1) .There was no significant change in PI3- ki- nase protein levels. These data suggest that chronic insulin treatm ent can induce alterations of IRβ,IRS- 1and PI 3- kinase three early steps in insulin action,which contributes significantly to insulin resistance,and may account for desensitization of insulin action.

Involvement of cAMP in ABA Signal Transduction in Tobacco Suspension Cells

Abscisic acid (ABA) plays an important role in plant growth and developmental processes. Although some ABA signal molecules, such as cADPR, Ca2+, etc., have been reported, there. was no evidence proving the involvement of cAMP in A-B-A, signal transduction. In this present study, the constructed gene ( rd29A-GUS) was transformed into Nicotiana tabacum, and calli was induced from the transgenic plant. The suspension cells obtained from the callus grew well and uniformly. Treatment of the suspension cells with ABA led to an increase in GUS activity, indicating that these transgenic suspension cells are useful for the study of ABA signaling. Addition of nicotinamide (cADPR inhibitor) or U-73122 (phospholiphase C inhibitor) could only partially inhibit the increase of GUS activity elicited by ABA. The inhibitory effect of nicotinamide was enhanced by application of K252a (inhibitor of protein kinase). Treatment of the suspension cells with 8-Br-cAMP, a membrane-permeable analogue of cAMP, could partially replace the effect of ABA. Furthermore, intracellular addition of IBMX (phosphodiesterase inhibitor) mimicked die effect of exogenous cAMP on the deduction of expression of rd29A promoter. These results suggested that cAMP was an important messenger in ABA signal transduction in tobacco suspension cell.

Interaction of signal transduction between angiotensin AT_1 and AT_2 receptor subtypes in rat senescent heart

Background Angiotensin Ⅱ （Ang Ⅱ） acting at angiotensin AT1 receptor （AT1R） has well documented effects on cardiovascular structure such as the promotion of cardiovascular hypertrophy and fibrosis, which are believed to be opposed by angiotensin AT2 receptor （AT2R） stimulation. The expressions of AT1R and AT2R are up-regulated in senescent hearts. The purpose of this study was to investigate the interaction of signal transduction between AT1R and AT2R, and to detect whether there is any difference in the interaction in rat hearts of different age.Methods In 3.5-, 12-, 18- and 24-month-old rats, the heart cell membrane activities of protein kinase C （PKC） and tyrosine kinase were measured when AT1R and AT2R were both activated by Ang Ⅱ or just the AT1R was activated by Ang Ⅱ and PD123319. The activities of cytosolic phospholipase A2 （cPLA2） and the levels of cGMP were investigated when AT1R and AT2R were both activated by Ang Ⅱ or just the AT2R was activated by Ang Ⅱ and losartan.Results When AT1R and AT2R were both activated compared to when the AT1R was activated, the activities of PKC were not different in hearts from 3.5- and 12-month-old rats, but decreased significantly in 18- and 24-month-old rats; the activities of tyrosine kinase were not different in 3.5-month-old rats but decreased significantly in 12-, 18- and 24-month-old rats. The activities of cPLA2 were all decreased significantly in rats of different age when AT1R and AT2R were both activated compared to when the AT2R was activated. Treatment with Ang Ⅱalone compared to Ang Ⅱ and Iosartan decreased the levels of cGMP （fmol/mg） in rats of different age （102.7±12.7 versus 86.0±8.0 in 3.5-month-old rats, P〈0.05; 81.0±9.4 versus 70.0±6.3 in 12-month-old rats, P〈0.05; 69.8±5.6 versus 54.2±5.3 in 18-month-old rats, P〈0.01 ; 57.7±8.0 versus 39.0±3.0 in 24-month-old rats, P〈0.01）.Conclusions The activation of AT1R inhibited the signal transduction of AT2R during the aging variation, and the activation of AT2R inhibited the signal transduction of AT1R in rat heart of different age.

The brassinosteroid signal transduction pathway

Steroids function as signaling molecules in both animals and plants. While animal steroid hormones are perceived by nuclear receptor family of transcription factors, brassinosteroids （BR） in plants are perceived by a cell surface receptor kinase, BRI 1. Recent studies have demonstrated that BR binding to the extracellular domain of BRI 1 induces kinase activation and dimerization with another receptor kinase, BAKI. Activated BRI 1 or BAKI then regulate, possibly indirectly, the activities of BIN2 kinase and/or BSU 1 phosphatase, which directly regulate the phosphorylation status and nuclear accumulation of two homologous transcription factors, BZRI and BES 1. BZRI and BES 1 directly bind to promoters of BR responsive genes to regulate their expression. The BR signaling pathway has become a paradigm for both receptor kinase signaling in plants and steroid signaling by cell surface receptors in general.

Signaling pathways involved in the inhibition of epidermal growth factor receptor by erlotinib in hepatocellular cancer

AIM： To examine the underlying mechanisms of erlotinib-induced growth inhibition in hepatocellular carcinoma （HCC）. METHODS： Erlotinib-induced alterations in gene expression were evaluated using cDNA array technology; changes in protein expression and/or protein activation due to erlotinib treatment as well as IGF-1-induced EGFR transactivation were investigated using Western blotting. RESULTS： Erlotinib treatment inhibited the mitogen activated protein （MAP）-kinase pathway and signal transducer of activation and transcription （STAT）- mediated signaling which led to an altered expression of apoptosis and cell cycle regulating genes as demonstrated by cDNA array technology. Overexpression of proapoptotic factors like caspases and gadds associated with a down-regulation of antiapoptotic factors like Bcl-2, Bcl-XL or jun D accounted for erlotinib＇s potency to induce apoptosis. Downregulation of cell cycle regulators promoting the G1/S-transition and overexpression of cyclin-dependent kinase inhibitors and gadds contributed to the induction of a G1/G0-arrest in response to erlotinib. Furthermore, we displayed the transactivation of EGFR-mediated signaling by the IGF-1-receptor and showed erlotinib＇s inhibitory effects on the receptor-receptor cross talk. CONCLUSION： Our study sheds light on the understanding of the mechanisms of action of EGFR-TK- inhibition in HCC-cells and thus might facilitate the design of combination therapies that act additively or synergistically. Moreover, our data on the pathways responding to erlotinib treatment could be helpful in predicting the responsiveness of tumors to EGFR-TKIs in the future.

Induction of Very Low Density Lipoprotein Receptor(VLDLR) Transcription by VLDL Is Mediated by the Extracellular Signal-Regulated Kinase Signaling Pathway

To elucidate the intracellular signaling pathways for VLDL-induced VLDLR transcription, Western blot analysis was used to examine phosphorylated ERK1/2 protein. It was found that that VLDL induced an increase in ERK1/2 activity in a protein kinase C (PKC)-dependent manner in murine RAW264. 7 macrophages. By using different protein kinases inhibitors or activators it was observed that the effect of VLDL-induced VLDL receptor transcription, which is monitored by RT-PCR analysis of VLDL receptor mRNA, was not affected by the inhibitor of p38 kinase and cAMP analog, but completely abolished by pretreatment of the cells with PD 98059, an inhibitor of MEK and GF 109203X, an inhibitor of PKC. These results demonstrated that the PKC/ERK1/2 cascade is the essential signaling pathway by which VLDL activates VLDL receptor mRNA expression.

Signal Peptide and Denaturing Temperature are Critical Factors for Efficient Mammalian Expression and Immunoblotting of Cannabinoid Receptors

Many researchers employed mammalian expression system to artificially express cannabinoid receptors, but immunoblot data that directly prove efficient protein expression can hardly be seen in related research reports. In present study, we demonstrated cannabinoid receptor protein was not able to be properly expressed with routine mammalian expression system. This inefficient expression was rescued by endowing an exogenous signal peptide ahead of cannabinoid receptor peptide. In addition, the artificially synthesized cannabinoid receptor was found to aggregate under routine sample denaturing temperatures (i.e.,≥95°C), forming a large molecular weight band when analyzed by immuno-blotting. Only denaturing temperatures ≤75°C yielded a clear band at the predicted molecular weight. Collectively, we showed that efficient mammalian expression of cannabinoid receptors need a signal peptide sequence, and described the requirement for a low sample denaturing temperature in immuno-blot analysis. These findings provide very useful information for efficient mammalian expression and immuno-blotting of membrane receptors.

Chemical Physics in Living Cells-using Light to Visualize and Control Intracellular Signal Transduction

Cells are crowded microenvironments filled with macromolecules undergoing constant phys- ical and chemical interactions. The physicochemical makeup of the cells aff）cts various cellular responses, determines cell-cell interactions and influences cell decisions. Chemical and physical properties diff）r between cells and within cells. Moreover, these properties are subject to dynamic changes in response to environmental signals, which often demand adjustments in the chemical or physical states of intracellular molecules. Indeed, cellular responses such as gene expression rely on the faithful relay of information from the outside to the inside of the cell, a process terrned signal transduction. The signal often traverses a complex path across subcellular spaces with variable physical chemistry, sometimes even influencing it. Understanding the molecular states of such signaling molecules and their intracellular environments is vital to our understanding of the cell. Exploring such intricate spaces is possible today largely because of experimental and theoretical tools. Here, we focus on one tool that is commonly used in chemical physics studies light. We summarize recent work which uses light to both visualize the cellular environment and also control intracel- lular processes along the axis of signal transduction. We highlight recent accomplishments in optical microscopy and optogenetics, an emerging experimental strategy which utilizes light to control the molecular processes in live cells. We believe that optogenetics lends un- precedented spatiotemporal precision to the manipulation of physicochemical properties in biological contexts. We hope to use this work to demonstrate new opportunities for chemical physicists who are interested in pursuing biological and biomedical questions.

The roles of the proteasome pathway in signal transduction and neurodegenerative diseases

There are two degradation systems in mammalian cells, autophagy/lysosomal pathway and ubiquitin-proteasome pathway. Proteasome is consist of multiple protein subunits and plays important roles in degradation of short-lived cellular proteins. Recent studies reveal that proteasomal degradation system is also involved in signal transduction and regulation of various cellular functions. Dysfunction or dysregulation of proteasomal function may thus be an important pathogenic mechanism in certain neurological disorders. This paper reviews the biological functions of proteasome in signal transduction and its potential roles in neurodegenerative diseases.

The mechanism of signal transduction during vascular smooth muscle cell proliferation induced by autoantibodies against angiotensin AT1 receptor from hypertension

Background Autoantibodies against angiotensin AT1 receptor have been discovered in patients with preeclampsia or malignant hypertension. Some studies have demonstrated that the autoantibodies are involved in the immunopathogenesis of hypertension and have an agonist effect similar to angiotensin II. Methods Autoantibodies against AT1 receptor were purified from sera of patients with primary hypertension by affinity chromatography. Proliferation of cultured rat vascular smooth muscle cells was detected by bromodeoxyuridine incorporation and activation of signalling molecules detected by Western blotting and electrophoretic mobility shift assay. Results The AT1-RAb caused a significant proliferation similar to the Ang II during first 24 hours. The levels of nuclear factor-KB （NF-KB）, phosphorylated JAK2., phosphorylated STAT1 （pSTAT1） and phosphorylated STAT3 （pSTAT3） molecules were increased in response to the autoantibodies. In contrast, the activations of NF-KB and JAK-STAT were blocked by Iosartan, pyrrolidinedithiocarbamate （a specific inhibitor of NF-KB） and AG490 （a specific inhibitor of the JAK2. tyrosine kinase）. The expressions of NF-KB, pSTAT1 and pSTAT3 reached peak levels at different times. Moreover, the relative densities of electrophoretic bands showed that activation of pSTAT3 was more significant than STAT1 induced by AT1 -RAb. Conclusions These results suggest that the autoantibodies against AT1 receptor have an agonist effect similar to Ang II in proliferation of VSMCs and the NF-KB and JAK-STAT proteins play essential roles. The effect is different from Angll in that STAT3 is the main downstream activating molecule in JAK-STAT signalling pathway.

Androgen receptor signaling and mutations in prostate cancer

Normal and neoplastic growth of the prostate gland are dependent on androgen receptor （AR） expression and function. Androgenic activation of the AR, in association with its coregulatory factors, is the classical pathway that leads to transcriptional activity of AR target genes. Alternatively, cytoplasmic signaling crosstalk of AR by growth factors, neurotrophic peptides, cytokines or nonandrogenic hormones may have important roles in prostate carcinogenesis and in metastatic or androgen-independent （AI） progression of the disease. In addition, cross-modulation by various nuclear transcription factors acting through basal transcriptional machinery could positively or negatively affect the AR or AR target genes expression and activity. Androgen ablation leads to an initial favorable response in a significant number of patients; however, almost invariably patients relapse with an aggressive form of the disease known as castration-resistant or hormone-refractory prostate cancer （PCa）. Understanding critical molecular events that lead PCa cells to resist androgen-deprivation therapy is essential in developing successful treatments for hormone-refractory disease. In a significant number of hormone-refractory patients, the AR is overexpressed, mutated or genomically amplified. These genetic alterations maintain an active presence for a highly sensitive AR, which is responsive to androgens, antiandrogens or nonandrogenic hormones and collectively confer a selective growth advantage to PCa cells. This review provides a brief synopsis of the AR structure, AR coregulators, posttranslational modifications of AR, duality of AR function in prostate epithelial and stromal cells, AR-dependent signaling, genetic changes in the form of somatic and germline mutations and their known functional significance in PCa cells and tissues.

Microwave Exposure Impairs Synaptic Plasticity in the Rat Hippocampus and PC12 Cells through Over-activation of the NMDA Receptor Signaling Pathway

Objective The aim of this study is to investigate whether microwave exposure would affect the N-methyI-D-aspartate receptor （NMDAR） signaling pathway to establish whether this plays a role in synaptic plasticity impairment. Methods 48 male Wistar rats were exposed to 30 mW/cm^2 microwave for 10 min every other day for three times. Hippocampal structure was observed through H＆E staining and transmission electron microscope. PC12 cells were exposed to 30 mW/cm^2 microwave for 5 min and the synapse morphology was visualized with scanning electron microscope and atomic force microscope. The release of amino acid neurotransmitters and calcium influx were detected. The expressions of several key NMDAR signaling molecules were evaluated. Results Microwave exposure caused injury in rat hippocampal structure and PC12 cells, especially the structure and quantity of synapses. The ratio of glutamic acid and gamma-aminobutyric acid neurotransmitters was increased and the intracellular calcium level was elevated in PC12 cells. A significant change in NMDAR subunits （NR1, NR2A, and NR2B） and related signaling molecules （CaZ＋/calmodulin-dependent kinase II gamma and phosphorylated cAMP-response element binding protein） were examined. Conclusion 30 mW/cm^2 microwave exposure resulted in alterations of synaptic structure, amino acid neurotransmitter release and calcium influx. NMDAR signaling molecules were closely associated with impaired synaptic plasticity.

Influence on Cellular Signal Transduction Pathway in Dairy Cow Mammary Gland Epithelial Cells by Galactopoietic Compound Isolated from Vaccariae segetalis

The galactopoietic mechanism of Vaccaria segetalis is still unknown. Understanding dibutyl phthalate （DBP） separated from Vaccaria segetalis on the expression of lactation signal transduction genes of mammary gland epithelial cells, including prlr, erα, akt1, socs2, pparγ and elf5, will be helpful to reveal the molecular mechanism. Western blot and qRT- PCR were used to study the change of prlr, erα, akt, socs2, pparγ, and elf5 expression at mRNA and protein level. Co- localization expression of prolactin receptor （PRLR） and estrogen receptor α （ERα） was observed by immunofluorescence; the expression changes of miRNAs （21, 125b, 143, and 195） and the secretion of β-casein and lactose were detected by qRT-PCR and RP-HPLC. The results showed that Vaccaria segetalis active compound had similar fuctions as estrogen and/or prolactin （PRL） in dairy cow mammary gland epithelial cells （DCMECs）, increased the expressions of prlr, erα, akt1, and elf5 genes, while repressed pparγ expressions. DBP promoted socs2 mRNA expression, but its protein expressions were repressed. Furthermore, both DBP and PRL could repress the expressions of miRNA-125b, miRNA-143 and miRNA- 195 in DCMECs. DBP could repress the expression of miRNA-21, while the influence of PRL on miRNA-21 was not certain. DBP could promote the lactation ability of DCMECs by regulating the ER and PRLR cellular signal transduction pathway.

Fibroblast growth factor receptor signaling as therapeutic targets in gastric cancer

Fibroblast growth factor receptors(FGFRs) regulate a variety of cellular functions, from embryogenesis to adult tissue homeostasis. FGFR signaling also plays significant roles in the proliferation, invasion, and survival of several types of tumor cells. FGFR-induced alterations, including gene amplification, chromosomal translocation, and mutations, have been shown to be associated with the tumor initiation and progression of gastric cancer, especially in diffuse-type cancers. Therefore, the FGFR signaling pathway might be one of the therapeutic targets in gastric cancer. This review aims to provide an overview of the role of FGFR signaling in tumorigenesis, tumor progression, proliferation, and chemoresistance. We also discuss the accumulating evidence that demonstrates the effectiveness of using clinical therapeutic agents to inhibit FGFR signaling for the treatment of gastric cancer.