Journal articles: 'CNTFR pathway'

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Ozog, Mark A., Suzanne M. Bernier, Dave C. Bates, Bishwanath Chatterjee, Cecilia W. Lo, and Christian C. G. Naus. "The Complex of Ciliary Neurotrophic Factor-Ciliary Neurotrophic Factor Receptor α Up-Regulates Connexin43 and Intercellular Coupling in Astrocytes via the Janus Tyrosine Kinase/Signal Transducer and Activator of Transcription Pathway." Molecular Biology of the Cell 15, no. 11 (November 2004): 4761–74. http://dx.doi.org/10.1091/mbc.e04-03-0271.

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Cytokines regulate numerous cell processes, including connexin expression and gap junctional coupling. In this study, we examined the effect of ciliary neurotrophic factor (CNTF) on connexin43 (Cx43) expression and intercellular coupling in astrocytes. Murine cortical astrocytes matured in vitro were treated with CNTF (20 ng/ml), soluble ciliary neurotrophic factor receptor α (CNTFRα) (200 ng/ml), or CNTF-CNTFRα. Although CNTF and CNTFRα alone had no effect on Cx43 expression, the heterodimer CNTF-CNTFRα significantly increased both Cx43 mRNA and protein levels. Cx43 immunostaining correlated with increased intercellular coupling as determined by dye transfer analysis. By using the pharmacological inhibitor α-cyano-(3,4-dihydroxy)-N-benzylcinnamide (AG490), the increase in Cx43 was found to be dependent on the Janus tyrosine kinase/signal transducer and activator of transcription (JAK/STAT) pathway. Immunocytochemical analysis revealed that CNTF-CNTFRα treatment produced nuclear localization of phosphorylated STAT3, whereas CNTF treatment alone did not. Transient transfection of constructs containing various sequences of the Cx43 promoter tagged to a LacZ reporter into ROS 17/2.8 cells confirmed that the promoter region between -838 to -1693 was deemed necessary for CNTF-CNTFRα to induce heightened expression. CNTF-CNTFRα did not alter Cx30 mRNA levels, suggesting selectivity of CNTF-CNTFRα for connexin signaling. Together in the presence of soluble receptor, CNTF activates the JAK/STAT pathway leading to enhanced Cx43 expression and intercellular coupling.

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Tossetta, Giovanni, Sonia Fantone, Rosaria Gesuita, Gaia Goteri, Martina Senzacqua, Fabio Marcheggiani, Luca Tiano, Daniela Marzioni, and Roberta Mazzucchelli. "Ciliary Neurotrophic Factor Modulates Multiple Downstream Signaling Pathways in Prostate Cancer Inhibiting Cell Invasiveness." Cancers 14, no. 23 (November 30, 2022): 5917. http://dx.doi.org/10.3390/cancers14235917.

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Background: Prostate cancer (PCa) remains the most common diagnosed tumor and is the second-leading cause of cancer-related death in men. If the cancer is organ-confined it can be treated by various ablative therapies such as RP (radical prostatectomy), RT (radiation therapy), brachytherapy, cryosurgery or HIFU (High-Intensity Focused Ultrasound). However, advanced or metastatic PCa treatment requires systemic therapy involving androgen deprivation, but such patients typically progress to refractory disease designated as castration-resistant prostate cancer (CRPC). Interleukin-6 (IL-6) has been established as a driver of prostate carcinogenesis and tumor progression while less is known about the role of ciliary neurotrophic factor (CNTF), a member of the IL-6 cytokine family in prostate cancer. Moreover, MAPK/ERK, AKT/PI3K and Jak/STAT pathways that regulate proliferative, invasive and glucose-uptake processes in cancer progression are triggered by CNTF. Methods: We investigate CNTF and its receptor CNTFRα expressions in human androgen-responsive and castration-resistant prostate cancer (CRPC) by immunohistochemistry. Moreover, we investigated the role of CNTF in proliferative, invasive processes as well as glucose uptake using two cell models mimicking the PCa (LNCaP cell line) and CRPC (22Rv1 cell line). Conclusions: Our results showed that CNTF and CNTFRa were expressed in PCa and CRPC tissues and that CNTF has a pivotal role in prostate cancer environment remodeling and as a negative modulator of invasion processes of CRPC cell models.

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Bortolotti, Sonia, Silvia Angelucci, Luca Montemurro, Damiano Bartolucci, Salvatore Raieli, Silvia Lampis, Camilla Amadesi, et al. "Antigene MYCN Silencing by BGA002 Inhibits SCLC Progression Blocking mTOR Pathway and Overcomes Multidrug Resistance." Cancers 15, no. 3 (February 3, 2023): 990. http://dx.doi.org/10.3390/cancers15030990.

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Small-cell lung cancer (SCLC) is the most aggressive lung cancer type, and is associated with smoking, low survival rate due to high vascularization, metastasis and drug resistance. Alterations in MYC family members are biomarkers of poor prognosis for a large number of SCLC. In particular, MYCN alterations define SCLC cases with immunotherapy failure. MYCN has a highly restricted pattern of expression in normal cells and is an ideal target for cancer therapy but is undruggable by traditional approaches. We propose an innovative approach to MYCN inhibition by an MYCN-specific antigene—PNA oligonucleotide (BGA002)—as a new precision medicine for MYCN-related SCLC. We found that BGA002 profoundly and specifically inhibited MYCN expression in SCLC cells, leading to cell-growth inhibition and apoptosis, while also overcoming multidrug resistance. These effects are driven by mTOR pathway block in concomitance with autophagy reactivation, thus avoiding the side effects of targeting mTOR in healthy cells. Moreover, we identified an MYCN-related SCLC gene signature comprehending CNTFR, DLX5 and TNFAIP3, that was reverted by BGA002. Finally, systemic treatment with BGA002 significantly increased survival in MYCN-amplified SCLC mouse models, including in a multidrug-resistant model in which tumor vascularization was also eliminated. These findings warrant the clinical testing of BGA002 in MYCN-related SCLC.

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Dutta, Ranjan, Jennifer McDonough, Ansi Chang, Lakshman Swamy, Alan Siu, Grahame J. Kidd, Richard Rudick, Karoly Mirnics, and Bruce D. Trapp. "Activation of the ciliary neurotrophic factor (CNTF) signalling pathway in cortical neurons of multiple sclerosis patients." Brain 130, no. 10 (October 1, 2007): 2566–76. http://dx.doi.org/10.1093/brain/awm206.

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Abstract Neuronal and axonal degeneration results in irreversible neurological disability in multiple sclerosis (MS) patients. A number of adaptive or neuroprotective mechanisms are thought to repress neurodegeneration and neurological disability in MS patients. To investigate possible neuroprotective pathways in the cerebral cortex of MS patients, we compared gene transcripts in cortices of six control and six MS patients. Out of 67 transcripts increased in MS cortex nine were related to the signalling mediated by the neurotrophin ciliary neurotrophic factor (CNTF). Therefore, we quantified and localized transcriptional (RT-PCR, in situ hybridization) and translational (western, immunohistochemistry) products of CNTF-related genes. CNTF-receptor complex members, CNTFRα, LIFRβ and GP130, were increased in MS cortical neurons. CNTF was increased and also expressed by neurons. Phosphorylated STAT3 and the anti-apoptotic molecule, Bcl2, known down stream products of CNTF signalling were also increased in MS cortical neurons. We hypothesize that in response to the chronic insults or stress of the pathogenesis of multiple sclerosis, cortical neurons up regulate a CNTF-mediated neuroprotective signalling pathway. Induction of CNTF signalling and the anti-apoptotic molecule, Bcl2, thus represents a compensatory response to disease pathogenesis and a potential therapeutic target in MS patients.

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Fan, Yi, Haishan Xu, Meiyan Lv, and Ning Li. "Preoperative Serum Calcitonin Level and Ultrasonographic Characteristics Predict the Risk of Metastatic Medullary Thyroid Carcinoma: Functional Analysis of Calcitonin-Related Genes." Disease Markers 2022 (March 2, 2022): 1–14. http://dx.doi.org/10.1155/2022/9980185.

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Background. Early cervical lymph node (LN) metastasis is an important cause of poor survival in patients with medullary thyroid cancer (MTC). This study evaluated whether the preoperative serum calcitonin level in combination with ultrasonographic features of MTC can be used to assess the LN status as well as predict the risk of metastasis in patients with MTC. Methods. We retrospectively analyzed the clinical data of 95 patients with MTC, and a nomogram model was constructed and validated. Using integrated database analysis of The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx), we mined pathways wherein CALCA is involved, identified calcitonin-related genes, and analyzed their functions. Results. Correlation analysis revealed a significant association between the infiltrating range, diameter, calcification, blood flow, the preoperative serum calcitonin level, and metastasis. The metastasis risk-prediction model showed great accuracy in determining the risk of metastasis in MTC (area under the curve of the receiver operating characteristic [ROC] curve: 0.979 [95% confidence interval 0.946–1.000]). Decision curve analysis (DCA) showed that the model has excellent clinical utilization potential. Significantly, CALCA, the mRNA for calcitonin, was highly expressed in thyroid cancer tissues and associated with the cytokine–cytokine receptor and neuroactive ligand-receptor interaction pathways as well as the cell-adhesion molecules. ROC curve indicated that the CNTFR, CD27, GDF6, and TSLP genes, which are related to the cytokine–cytokine receptor interaction pathway, could indicate the risk of metastasis in MTC. Conclusions. The preoperative serum calcitonin level, in combination with ultrasonographic features, can be used to predict the risk of metastasis in patients with MTC and constitute a noninvasive accurate method for preoperative diagnosis of MTC.

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Rousseau, Marine, Véronique Laplante, Ulysse Nadeau, Sarah Pasquin, Ernesto Fajardo, Sylvie Lesage, and Jean-François Gauchat. "Characterization of a new cytokine complex from the IL-6/IL-12 family." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 46.13. http://dx.doi.org/10.4049/jimmunol.208.supp.46.13.

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Abstract Cardiotrophin-like cytokine factor 1 (CLCF1) is a neurotrophic factor initially identified as a B lymphocyte stimulating factor. Mutations in CLCF1 cause type 2 Cold-Induced Sweating Syndrome, a severe multisystem disorder coupled with recurrent childhood infections. The CLCF1-CRLF1 composite cytokine mediate its neurotrophic effects via the CNTF receptor (CNTFR). Although immune cells do not express CNTFR, immunological activities of CLCF1 have been described, suggesting the existence of an alternative receptor. Preliminary results suggest that CLCF1 can associate with the Epstein-Barr virus-induced gene 3(EBI3). EBI3 is a subunit of the composite cytokines IL-27, IL-35 and IL-39, which exhibits immunoregulatory functions. Our hypothesis is that CLCF1 associates with EBI3 to activate an alternative receptor expressed by immune cells. The aim of the project is to identify the cells producing CLCF1/EBI3, to define its receptor and to characterize the influence of CLCF1/EBI3 on lymphocyte proliferation, differentiation, and function. We find that EBI3 and CLCF1 subunits can associate extracellularly to form a CLCF1/EBI3 complex. Moreover, we uncovered that this complex can bind to IL-12Rß1, IL-23R and CNTFRα receptor chains. Altogether, our data strongly suggest that the CLCF1/EBI3 complex is likely to assemble in vivo and act as a cytokine through known receptor chains. Overall, defining the cellular targets and biological activities of CLCF1/EBI3 will pave the way for the development of treatments in autoimmune diseases involving CLCF1 and EBI3, adding to the increasing number of biologic drugs targeting cytokines, their receptors, or signaling pathways that are used clinically to treat inflammatory diseases. Supported by IRSC (RNI00404)

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Wong, Grace L., Sherona R. Sirkisoon, Noah R. Aguayo, Daniel L. Doheny, Dongqin Zhu, Angelina T. Regua, Austin Arrigo, et al. "Abstract 2354: Astrocytes activated by tGLI1-expressing breast cancer brain metastases upregulate CNTF to activate astrocytes and promote breast cancer stem cells." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2354. http://dx.doi.org/10.1158/1538-7445.am2022-2354.

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Abstract Breast cancer is the most frequently diagnosed cancer, and second most common source of brain metastasis in women. Despite recent advances in detection and therapeutics, patients with breast cancer brain metastases (BCBM) survive only 6-18 months after diagnosis. HER2-enriched breast cancer and triple-negative breast cancer (TNBC) subtypes have the highest propensity to metastasize to the brain. Mechanisms that drive BCBM remain unclear, contributing to limited effective treatments and poor prognoses for HER2-enriched breast cancer and TNBC patients. Truncated glioma-associated oncogene homolog 1 (tGLI1), a gain-of-function GLI1 transcription factor discovered in our lab, promotes BCBM of circulating tumor cells in vivo. We previously reported that tGLI1 enriches the breast cancer stem cell (BCSC) subpopulation, and that tGLI1-positive BCSCs strongly activate astrocytes, the most abundant glial cell type in the brain. The mechanisms by which tGLI1-activated astrocytes promote BCBM have not been investigated. Since tumor-associated astrocytes have been reported to secrete specific cytokines, such as ciliary neurotrophic factor (CNTF), to activate astrocytes and cancer cells by binding to IL-6R and CNTF receptor-alpha (CNTFRα), we determined whether astrocytes activated by tGLI1-positive breast cancer cells secrete elevated levels of CNTF. Results of CNTF ELISA revealed that conditioned media from tGLI1-positive breast cancer cells increases the ability of astrocytes to secrete CNTF compared to GLI1-positive or control cells. Furthermore, we found that exogenous CNTF significantly activates astrocytes and promotes BCSCs, important mediators of tumor progression and metastasis in breast cancer. Analysis of patient datasets reveals CNTFRα is more highly expressed in brain metastases compared to breast cancer and normal breast tissues, suggesting that CNTF secreted by activated astrocytes can promote the growth of BCSCs in the brain. We further found that CNTF and CNTFRα gene signatures are significantly associated with worse brain metastasis-free survival, suggesting an important role for the tGLI1-CNTF-CNTFRα pathway in BCBM development. In summary, our study demonstrates for the first time that astrocytes activated by tGLI1-expressing BCBM secrete CNTF, CNTF further activates astrocytes and promotes BCSCs, and that this tumor-astrocyte interaction could be a novel mechanism for BCBM development and progression. Citation Format: Grace L. Wong, Sherona R. Sirkisoon, Noah R. Aguayo, Daniel L. Doheny, Dongqin Zhu, Angelina T. Regua, Austin Arrigo, Sara G. Manore, Calvin J. Wagner, Alexandra Thomas, Ravi Singh, Fei Xing, Guangxu Jin, Kounosuke Watabe, Hui-Wen Lo. Astrocytes activated by tGLI1-expressing breast cancer brain metastases upregulate CNTF to activate astrocytes and promote breast cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2354.

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Bilous, Iryna I., Larysa L. Pavlovych, and Aleksandr M. Kamyshnyi. "Primary hypothyroidism and autoimmune thyroiditis alter the transcriptional activity of genes regulating neurogenesis in the blood of patients." Endocrine Regulations 55, no. 1 (January 1, 2021): 5–15. http://dx.doi.org/10.2478/enr-2021-0002.

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Abstract Objective. Thyroid hormones play an important role in the development and maturation of the central nervous symptom and their failure in the prenatal period leading to an irreversible brain damage. Their effect on the brain of adult, however, has not been fully studied. With the discovery of neurogenesis in the adult brain, many recent studies have been focused on the understanding the basic mechanisms controlling this process. Many neurogenesis regulatory genes are not only transcribed but also translated into the blood cells. The goal of our study was to analyze the transcriptional activity of neurogenesis regulatory genes in peripheral blood cells in patients with thyroid pathology. Methods. The pathway-specific PCR array (Neurotrophins and Receptors RT2 Profiler PCR Array, QIAGEN, Germany) was used to identify and validate the neurogenesis regulatory genes expression in patients with thyroid pathology and control group. Results. The results showed that GFRA3, NGFR, NRG1, NTF3, NTRK1, and NTRK2 significantly decreased their expression in patients with autoimmune thyroiditis with rising serum of autoantibodies. The patients with primary hypothyroidism, as a result of autoimmune thyroiditis and postoperative hypothyroidism, had significantly lower expression of FGF2, NGFR, NRG1, and NTF3. The mRNA level of CNTFR was markedly decreased in the group of patients with postoperative hypothyroidism. No change in the ARTN, PSPN, TFG, MT3, and NELL1 expression was observed in any group of patients. Conclusion. The finding indicates that a decrease in thyroid hormones and a high level of autoantibodies, such as anti-thyroglobulin antibody and anti-thyroid peroxidase antibody, affect the expression of mRNA neurogenesis-regulated genes in patients with thyroid pathology.

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Lu, Jie, Alexander Ksendzovsky, Chunzhang Yang, Gautam U. Mehta, Raymund L. Yong, Robert J. Weil, Deric M. Park, et al. "CNTF receptor subunit α as a marker for glioma tumor-initiating cells and tumor grade." Journal of Neurosurgery 117, no. 6 (December 2012): 1022–31. http://dx.doi.org/10.3171/2012.9.jns1212.

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Object Tumor-initiating cells are uniquely resilient to current treatment modalities and play an important role in tumor resistance and recurrence. The lack of specific tumor-initiating cell markers to identify and target these cells presents a major obstacle to effective directed therapy. Methods To identify tumor-initiating cell markers in primary brain tumors, the authors compared the proteomes of glioma tumor-initiating cells to their differentiated progeny using a novel, nongel/shotgun-based, multidimensional liquid-chromatography protein separation technique. An in vivo xenograft model was used to demonstrate the tumorigenic and stem cell properties of these cells. Western blot and immunofluorescence analyses were used to confirm findings of upregulated ciliary neurotrophic factor receptor subunit–α (CNTFRα) in undifferentiated tumor-initiating cells and gliomas of increasing tumor grade. Sequencing of the CNTFRα coding regions was performed for mutation analysis. Finally, antibody-dependent cell-mediated cytotoxicity was used to establish the role of CNTFRα as a potential immunotherapeutic target. Results Ciliary neurotrophic factor receptor subunit–α expression was increased in tumor-initiating cells and was decreased in the cells' differentiated progeny, and expression levels increased with glioma grade. Mutations of CNTFRα are not common in gliomas. Functional studies using CNTF treatment in glioma tumor-initiating cells showed induction of differentiation through the CNTFRα pathway. Treatment with anti-CNTFRα antibody resulted in increased antibody-dependent cell-mediated cytotoxicity in CNTFRα expressing DAOY cells but not in cell lines that lack CNTFRα. Conclusions These data indicate that CNTFRα plays a role in the formation or maintenance of tumor-initiating cells in gliomas, is a marker that correlates with histological grade, may underlie treatment resistance in some cases, and is a potential therapeutic target.

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Benomar, Yacir, Flavien Berthou, Claire-Marie Vacher, Virginie Bailleux, Arieh Gertler, Jean Djiane, and Mohammed Taouis. "Leptin But Not Ciliary Neurotrophic Factor (CNTF) Induces Phosphotyrosine Phosphatase-1B Expression in Human Neuronal Cells (SH-SY5Y): Putative Explanation of CNTF Efficacy in Leptin-Resistant State." Endocrinology 150, no. 3 (November 13, 2008): 1182–91. http://dx.doi.org/10.1210/en.2008-1097.

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Growing evidences suggest that obesity is associated with hypothalamic leptin resistance, leading to the alteration of food intake control. Alternative treatment using ciliary neurotrophic factor (CNTF) has been suggested because CNTF exerts a leptin-like effect, even in leptin-resistant states, but the mechanisms by which CNTF maintains this effect are not yet understood. Both leptin and CNTF act in the hypothalamus through similar signaling pathways including janus kinase-2/signal transducer and activator of transcription (STAT)-3 pathway. To explore the differences and interactions between leptin and CNTF signaling pathways, differentiated human neuroblastoma cells (SH-SY5Y) were exposed to either leptin or CNTF and then challenged for each cytokine. Leptin pretreatment completely abolished leptin-dependent STAT-3 and ERK 1/2 phosphorylations without affecting CNTF action. The lack of cross-desensitization between leptin and CNTF signaling pathways occurred despite the induction of suppressor of cytokine signaling-3 in response to both cytokines. Interestingly, leptin as well as insulin induced the expression of phosphotyrosine phosphatase (PTP)-1B, whereas CNTF treatment did not affect its expression. In addition, acute leptin treatment but not CNTF induced PTP-1B expression in mouse hypothalamic arcuate nucleus. Furthermore, the overexpression of human PTP-1B in SH-SY5Y cells completely abolished leptin- and insulin-dependent janus kinase-2, STAT-3, and ERK 1/2 phosphorylations, but CNTF action was not altered. Collectively, our results suggest that PTP-1B constitutes a key divergent element between leptin/insulin and CNTF signaling pathways at the neuronal level, which may constitute a possible mechanism that explains the efficacy of CNTF in leptin-resistant states. Phosphotyrosine phosphatase 1B has a critical role in the onset of neuronal leptin resistance and is unable to inhibit CNTF-dependent signaling pathways in leptin-resistant states.

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Jeong, Kyoung Hoon, Jin Han Nam, Byung Kwan Jin, and Sang Ryong Kim. "Activation of CNTF/CNTFRα Signaling Pathway by hRheb(S16H) Transduction of Dopaminergic Neurons In Vivo." PLOS ONE 10, no. 3 (March 23, 2015): e0121803. http://dx.doi.org/10.1371/journal.pone.0121803.

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Rezende, Luiz F., Luiz F. Stoppiglia, Kleber L. A. Souza, Alessandro Negro, Francesco Langone, and Antonio C. Boschero. "Ciliary neurotrophic factor promotes survival of neonatal rat islets via the BCL-2 anti-apoptotic pathway." Journal of Endocrinology 195, no. 1 (October 2007): 157–65. http://dx.doi.org/10.1677/joe-07-0016.

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Ciliary neurotrophic factor (CNTF) belongs to the cytokine family and increases neuron differentiation and/or survival. Pancreatic islets are richly innervated and express receptors for nerve growth factors (NGFs) and may undergo neurotypic responses. CNTF is found in pancreatic islets and exerts paracrine effects in neighboring cells. The aim of this study was to investigate possible effects of CNTF on neonatal rat pancreatic islet differentiation and/or survival. For this purpose, we isolated pancreatic islets from neonatal rats (1–2 days old) by the collagenase method and cultured for 3 days in RPMI medium with (CNTF) or without (CTL) 1 nM CNTF. Thereafter, glucose-stimulated insulin secretion (RIA), general metabolism by (NAD(P)H production; MTS), glucose metabolism (14CO2 production), gene (RT-PCR), protein expression (western blotting), caspase-3 activity (Asp–Glu–Val–Asp (DEVD)), and apoptosis (DNA fragmentation) were analyzed. Our results showed that CNTF-treated islets demonstrated reduced glucose-induced insulin secretion. CNTF treatment did not affect glucose metabolism, as well as the expression of mRNAs and proteins that are crucial for the secretory process. Conversely, CNTF significantly increased mRNA and protein levels related to cell survival, such as Cx36, PAX4, and BCL-2, reduced caspase-3 activity, and islet cells apoptosis, suggesting that CNTF does not affect islet cell differentiation and, instead, acts as a survival factor reducing apoptosis by increasing the expression of the anti-apoptotic BCL-2 protein and decreasing caspase-3 activity.

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Liu, Juan, and Ming Li. "Preparation of Neuropeptide Nanoparticle and Its Mechanism in Corneal Nerve Regeneration in Substance P-Neurokinin 1 Receptor Signaling Pathway." Science of Advanced Materials 13, no. 2 (February 1, 2021): 254–63. http://dx.doi.org/10.1166/sam.2021.3917.

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The multiple emulsion method was applied to prepare the 1.5 mL solution of ciliary neurotrophic factor (CNTF), and dichloromethane solution with 2.5% polylactic acid (PLA) was added into the CNTF solution during the colostrum process, and then, polyethylene glycol solution was added into the mixed solution under ultrasonic conditions to form multiple emulsion; finally, it was stirred magnetically and centrifuged to obtain CNTF nanoparticles. The transmission electron microscope (TEM) was applied to characterize the prepared nanoparticles that detected their drug loading rate, encapsulation rate, and their drug release in vitro and in vivo. In the demonstration of neuropeptide nanoparticles participating in corneal nerve regeneration in the substance p-neurokinin 1 receptor (SP-NK-1R) signaling pathway, it was to detect the gene expression in the trigeminal ganglion cells based on the different groups like normal group, advanced glycation end products (AGE)/Stattic group, and AGE + CNTF/Stattic + CNTF group. In the characterization experiment of CNTF nanoparticles, their surfaces were smooth, they evenly distributed, and the average drug loading rate reached 1.27% ± 0.032%; the nanoparticles were able to continuously release CNTF molecules within 30 hours; what’s more, CNTF group (low concentration to high concentration) and CNTF nanoparticles group (low concentration to high concentration) could both enhance the expression of mouse optic nerve cells. Compared to AGE group, the expressions of substance p-signal transducer and activator of transcription 3 (p-STAT3) in trigeminal ganglion cells increased after adding CNTF and CNTF nanoparticles, respectively (P < 0.05); and the expression of p-STAT3 increased remarkably after the addition of CNTF nanoparticles (P < 0.05), with an obvious increase on the growth of nerve axon. On the other hand, it had the same results as the above, compared with Stattic group.

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Chen, Xiaoping, Zebin Mao, Shuhong Liu, Hong Liu, Xuan Wang, Haitao Wu, Yan Wu, et al. "Dedifferentiation of Adult Human Myoblasts Induced by Ciliary Neurotrophic Factor In Vitro." Molecular Biology of the Cell 16, no. 7 (July 2005): 3140–51. http://dx.doi.org/10.1091/mbc.e05-03-0218.

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Ciliary neurotrophic factor (CNTF) is primarily known for its important cellular effects within the nervous system. However, recent studies indicate that its receptor can be highly expressed in denervated skeletal muscle. Here, we investigated the direct effect of CNTF on skeletal myoblasts of adult human. Surprisingly, we found that CNTF induced the myogenic lineage-committed myoblasts at a clonal level to dedifferentiate into multipotent progenitor cells—they not only could proliferate for over 20 passages with the expression absence of myogenic specific factors Myf5 and MyoD, but they were also capable of differentiating into new phenotypes, mainly neurons, glial cells, smooth muscle cells, and adipocytes. These “progenitor cells” retained their myogenic memory and were capable of redifferentiating into myotubes. Furthermore, CNTF could activate the p44/p42 MAPK and down-regulate the expression of myogenic regulatory factors (MRFs). Finally, PD98059, a specific inhibitor of p44/p42 MAPK pathway, was able to abolish the effects of CNTF on both myoblast fate and MRF expression. Our results demonstrate the myogenic lineage-committed human myoblasts can dedifferentiate at a clonal level and CNTF is a novel regulator of skeletal myoblast dedifferentiation via p44/p42 MAPK pathway.

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Jiang, Lina, Zhengqi Fan, Ran Tong, Xingwen Zhou, Jiyuan Li, and Hengfu Yin. "Functional Diversification of the Dihydroflavonol 4-Reductase from Camellia nitidissima Chi. in the Control of Polyphenol Biosynthesis." Genes 11, no. 11 (November 12, 2020): 1341. http://dx.doi.org/10.3390/genes11111341.

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Plant secondary metabolism is complex in its diverse chemical composition and dynamic regulation of biosynthesis. How the functional diversification of enzymes contributes to the diversity is largely unknown. In the flavonoids pathway, dihydroflavonol 4-reductase (DFR) is a key enzyme mediating dihydroflavanol into anthocyanins biosynthesis. Here, the DFR homolog was identified from Camellia nitidissima Chi. (CnDFR) which is a unique species of the genus Camellia with golden yellow petals. Sequence analysis showed that CnDFR possessed not only conserved catalytic domains, but also some amino acids peculiar to Camellia species. Gene expression analysis revealed that CnDFR was expressed in all tissues and the expression of CnDFR was positively correlated with polyphenols but negatively with yellow coloration. The subcellular localization of CnDFR by the tobacco infiltration assay showed a likely dual localization in the nucleus and cell membrane. Furthermore, overexpression transgenic lines were generated in tobacco to understand the molecular function of CnDFR. The analyses of metabolites suggested that ectopic expression of CnDFR enhanced the biosynthesis of polyphenols, while no accumulation of anthocyanins was detected. These results indicate a functional diversification of the reductase activities in Camellia plants and provide molecular insights into the regulation of floral color.

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Couvreur, Odile, Alain Aubourg, Delphine Crépin, Jéril Degrouard, Arieh Gertler, Mohammed Taouis, and Claire-Marie Vacher. "The anorexigenic cytokine ciliary neurotrophic factor stimulates POMC gene expression via receptors localized in the nucleus of arcuate neurons." American Journal of Physiology-Endocrinology and Metabolism 302, no. 4 (February 15, 2012): E458—E467. http://dx.doi.org/10.1152/ajpendo.00388.2011.

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Ciliary neurotrophic factor (CNTF) is a neural cytokine that reduces appetite and body weight when administrated to rodents or humans. We have demonstrated recently that the level of CNTF in the arcuate nucleus (ARC), a key hypothalamic region involved in food intake regulation, is positively correlated with protection against diet-induced obesity. However, the comprehension of the physiological significance of neural CNTF action was still incomplete because CNTF lacks a signal peptide and thus may not be secreted by the classical exocytosis pathways. Knowing that CNTF distribution shares similarities with that of its receptor subunits in the rat ARC, we hypothesized that CNTF could exert a direct intracrine effect in ARC cells. Here, we demonstrate that CNTF, together with its receptor subunits, translocates to the cell nucleus of anorexigenic POMC neurons in the rat ARC. Furthermore, the stimulation of hypothalamic nuclear fractions with CNTF induces the phosphorylation of several signaling proteins, including Akt, as well as the transcription of the POMC gene. These data strongly suggest that intracellular CNTF may directly modulate POMC gene expression via the activation of receptors localized in the cell nucleus, providing a novel plausible mechanism of CNTF action in regulating energy homeostasis.

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Fudalej, Ewa, Magdalena Justyniarska, Kaja Kasarełło, Jacek Dziedziak, Jacek P. Szaflik, and Agnieszka Cudnoch-Jędrzejewska. "Neuroprotective Factors of the Retina and Their Role in Promoting Survival of Retinal Ganglion Cells: A Review." Ophthalmic Research 64, no. 3 (2021): 345–55. http://dx.doi.org/10.1159/000514441.

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Retinal ganglion cells (RGCs) play a crucial role in the visual pathway. As their axons form the optic nerve, apoptosis of these cells causes neurodegenerative vision loss. RGC death could be triggered by increased intraocular pressure, advanced glycation end products, or mitochondrial dysfunction. In this review, we summarize the role of some neuroprotective factors in RGC injury: ciliary neurotrophic factor (CNTF), nerve growth factor (NGF), brain-derived neurotrophic factor, vascular endothelial growth factor, pigment epithelium-derived factor, glial cell line-derived neurotrophic factor, and Norrin. Each, in their own unique way, prevents RGC damage caused by glaucoma, ocular hypertension, ischemic neuropathy, and even oxygen-induced retinopathy. These factors are produced mainly by neurons, leukocytes, glial cells, and epithelial cells. Neuroprotective factors act via various signaling pathways, including JAK/STAT, MAPK, TrkA, and TrkB, which promotes RGC survival. Many attempts have been made to develop therapeutic strategies using these factors. There are ongoing clinical trials with CNTF and NGF, but they have not yet been accepted for clinical use.

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Baenas, I., N. Solé-Morata, M. Etxandi, R. Granero, M. Gené, C. Barrot, P. Gorwood, N. Ramoz, F. Fernandez-Aranda, and S. Jimenez-Murcia. "Are Neurotrophin Genes Involved in the Pathophysiology of Gambling Disorder?" European Psychiatry 65, S1 (June 2022): S240—S241. http://dx.doi.org/10.1192/j.eurpsy.2022.621.

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Introduction Gambling Disorder (GD) is considered a multifactorial behavioral addictive disorder, leading to severe psychological, social and economic consequences. Previous studies have investigated genetic mechanisms underlying GD. Growing literature showed a possible link between addiction-related disorders and neurotrophic factors (NTF), involved in synaptic plasticity and neuronal survival. Thus, the study of NTF genes emerged as promising targets in the field of GD. Objectives To evaluate genetic implications of the NTF family in the pathophysiology GD. We hypothesized the involvement of some NTF genes polymorphisms in the onset and progression of GD as potential biological risk factors. Methods The sample was composed by 166 individuals with GD and 191 healthy controls. 36 Single nucleotide polymorphisms (SNPs) from NTF (NGF, NGFR, NTRK1, BDNF, NTRK2, NTF3, NTRK3, NTF4, CNTF and CNTFR) were selected and genotyped. Linkage disequilibrium and haplotype constructions were assessed, related to the presence of GD. Moreover, regulatory elements overlapping the identified SNPs variants associated with GD was also analyzed. Results 6 SNPs were potentially associated to GD after the comparisons of allele frequencies between groups. Single and multiple-marker analyses showed a strong association between both NTF3 and NTRK2 genes, and GD. Conclusions This study suggests the implication of NTF genes in the development of GD, being the altered cross-regulation of some NTF factors signalling pathways, a potential biological vulnerability factor in GD. Fundings and Acknowledgements: Ministerio de Ciencia, Innovación y Universidades (RTI2018-101837-B-100) Delegación del Gobierno para el Plan Nacional sobre Drogas (2017I067, 2019I47), Instituto Salud Carlos III (ISCIII) (PI17/01167, PI20/00132) and CIBERObn, an initiative of ISCIII. Disclosure No significant relationships.

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Yan, Jin, Cheng He, Changlin Lu, Chenghai Wang, Xuan Bao, Tieshan Tang, Xiuying Huang, and Fangzhen Sun. "The new sideway of CNTF signal transduction pathway." Chinese Science Bulletin 46, no. 6 (March 2001): 477–80. http://dx.doi.org/10.1007/bf03187260.

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Zhu, Yaling, Huirong Mao, Gang Peng, Qingjie Zeng, Qing Wei, Jiming Ruan, and Jianzhen Huang. "Effect of JAK-STAT pathway in regulation of fatty liver hemorrhagic syndrome in chickens." Animal Bioscience 34, no. 1 (January 1, 2021): 143–53. http://dx.doi.org/10.5713/ajas.19.0874.

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Objective: To explore the molecular mechanisms of fatty liver hemorrhagic syndrome (FLHS) in laying hens, an experiment was conducted to reveal the differences in histopathological observation and gene expression between FLHS group and normal group.Methods: We compared the histopathological difference using hematoxylin and eosin staining and proceeded with RNA sequencing of adipose tissue to search differentially expressed genes and enriched biological processes and pathways. Then we validated the mRNA expression levels by real-time polymerase chain reaction and quantified protein levels in the circulation by enzyme-linked immunosorbent assay.Results: We identified 100 differentially expressed transcripts corresponding to 66 genes (DEGs) were identified between FLHS-affected group and normal group. Seven DEGs were significantly enriched in the immune response process and lipid metabolic process, including phospholipase A2 group V, WAP kunitz and netrin domain containing 2, delta 4-desaturase sphingolipid 2, perilipin 3, interleukin-6 (IL-6), ciliary neurotrophic factor (CNTF), and suppressor of cytokine signaling 3 (SOCS3). And these genes could be the targets of immune response and be involved in metabolic homeostasis during the process of FLHS in laying hens. Based on functional categories of the DEGs, we further proposed a model to explain the etiology and pathogenesis of FLHS. IL-6 and SOCS3 mediate inflammatory responses and the satiety hormone of leptin, induce dysfunction of Jak-STAT signaling pathway, leading to insulin resistance and lipid metabolic disorders. Conversely, CNTF may reduce tissue destruction during inflammatory attacks and confer protection from inflammation-induced insulin resistance in FLHS chickens.Conclusion: These findings highlight the therapeutic implications of targeting the JAK-STAT pathway. Inhibition of IL6 and SOCS3 and facilitation of CNTF could serve as a favorable strategy to enhance insulin action and improve glucose homoeostasis, which are of importance for treating obesity-related disorders for chickens.

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Mayer, M., K. Bhakoo, and M. Noble. "Ciliary neurotrophic factor and leukemia inhibitory factor promote the generation, maturation and survival of oligodendrocytes in vitro." Development 120, no. 1 (January 1, 1994): 143–53. http://dx.doi.org/10.1242/dev.120.1.143.

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We have found that CNTF and LIF are pleiotropic modulators of development in the O-2A lineage. Both molecules enhanced the generation of oligodendrocytes in cultures of dividing O-2A progenitors. CNTF and LIF also promoted oligodendrocyte maturation, as determined by expression of myelin basic protein, and could promote oligodendrocyte survival to an extent comparable with insulin-like growth factor-1 or insulin. In addition, LIF and CNTF both promoted the differentiation of O-2A progenitors into type-2 astrocytes but only when applied in the presence of extracellular matrix (EnMx) derived from cultures of endothelial cells. The ability of CNTF and LIF to enhance differentiation of O-2A progenitors along either of the alternative pathways of oligodendrocyte and astrocyte differentiation suggests that these proteins are able to enhance the process of differentiation per se, while the actual path of differentiation promoted is determined by the presence or absence of additional molecules in the extracellular environment.

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BERSE, Brygida, Ignacio LOPEZ-COVIELLA, and J. Krzysztof BLUSZTAJN. "Activation of TrkA by nerve growth factor upregulates expression of the cholinergic gene locus but attenuates the response to ciliary neurotrophic growth factor." Biochemical Journal 342, no. 2 (August 24, 1999): 301–8. http://dx.doi.org/10.1042/bj3420301.

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Nerve growth factor (NGF) stimulates the expression of the cholinergic gene locus, which encodes choline acetyltransferase (ChAT) and vesicular acetylcholine transporter (VAChT), the proteins necessary for the synthesis and storage of the neurotransmitter acetylcholine (ACh). To determine whether this action of NGF is mediated by the p140TrkA NGF receptor (a member of the Trk tyrosine kinase family) we used a murine basal forebrain cholinergic cell line, SN56, stably transfected with rat trkA cDNA. Treatment of these transfectants with NGF activated mitogen-activated protein kinase and increased cytosolic free calcium concentrations, confirming the reconstitution of TrkA-mediated signalling pathways. The expression of ChAT and VAChT mRNA, as well as ACh content, were coordinately up-regulated by NGF in SN56-trkA transfectants. None of these responses occurred in the parental SN56 cells, which do not express endogenous TrkA, indicating that these actions of NGF required TrkA. We previously reported that ciliary neurotrophic factor (CNTF) upregulates the expression of ChAT and VAChT, as well as ACh production, in SN56 cells. The combined treatment of SN56-trkA cells with CNTF and NGF revealed a complex interaction of these factors in the regulation of cholinergic gene locus expression. At low concentrations of CNTF (< 1 ng/ml), the upregulation of ACh synthesis evoked by these factors was additive. However, at higher concentrations of CNTF (> 1 ng/ml), NGF attenuated the stimulatory effect of CNTF on ChAT and VAChT mRNA and ACh content. This attenuation was not due to interference with early steps of CNTF receptor signalling, as pre-treatment of SN56-trkA cells with NGF did not affect the nuclear translocation of the transcription factor, Stat3, evoked by CNTF.

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Gottschalk, Wolfram A., Hao Jiang, Nicole Tartaglia, Linyin Feng, Alexander Figurov, and Bai Lu. "Signaling Mechanisms Mediating BDNF Modulation of Synaptic Plasticity in the Hippocampus." Learning & Memory 6, no. 3 (May 1, 1999): 243–56. http://dx.doi.org/10.1101/lm.6.3.243.

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Although recent studies indicate that brain-derived neurotrophic factor (BDNF) plays an important role in hippocampal synaptic plasticity, the underlying signaling mechanisms remain largely unknown. Here, we have characterized the signaling events that mediate the BDNF modulation of high-frequency synaptic transmission. Mitogen-associated protein kinase (MAPK), phosphotidylinositol-3 kinase (PI3K), and phospholipase C-γ (PLC-γ) are the three signaling pathways known to mediate neurotrophin signaling in other systems. In neonatal hippocampal slices, application of BDNF rapidly activated MAPK and PI3K but not PLC-γ. BDNF greatly attenuated synaptic fatigue at CA1 synapses induced by a train of high-frequency, tetanic stimulation (HFS). Inhibition of the MAPK and PI3K, but not PLC-γ, prevented the BDNF modulation of high-frequency synaptic transmission. Neurotrophin-3 (NT-3), a close relative of BDNF, did not activate MAPK or PI3K and had no effect on synaptic fatigue in the neonatal hippocampus. Neither forskolin, which activated MAPK but not PI3 kinase, nor ciliary neurotrophic factor (CNTF), which activated PI3K but not MAPK, affected HFS-induced synaptic fatigue. Treatment of the slices with forskolin together with CNTF still had no effect on synaptic fatigue. Thus, although the activation of MAPK and PI3K is required, the two together are not sufficient to mediate the BDNF effect. Inhibition of new protein synthesis by anisomycin or cycloheximide did not prevent the BDNF effect. These data suggest that BDNF modulation of high-frequency transmission is independent of protein synthesis but requires MAPK and PI3K and yet another signaling pathway to act together in the hippocampus.

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Liao, Chunxiao, Biqi Wang, Wenjing Gao, Weihua Cao, Jun Lv, Canqing Yu, Tao Huang, et al. "Associations of Obesity Measurements with Serum Metabolomic Profile: A Chinese Twin Study." Twin Research and Human Genetics 24, no. 1 (February 2021): 14–21. http://dx.doi.org/10.1017/thg.2021.3.

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AbstractThe objective of this study was to investigate how different obesity measures link to circulating metabolites, and whether the connections are due to genetic or environmental factors. A cross-sectional analysis was performed on follow-up survey data at the Chinese National Twin Registry (CNTR), which was conducted in four areas of China (Shandong, Jiangsu, Zhejiang and Sichuan) in 2013. The survey collected detailed questionnaire information and conducted physical examinations, fasting blood sampling and untargeted metabolomic measurements among 439 adult twins. Linear regression models and bioinformatics analysis were used to examine the relation of obesity measures, including body mass index (BMI), waist circumference (WC) and waist-to-hip ratio (WHR) with serum metabolite levels and related pathways. A co-twin control study was additionally conducted among 15 obesity-discordant monozygotic (MZ) pairs (intrapair BMI difference >3 kg/m2) to examine any differences in metabolites controlling for genetic factors. Eleven metabolites were associated with BMI, WC and WHR after controlling for genetic and shared environmental factors. Pathway analysis identified pathways such as phenylalanine metabolism, purine metabolism, valine, leucine and isoleucine biosynthesis that were associated with obesity. A wide range of unfavorable alterations in the serum metabolome was associated with obesity. Obesity-discordant twin analysis suggests that these associations are independent of genetic liability.

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Cagnon, Laurène, and Olivier Braissant. "CNTF protects oligodendrocytes from ammonia toxicity: Intracellular signaling pathways involved." Neurobiology of Disease 33, no. 1 (January 2009): 133–42. http://dx.doi.org/10.1016/j.nbd.2008.09.025.

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Brandt, Nina, Hayley M. O'Neill, Maximilian Kleinert, Peter Schjerling, Erik Vernet, Gregory R. Steinberg, Erik A. Richter, and Sebastian B. Jørgensen. "Leukemia inhibitory factor increases glucose uptake in mouse skeletal muscle." American Journal of Physiology-Endocrinology and Metabolism 309, no. 2 (July 15, 2015): E142—E153. http://dx.doi.org/10.1152/ajpendo.00313.2014.

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Members of the IL-6 family, IL-6 and ciliary neurotrophic factor (CNTF), have been shown to increase glucose uptake and fatty acid oxidation in skeletal muscle. However, the metabolic effects of another family member, leukemia inhibitory factor (LIF), are not well characterized. Effects of LIF on skeletal muscle glucose uptake and palmitate oxidation and signaling were investigated in ex vivo incubated mouse soleus and EDL muscles from muscle-specific AMPKα2 kinase-dead, muscle-specific SOCS3 knockout, and lean and high-fat-fed mice. Inhibitors were used to investigate involvement of specific signaling pathways. LIF increased muscle glucose uptake in dose (50-5,000 pM/l) and time-dependent manners with maximal effects at the 30-min time point. LIF increased Akt Ser473 phosphorylation (P) in soleus and EDL, whereas AMPK Thr172 P was unaffected. Incubation with parthenolide abolished LIF-induced glucose uptake and STAT3 Tyr705 P, whereas incubation with LY-294002 and wortmannin suppressed both basal and LIF-induced glucose uptake and Akt Ser473 P, indicating that JAK and PI 3-kinase signaling is required for LIF-stimulated glucose uptake. Incubation with rapamycin and AZD8055 indicated that mammalian target of rapamycin complex (mTORC)2, but not mTORC1, also is required for LIF-stimulated glucose uptake. In contrast to CNTF, LIF stimulation did not alter palmitate oxidation. LIF-stimulated glucose uptake was maintained in EDL from obese insulin-resistant mice, whereas soleus developed LIF resistance. Lack of SOCS3 and AMPKα2 did not affect LIF-stimulated glucose uptake. In conclusion, LIF acutely increased muscle glucose uptake by a mechanism potentially involving the PI 3-kinase/mTORC2/Akt pathway and is not impaired in EDL muscle from obese insulin-resistant mice.

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Schweizer, Ulrich, Jennifer Gunnersen, Christoph Karch, Stefan Wiese, Bettina Holtmann, Kiyoshi Takeda, Shizuo Akira, and Michael Sendtner. "Conditional gene ablation of Stat3 reveals differential signaling requirements for survival of motoneurons during development and after nerve injury in the adult." Journal of Cell Biology 156, no. 2 (January 21, 2002): 287–98. http://dx.doi.org/10.1083/jcb.200107009.

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Members of the ciliary neurotrophic factor (CNTF)/leukemia inhibitory factor (LIF)/cardiotrophin gene family are potent survival factors for embryonic and lesioned motoneurons. These factors act via receptor complexes involving gp130 and LIFR-β and ligand binding leads to activation of various signaling pathways, including phosphorylation of Stat3. The role of Stat3 in neuronal survival was investigated in mice by Cre-mediated gene ablation in motoneurons. Cre is expressed under the neurofilament light chain (NF-L) promoter, starting around E12 when these neurons become dependent on neurotrophic support. Loss of motoneurons during the embryonic period of naturally occurring cell death is not enhanced in NF-L–Cre; Stat3flox/KO mice although motoneurons isolated from these mice need higher concentrations of CNTF for maximal survival in culture. In contrast, motoneuron survival is significantly reduced after facial nerve lesion in the adult. These neurons, however, can be rescued by the addition of neurotrophic factors, including CNTF. Stat3 is essential for upregulation of Reg-2 and Bcl-xl expression in lesioned motoneurons. Our data show that Stat3 activation plays an essential role for motoneuron survival after nerve lesion in postnatal life but not during embryonic development, indicating that signaling requirements for motoneuron survival change during maturation.

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Azadi, Seifollah, Leif E. Johnson, François Paquet-Durand, Maria-Thereza R. Perez, Yiqin Zhang, Per A. R. Ekström, and Theo van Veen. "CNTF+BDNF treatment and neuroprotective pathways in the rd1 mouse retina." Brain Research 1129 (January 2007): 116–29. http://dx.doi.org/10.1016/j.brainres.2006.10.031.

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Nazarians-Armavil, Anaies, Jennifer A. Chalmers, Claire B. Lee, Wenqing Ye, and Denise D. Belsham. "Cellular insulin resistance disrupts hypothalamic mHypoA-POMC/GFP neuronal signaling pathways." Journal of Endocrinology 220, no. 1 (October 17, 2013): 13–24. http://dx.doi.org/10.1530/joe-13-0334.

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POMC neurons play a central role in the maintenance of whole-body energy homeostasis. This balance requires proper regulation of POMC neurons by metabolic hormones, such as insulin. However, the heterogeneous cellular population of the intact hypothalamus presents challenges for examining the molecular mechanisms underlying the potent anorexigenic effects of POMC neurons, and there is currently a complete lack of mature POMC neuronal cell models for study. To this end, we have generated novel, immortalized, adult-derived POMC-expressing/α-MSH-secreting cell models, mHypoA-POMC/GFP lines 1–4, representing the fluorescence-activated cell-sorted POMC population from primary POMC-eGFP mouse hypothalamus. The presence of Pomc mRNA in these cell lines was confirmed, and α-MSH was detected via immunofluorescence. α-MSH secretion in the mHypoA-POMC/GFP-1 was found to increase in response to 10 ng/ml ciliary neurotrophic factor (CNTF) or 10 nM insulin as determined by enzyme immunoassay. Further experiments using the mHypoA-POMC/GFP-1 cell line revealed that 10 ng/ml CNTF increases Pomc mRNA at 1 and 2 h after treatment, whereas insulin elicited an increase in Pomc mRNA level and decreases in insulin receptor (Insr (Ir)) mRNA level at 4 h. Furthermore, the activation of IR-mediated downstream second messengers was examined by western blot analysis, following the induction of cellular insulin resistance, which resulted in a loss of insulin-mediated regulation of Pomc and Ir mRNAs. The development of these immortalized neurons will be invaluable for the elucidation of the cellular and molecular mechanisms that underlie POMC neuronal function under normal and perturbed physiological conditions.

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Huang, Tzu-Lun, Yao-Tseng Wen, Yu-Chieh Ho, Jia-Kang Wang, Kuan-Hung Lin, and Rong-Kung Tsai. "Algae Oil Treatment Protects Retinal Ganglion Cells (RGCs) via ERK Signaling Pathway in Experimental Optic Nerve Ischemia." Marine Drugs 18, no. 2 (January 27, 2020): 83. http://dx.doi.org/10.3390/md18020083.

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Background: We investigated the therapeutic effects and related mechanisms of algae oil (ALG) to protect retinal ganglion cells (RGCs) in a rat model of anterior ischemic optic neuropathy (rAION). Methods: Rats were daily gavaged with ALG after rAION induction for seven days. The therapeutic effects of ALG on rAION were evaluated using flash visual evoked potentials (FVEPs), retrograde labeling of RGCs, TUNEL assay of the retina, and ED1 staining of optic nerves (ONs). The levels of inducible nitric oxide synthase (iNOS), IL-1β, TNF-α, Cl-caspase-3, ciliary neurotrophic factor (CNTF), and p-ERK were analyzed by using western blots. Results: Protection of visual function in FVEPs amplitude was noted, with a better preservation of the P1–N2 amplitude in the ALG-treated group (p = 0.032) than in the rAION group. The density of RGCs was 2.4-fold higher in the ALG-treated group compared to that in the rAION group (p < 0.0001). The number of ED1-positive cells in ONs was significantly reduced 4.1-fold in the ALG-treated group compared to those in the rAION group (p = 0.029). The number of apoptotic RGCs was 3.2-fold lower in number in the ALG-treated group (p = 0.001) than that in the rAION group. The ALG treatment inhibited ERK activation to reduce the levels of iNOS, IL-1β, TNF-α, and Cl-caspase-3 and to increase the level of CNTF in the rAION model. Conclusion: The treatment with ALG after rAION induction inhibits ERK activation to provide both anti-inflammatory and antiapoptotic effects in rAION.

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Keasey, Matthew P., Seong Kang, Chiharu Lovins, and Theo Hagg. "Inhibition of a novel specific neuroglial integrin signaling pathway increases STAT3-mediated CNTF expression." Cell Communication and Signaling 11, no. 1 (2013): 35. http://dx.doi.org/10.1186/1478-811x-11-35.

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Li, Ping, Zongwen Wang, Jin Yan, Zhaoshen Li, Chunlei Jiang, Xin Ni, Yongji Yang, Fang Liu, and Changlin Lu. "Neuro-protective effects of CNTF on hippocampal neurons via an unknown signal transduction pathway." Chinese Science Bulletin 51, no. 1 (January 2006): 48–53. http://dx.doi.org/10.1007/s11434-005-0978-z.

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Udovin, Lucas, Cecilia Quarracino, María I. Herrera, Francisco Capani, Matilde Otero-Losada, and Santiago Perez-Lloret. "Role of Astrocytic Dysfunction in the Pathogenesis of Parkinson’s Disease Animal Models from a Molecular Signaling Perspective." Neural Plasticity 2020 (February 7, 2020): 1–10. http://dx.doi.org/10.1155/2020/1859431.

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Despite the fact that astrocytes are the most abundant glial cells, critical for brain function, few studies have dealt with their possible role in neurodegenerative diseases like Parkinson’s disease (PD). This article explores relevant evidence on the involvement of astrocytes in experimental PD neurodegeneration from a molecular signaling perspective. For a long time, astrocytic proliferation was merely considered a byproduct of neuroinflammation, but by the time being, it is clear that astrocytic dysfunction plays a far more important role in PD pathophysiology. Indeed, ongoing experimental evidence suggests the importance of astrocytes and dopaminergic neurons’ cross-linking signaling pathways. The Wnt-1 (wingless-type MMTV integration site family, member 1) pathway regulates several processes including neuron survival, synapse plasticity, and neurogenesis. In PD animal models, Frizzled (Fzd) neuronal receptors’ activation by the Wnt-1 normally released by astrocytes following injuries leads to β-catenin-dependent gene expression, favoring neuron survival and viability. The transient receptor potential vanilloid 1 (TRPV1) capsaicin receptor also participates in experimental PD genesis. Activation of astrocyte TRPV1 receptors by noxious stimuli results in reduced inflammatory response and increased ciliary neurotrophic factor (CNTF) synthesis, which enhances neuronal survival and differentiation. Another major pathway involves IκB kinase (IKK) downregulation by ARL6ip5 (ADP-ribosylation-like factor 6 interacting protein 5, encoded by the cell differentiation-associated, JWA, gene). Typically, IKK releases the proinflammatory NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) molecule from its inhibitor. Therefore, by downregulating NF-κB inhibitor, ARL6ip5 promotes an anti-inflammatory response. The evidence provided by neurotoxin-induced PD animal models guarantees further research on the neuroprotective potential of normalizing astrocyte function in PD.

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Borasio, G. D., A. Markus, A. Wittinghofer, Y. A. Barde, and R. Heumann. "Involvement of ras p21 in neurotrophin-induced response of sensory, but not sympathetic neurons." Journal of Cell Biology 121, no. 3 (May 1, 1993): 665–72. http://dx.doi.org/10.1083/jcb.121.3.665.

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Little is known about the signal transduction mechanisms involved in the response to neurotrophins and other neurotrophic factors in neurons, beyond the activation of the tyrosine kinase activity of the neurotrophin receptors belonging to the trk family. We have previously shown that the introduction of the oncogene product ras p21 into the cytoplasm of chick embryonic neurons can reproduce the survival and neurite-outgrowth promoting effects of the neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), and of ciliary neurotrophic factor (CNTF). To assess the potential signal-transducing role of endogenous ras p21, we introduced function-blocking anti-ras antibodies or their Fab fragments into cultured chick embryonic neurons. The BDNF-induced neurite outgrowth in E12 nodose ganglion neurons was reduced to below control levels, and the NGF-induced survival of E9 dorsal root ganglion (DRG) neurons was inhibited in a specific and dose-dependent fashion. Both effects could be reversed by saturating the epitope-binding sites with biologically inactive ras p21 before microinjection. Surprisingly, ras p21 did not promote the survival of NGF-dependent E12 chick sympathetic neurons, and the NGF-induced survival in these cells was not inhibited by the Fab-fragments. The survival effect of CNTF on ras-responsive ciliary neurons could not be blocked by anti-ras Fab fragments. These results indicate an involvement of ras p21 in the signal transduction of neurotrophic factors in sensory, but not sympathetic or ciliary neurons, pointing to the existence of different signaling pathways not only in CNTF-responsive, but also in neurotrophin-responsive neuronal populations.

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Sheng, Z., D. Pennica, W. I. Wood, and K. R. Chien. "Cardiotrophin-1 displays early expression in the murine heart tube and promotes cardiac myocyte survival." Development 122, no. 2 (February 1, 1996): 419–28. http://dx.doi.org/10.1242/dev.122.2.419.

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We have recently isolated a novel cytokine, cardiotrophin-1 (CT-1), from an in vitro embryonic stem cell system of cardiogenesis that can activate embryonic markers in neonatal rat cardiac myocytes. CT-1 is a new member of the interleukin 6 (IL-6)/leukemia inhibitory factor (LIF) cytokines, which activate downstream signals via gp130-dependent pathways. To define the developmental pattern of expression of CT-1 during murine embryogenesis, we have developed antibodies directed against a CT-1 fusion protein. As assessed by immunolocalization, CT-1 is predominantly expressed in the early mouse embryonic heart tube (E8.5-10.5). In the heart, CT-1 is primarily expressed in myocardial cells, and not in endocardial cushion or outflow tract tissues. After E12.5, CT-1 expression is found in other tissues, including skeletal, liver and dorsal root ganglia. Given the effects of a related family member (ciliary neurotrophic factor, CNTF) on neuronal cell survival, we studied the ability of CT-1 to promote cardiac myocyte survival and proliferation in vitro. Both CT-1 and LIF, which share the same receptors, dramatically promote neonatal cardiac myocyte survival, while IL-6 and CNTF are without effect. A cell proliferation assay documents that CT-1 provokes an approximate 2-fold increase in embryonic cardiac myocyte proliferation. Thus, CT-1 may play an autocrine role during cardiac chamber growth and morphogenesis by promoting the survival and proliferation of immature myocytes, most likely via gp130-dependent signaling pathways.

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Smedowski, Adrian, Marita Pietrucha-Dutczak, Ruchi Maniar, Michael Ajeleti, Iwona Matuszek, and Joanna Lewin-Kowalik. "FluoroGold-Labeled Organotypic Retinal Explant Culture for Neurotoxicity Screening Studies." Oxidative Medicine and Cellular Longevity 2018 (2018): 1–11. http://dx.doi.org/10.1155/2018/2487473.

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Preclinical toxicity screening of the new retinal compounds is an absolute requirement in the pathway of further drug development. Since retinal neuron cultivation and in vivo studies are relatively expensive and time consuming, we aimed to create a fast and reproducible ex vivo system for retinal toxicity screening. For this purpose, we used rat retinal explant culture that was retrogradely labeled with the FluoroGold before the isolation. Explants were exposed to a toxic concentration of gentamicin and ciliary neurotrophic factor (CNTF), a known neuroprotective agent. The measured outcomes showed the cell density in retinal ganglion cell layer (GCL) and the activity of lactate dehydrogenase (LDH) in the culture medium. Gentamicin-induced oxidative stress resulted in retinal cell damage and rapid LDH release to the culture medium (p<0.05). Additional CNTF supplementation minimized the cell damage, and the increase of LDH release was insignificant when compared to LDH levels before gentamicin insult (p>0.05). As well as this, the LDH activity was directly correlated with the cell count in GCL (R=−0.84, p<0.00001), making a sensitive marker of retinal neuron damage. The FLOREC protocol could be considered as a fast, reproducible, and sensitive method to detect neurotoxicity in the screening studies of the retinal drugs.

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Dell'Albani, P., M. A. Kahn, R. Cole, D. F. Condorelli, A. M. Giuffrida-Stella, and J. de Vellis. "Oligodendroglial survival factors, PDGF-AA and CNTF, activate similar JAK/STAT signaling pathways." Journal of Neuroscience Research 54, no. 2 (October 15, 1998): 191–205. http://dx.doi.org/10.1002/(sici)1097-4547(19981015)54:2<191::aid-jnr7>3.0.co;2-9.

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Saygili, Erol, Maimouna Pekassa, Esra Saygili, Gediminas Rackauskas, Dorothee Hommes, Fawad Noor-Ebad, Christopher Gemein, et al. "Mechanical stretch of sympathetic neurons induces VEGF expression via a NGF and CNTF signaling pathway." Biochemical and Biophysical Research Communications 410, no. 1 (June 2011): 62–67. http://dx.doi.org/10.1016/j.bbrc.2011.05.105.

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Nishimune, Hiroshi, Sophie Vasseur, Stefan Wiese, Marie-Christine Birling, Bettina Holtmann, Michael Sendtner, Juan L. Iovanna, and Christopher E. Henderson. "Reg-2 is a motoneuron neurotrophic factor and a signalling intermediate in the CNTF survival pathway." Nature Cell Biology 2, no. 12 (November 14, 2000): 906–14. http://dx.doi.org/10.1038/35046558.

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Zein, Wadih M., Brett G. Jeffrey, Henry E. Wiley, Amy E. Turriff, Santa J. Tumminia, Weng Tao, Ronald A. Bush, et al. "CNGB3-Achromatopsia Clinical Trial With CNTF: Diminished Rod Pathway Responses With No Evidence of Improvement in Cone Function." Investigative Opthalmology & Visual Science 55, no. 10 (October 8, 2014): 6301. http://dx.doi.org/10.1167/iovs.14-14860.

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Langlo, C., A. Dubis, M. Michaelides, and J. Carroll. "CNGB3-Achromatopsia Clinical Trial With CNTF: Diminished Rod Pathway Responses With No Evidence of Improvement in Cone Function." Investigative Ophthalmology & Visual Science 56, no. 3 (March 3, 2015): 1505. http://dx.doi.org/10.1167/iovs.14-15897.

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Cui, Wei, Chen-Xi Liu, Jie Wang, Yu-Chao Zhang, Qi Shen, Zhen-Hua Feng, Jing Wu, and Jian-Xin Li. "An oleanolic acid derivative reduces denervation-induced muscle atrophy via activation of CNTF-mediated JAK2/STAT3 signaling pathway." European Journal of Pharmacology 861 (October 2019): 172612. http://dx.doi.org/10.1016/j.ejphar.2019.172612.

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Rezende, Luiz F., André S. Vieira, Alessandro Negro, Francesco Langone, and Antonio C. Boschero. "Ciliary neurotrophic factor (CNTF) signals through STAT3–SOCS3 pathway and protects rat pancreatic islets from cytokine-induced apoptosis." Cytokine 46, no. 1 (April 2009): 65–71. http://dx.doi.org/10.1016/j.cyto.2008.12.014.

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Santos, G. J., S. M. Ferreira, C. A. M. Oliveira, A. C. Boschero, and L. F. Rezende. "P043 Ciliary neurotrophic factor (CNTF) downregulates CAMKII-AMPK pathway protecting MIN6 cells against apoptosis induced by IL-1beta." Cytokine 59, no. 3 (September 2012): 532. http://dx.doi.org/10.1016/j.cyto.2012.06.127.

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Santos, Gustavo J., Camila A. M. Oliveira, Antonio C. Boschero, and Luiz F. Rezende. "CNTF protects MIN6 cells against apoptosis induced by Alloxan and IL-1β through downregulation of the AMPK pathway." Cellular Signalling 23, no. 10 (October 2011): 1669–76. http://dx.doi.org/10.1016/j.cellsig.2011.06.001.

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Hiatt, Kelly, Davina Lewis, Mathew Shew, Khadijeh Bijangi-Vishehsaraei, and Stacey Halum. "Ciliary neurotrophic factor (CNTF) promotes skeletal muscle progenitor cell (MPC) viability via the phosphatidylinositol 3-kinase-Akt pathway." Journal of Tissue Engineering and Regenerative Medicine 8, no. 12 (November 13, 2012): 963–68. http://dx.doi.org/10.1002/term.1598.

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Young, Win-Jing, Yi-Fen Lee, Susan M. Smith, and Chawnshang Chang. "A Bidirectional Regulation between the TR2/TR4 Orphan Receptors (TR2/TR4) and the Ciliary Neurotrophic Factor (CNTF) Signaling Pathway." Journal of Biological Chemistry 273, no. 33 (August 14, 1998): 20877–85. http://dx.doi.org/10.1074/jbc.273.33.20877.

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Askvig, Jason M., and John A. Watt. "The MAPK and PI3K pathways mediate CNTF-induced neuronal survival and process outgrowth in hypothalamic organotypic cultures." Journal of Cell Communication and Signaling 9, no. 3 (February 20, 2015): 217–31. http://dx.doi.org/10.1007/s12079-015-0268-8.

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Ji, Jian-Zhong, Wassim Elyaman, Henry K. Yip, Vincent W. H. Lee, Leung-Wah Yick, Jacques Hugon, and Kwok-Fai So. "CNTF promotes survival of retinal ganglion cells after induction of ocular hypertension in rats: the possible involvement of STAT3 pathway." European Journal of Neuroscience 19, no. 2 (January 2004): 265–72. http://dx.doi.org/10.1111/j.0953-816x.2003.03107.x.

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Zeng, Xiaoning, Shu Zhang, Luwei Xu, Haiwei Yang, and Shaoheng He. "Activation of Protease-Activated Receptor 2-Mediated Signaling by Mast Cell Tryptase Modulates Cytokine Production in Primary Cultured Astrocytes." Mediators of Inflammation 2013 (2013): 1–10. http://dx.doi.org/10.1155/2013/140812.

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Abstract:

Protease-activated receptor 2 (PAR-2), which is abundantly expressed in astrocytes, is known to play major roles in brain inflammation. However, the influence of the natural agonist of PAR-2, tryptase, on proinflammatory mediator releasedfrom astrocytes remains uninvestigated. In the present study, we found that tryptase at lower concentrations modestly reduced intracellular ROS production but significantly increased IL-6 and TNF-αsecretion at higher concentrations without affecting astrocytic viability and proliferation. The actions of tryptase were alleviated by specific PAR-2 antagonist FSLLRY-NH2 (FS), indicating that the actions of tryptase were via PAR-2. PI3K/AKT inhibitor LY294002 reversed the effect of tryptase on IL-6 production, whereas inhibitors specific for p38, JNK, and ERK1/2 abolished the effect of tryptase on TNF-αproduction, suggesting that different signaling pathways are involved. Moreover, tryptase-induced activation of MAPKs and AKT was eliminated by FS, implicating that PAR-2 is responsible for transmitting tryptase biosignals to MAPKs and AKT. Tryptase provoked also expression of TGF-βand CNTF in astrocytes. The present findings suggest for the first time that tryptase can regulate the release of cytokines from astrocytes via PAR-2-MAPKs or PAR-2-PI3K/AKT signaling pathways, which reveals PAR-2 as a new target actively participating in the regulation of astrocytic functions.

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Journal articles on the topic 'CNTFR pathway'

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