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Rodolfo G Goya - One of the best experts on this subject based on the ideXlab platform.
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PHYSIOLOGY, MOLECULAR BIOLOGY AND THERAPEUTIC POTENTIAL OF THE THYMIC PEPTIDE Thymulin
2020Co-Authors: Joaquín Pardo, Oscar A Brown, Paula C Reggiani, Jose I Schwerdt, Maria F. Zappa, Andrea Pereyra, Rodolfo G GoyaAbstract:Thymulin is a thymic hormone exclusively produced by the thymic epithelial cells. After its discovery and initial characterization in the '70s, it was demonstrated that Thymulin production and secretion is strongly influenced by the neuroendocrine system. Conversely, a growing core of information, to be reviewed here, points to Thymulin as a hypophysiotropic peptide. Additionally, the substantial body of evidence pointing to Thymulin and some synthetic analogs as anti-inflammatory and analgesic molecules in the brain and other organs will be also reviewed. In recent years, a synthetic DNA sequence coding for a biologically active analog of Thymulin, metFTS, was constructed and cloned in different adenoviral vectors. A number of recent studies suggest that Thymulin gene therapy may be a suitable therapeutic strategy to prevent some of the endocrine and reproductive alterations that typically appear in congenitally athymic (nude) mice, used as a suitable model of neuroendocrine and reproductive aging. Summing up, the present article briefly reviews the literature on the physiology of the Thymulin-neuroendocrine axis and the anti-inflammatory properties of the molecule and its analogs. The availability of novel biotechnological tools should boost basic studies on the molecular biology of Thymulin and should also allow an assessment of the potential of gene therapy to restore circulating Thymulin levels in thymodeficient animal models and eventually, in humans
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a new adenovector system for implementing Thymulin gene therapy for inflammatory disorders
Molecular Immunology, 2017Co-Authors: Maria F Zappavillar, Rodolfo G Goya, Mireille Dardenne, Joaquín Pardo, Micaela Lopezleon, Mariana Costa, Rosana Crespo, Paula C ReggianiAbstract:Abstract Thymulin is a thymic peptide possessing anti-inflammatory effects. In order to manipulate Thymulin expression in gene therapy studies, we built a bidirectional regulatable two-vector Tet-Off system and the corresponding control system. The experimental two-vector system, ETV, consists of a recombinant adenovector (RAd) harboring an expression cassette centered on a Tet-Off bidirectional promoter flanked by a synthetic gene for Thymulin and the gene for humanized Green Fluorescent Protein (hGFP). The second adenovector of this system, RAd-tTA, constitutively expresses the regulatory protein tTA. When cells are co-transduced by the two adenovector components, tTA activates the bidirectional promoter and both transgenes are expressed. In the presence of the antibiotic doxycycline (DOX) transgene expression is deactivated. The control two-vector system, termed CTV, is similar to ETV but only expresses hGFP. In CHO-K1, BHK, and C2C12 cells, ETV and CTV induced a dose-dependent hGFP expression. In CHO-K1 cells, transgene expression was almost completely inhibited by DOX (1 mg/ml). After intracerebroventricular injection of ETV in rats, Thymulin levels increased significantly in the cerebrospinal fluid and there was high hGFP expression in the ependymal cell layer. When injected intramuscularly the ETV system induced a progressive increase in serum Thymulin levels, which were inhibited when DOX was added to the drinking water. We conclude that our regulatable two-adenovector system is an effective molecular tool for implementing short and long-term anti-inflammatory Thymulin gene therapy in animal models of acute or chronic inflammation.
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physiology and therapeutic potential of the thymic peptide Thymulin
Current Pharmaceutical Design, 2014Co-Authors: Paula C Reggiani, Mireille Dardenne, Gloria M Cónsole, Jose I Schwerdt, Eduardo A Roggero, Rodolfo G GoyaAbstract:Thymulin is a thymic hormone exclusively produced by the epithelial cells of the thymus. After its discovery and initial characterization in the ‘70s, it was demonstrated that the production and secretion of Thymulin are strongly influenced by the neuro-endocrine system. Conversely, a growing body of evidence, to be reviewed here, suggests that Thymulin is a hypophysiotropic peptide. Additionally, a substantial body of information pointing to Thymulin and a synthetic analog as anti-inflammatory and analgesic peptides in the central nervous system brain and other organs will be also reviewed. In recent years, a synthetic DNA sequence encoding a biologically active analog of Thymulin, metFTS, was constructed and cloned in a number of adenovectors. These include bidirectional regulatable Tet-Off vector systems that simultaneously express metFTS and green fluorescent protein and that can be down-regulated reversibly by the addition of the antibiotic doxycycline. A number of recent studies indicate that gene therapy for Thymulin may be an effective therapeutic strategy to prevent some of the hormonal and reproductive abnormalities that typically appear in congenitally athymic (nude) mice, used as a suitable model of neuroendocrine and reproductive aging. Summing up, this article briefly reviews the publications on the physiology of the Thymulin-neuroendocrine axis and the anti-inflammatory properties of the molecule and its analog. The availability of novel biotechnological tools should boost basic studies on the molecular biology of Thymulin and should also allow an assessment of the potential of gene therapy to restore circulating Thymulin levels in thymodeficient animal models and eventually, in humans.
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dna nanoparticle mediated Thymulin gene therapy prevents airway remodeling in experimental allergic asthma
Journal of Controlled Release, 2014Co-Authors: Adriana L Silva, Sabrina V Martini, Soraia C Abreu, Cynthia S Samary, Bruno L Diaz, Sandra Fernezlian, Vera Luiza Capelozzi, Nicholas J Boylan, Rodolfo G GoyaAbstract:Abstract Thymulin has been shown to present anti-inflammatory and anti-fibrotic properties in experimental lung diseases. We hypothesized that a biologically active Thymulin analog gene, methionine serum thymus factor, delivered by highly compacted DNA nanoparticles may prevent lung inflammation and remodeling in a mouse model of allergic asthma. The DNA nanoparticles are composed of a single molecule of plasmid DNA compacted with block copolymers of poly-L-lysine and polyethylene glycol (CK 30 PEG), which have been found safe in a human phase I/II clinical trial. Thymulin plasmids were detected in the lungs of ovalbumin-challenged asthmatic mice up to 27 days after administration of DNA nanoparticles carrying Thymulin plasmids. A single dose of DNA nanoparticles carrying Thymulin plasmids prevented lung inflammation, collagen deposition and smooth muscle hypertrophy in the lungs of a murine model of ovalbumin-challenged allergic asthma, leading to improved lung mechanics. In the present model of chronic allergic asthma, highly compacted DNA nanoparticles using Thymulin analog gene modulated the inflammatory and remodeling processes improving lung mechanics.
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role of Thymulin on the somatotropic axis in vivo
Life Sciences, 2012Co-Authors: Paula C Reggiani, Rodolfo G Goya, Eliana Martines, Gisela Camihort, Brenda Poch, G M ConsoleAbstract:Abstract Aims There is clear evidence for the existence of a bi-directional thymus–somatotropic axis and several studies suggest that the thymic peptide Thymulin may be involved in this communication. We undertook to assess the impact of serum Thymulin immunoneutralization in C57BL/6 mice and that of neonatal Thymulin gene therapy (NTGT) in nude mice on body weight (BW) gain and on the histomorphometric profile of the somatotrope population. Main methods Immunoneutralization of Thymulin was done from postnatal day 1 to 35 by i.p. injections of rabbit anti-Thymulin serum (α-FTS) and normal rabbit serum (NRS) in controls. NTGT was implemented in nudes using an adenoviral vector expressing a synthetic gene for Thymulin (RAd-FTS). On postnatal day 1, heterozygous (nu/+) and homozygous (nu/nu) pups received a single bilateral i.m. injection either RAd-FTS or RAd-GFP (a control vector expressing green fluorescent protein). BW gain was recorded and at the end of the study the pituitaries were immunostained for growth hormone (GH). Serum GH and Thymulin were determined by radioimmunoassay and bioassay, respectively. Key findings Thymulin immunoneutralization induced a significant decrease in BW gain, serum GH and somatotrope cell density as well as an increase in somatotrope cell size. NTGT markedly increased BW gain, serum Thymulin (P Significance Our results suggest that Thymulin plays a relevant physiological role on the thymus–somatotropic axis in mice.
Mireille Dardenne - One of the best experts on this subject based on the ideXlab platform.
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Comparison of Thymulin Activity with Other Measures of Marginal Zinc Deficiency
Biological Trace Element Research, 2020Co-Authors: Robert A. Disilvestro, Mireille Dardenne, Elizabeth JosephAbstract:Activity of the immunoregulatory peptide Thymulin reflects differences in zinc status. This study compared Thymulin activity with four other zinc status measures in rats fed zinc at either 5 or 25 ppm. Rats fed the lower zinc showed the following results compared with rats with adequate zinc intake: serum Thymulin activity 61% lower, serum zinc 31% lower, serum extracellular superoxide dismutase 18% lower, serum 5′-nucleotidase activity 26% lower, and liver metallothionein 28% lower. Thus, Thymulin activities showed more sensitivity to restricted zinc intake than did four other parameters.
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a new adenovector system for implementing Thymulin gene therapy for inflammatory disorders
Molecular Immunology, 2017Co-Authors: Maria F Zappavillar, Rodolfo G Goya, Mireille Dardenne, Joaquín Pardo, Micaela Lopezleon, Mariana Costa, Rosana Crespo, Paula C ReggianiAbstract:Abstract Thymulin is a thymic peptide possessing anti-inflammatory effects. In order to manipulate Thymulin expression in gene therapy studies, we built a bidirectional regulatable two-vector Tet-Off system and the corresponding control system. The experimental two-vector system, ETV, consists of a recombinant adenovector (RAd) harboring an expression cassette centered on a Tet-Off bidirectional promoter flanked by a synthetic gene for Thymulin and the gene for humanized Green Fluorescent Protein (hGFP). The second adenovector of this system, RAd-tTA, constitutively expresses the regulatory protein tTA. When cells are co-transduced by the two adenovector components, tTA activates the bidirectional promoter and both transgenes are expressed. In the presence of the antibiotic doxycycline (DOX) transgene expression is deactivated. The control two-vector system, termed CTV, is similar to ETV but only expresses hGFP. In CHO-K1, BHK, and C2C12 cells, ETV and CTV induced a dose-dependent hGFP expression. In CHO-K1 cells, transgene expression was almost completely inhibited by DOX (1 mg/ml). After intracerebroventricular injection of ETV in rats, Thymulin levels increased significantly in the cerebrospinal fluid and there was high hGFP expression in the ependymal cell layer. When injected intramuscularly the ETV system induced a progressive increase in serum Thymulin levels, which were inhibited when DOX was added to the drinking water. We conclude that our regulatable two-adenovector system is an effective molecular tool for implementing short and long-term anti-inflammatory Thymulin gene therapy in animal models of acute or chronic inflammation.
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physiology and therapeutic potential of the thymic peptide Thymulin
Current Pharmaceutical Design, 2014Co-Authors: Paula C Reggiani, Mireille Dardenne, Gloria M Cónsole, Jose I Schwerdt, Eduardo A Roggero, Rodolfo G GoyaAbstract:Thymulin is a thymic hormone exclusively produced by the epithelial cells of the thymus. After its discovery and initial characterization in the ‘70s, it was demonstrated that the production and secretion of Thymulin are strongly influenced by the neuro-endocrine system. Conversely, a growing body of evidence, to be reviewed here, suggests that Thymulin is a hypophysiotropic peptide. Additionally, a substantial body of information pointing to Thymulin and a synthetic analog as anti-inflammatory and analgesic peptides in the central nervous system brain and other organs will be also reviewed. In recent years, a synthetic DNA sequence encoding a biologically active analog of Thymulin, metFTS, was constructed and cloned in a number of adenovectors. These include bidirectional regulatable Tet-Off vector systems that simultaneously express metFTS and green fluorescent protein and that can be down-regulated reversibly by the addition of the antibiotic doxycycline. A number of recent studies indicate that gene therapy for Thymulin may be an effective therapeutic strategy to prevent some of the hormonal and reproductive abnormalities that typically appear in congenitally athymic (nude) mice, used as a suitable model of neuroendocrine and reproductive aging. Summing up, this article briefly reviews the publications on the physiology of the Thymulin-neuroendocrine axis and the anti-inflammatory properties of the molecule and its analog. The availability of novel biotechnological tools should boost basic studies on the molecular biology of Thymulin and should also allow an assessment of the potential of gene therapy to restore circulating Thymulin levels in thymodeficient animal models and eventually, in humans.
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neonatal Thymulin gene therapy prevents ovarian dysgenesis and attenuates reproductive derangements in nude female mice
Endocrinology, 2012Co-Authors: Paula C Reggiani, Mireille Dardenne, Claudio Gustavo Barbeito, Gloria M Cónsole, Gustavo Oscar Zuccolilli, Alicia M Flamini, Rodolfo G GoyaAbstract:Congenitally athymic (nude) female mice show severe ovarian dysgenesis after puberty, which seems to be consequential to a number of neuroendocrine derangements described in these mutants. Thus, considerable evidence suggests that Thymulin, a thymic peptide, may be involved in thymus-pituitary communication. In order to clarify the relevance of Thymulin for the maturation of the female reproductive system, we assessed at hypothalamic, pituitary, ovarian, and uterine level the preventive action of neonatal Thymulin gene therapy (NTGT) on the changes that typically occur after puberty in congenitally athymic female mice. We injected (im) an adenoviral vector harboring a synthetic DNA sequence encoding a biologically active analog of Thymulin, methionine-serum thymic factor, in newborn nude mice (which are Thymulin deficient) and killed the animals at 70–71 d of age. NTGT in the athymic mice restored the serum Thymulin levels. Morphometric analysis revealed that athymic nudes have reduced numbers of brain Gn...
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Thymulin based gene therapy and pituitary function in animal models of aging
Neuroimmunomodulation, 2011Co-Authors: Paula C Reggiani, Mireille Dardenne, Brenda Poch, Gloria M Cónsole, Omar J Rimoldi, Jose I Schwerdt, Victoria Tungler, Margarita M Garciabravo, Rodolfo G GoyaAbstract:Thymulin is a thymic hormone exclusively produced by the thymic epithelial cells. After its discovery and initial characterization in the 1970s, it was demonstrated that Thymulin production and secretion is strongly influenced by the neuroendocrine system. Conversely, a growing core of information, to be reviewed here, points to Thymulin as a hypophysiotropic peptide. Additionally, Thymulin was shown to possess anti-inflammatory and analgesic properties in the brain. In recent years, a synthetic DNA sequence coding for a biologically active analog of Thymulin, metFTS, was constructed and cloned in different adenoviral vectors. These include bidirectional regulatable Tet-Off vector systems that simultaneously express metFTS and green fluorescent protein and that can be downregulated reversibly by the addition of the antibiotic doxycycline. A number of recent studies suggest that Thymulin gene therapy may be a suitable therapeutic strategy to prevent some of the endocrine and reproductive alterations that typically appear in congenitally athymic (nude) mice, taken as a suitable model of neuroendocrine and reproductive aging. The present article briefly reviews the literature on the physiology of the Thymulin-pituitary axis as well as on the new molecular tools available to exploit the therapeutic potential of Thymulin.
Paula C Reggiani - One of the best experts on this subject based on the ideXlab platform.
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PHYSIOLOGY, MOLECULAR BIOLOGY AND THERAPEUTIC POTENTIAL OF THE THYMIC PEPTIDE Thymulin
2020Co-Authors: Joaquín Pardo, Oscar A Brown, Paula C Reggiani, Jose I Schwerdt, Maria F. Zappa, Andrea Pereyra, Rodolfo G GoyaAbstract:Thymulin is a thymic hormone exclusively produced by the thymic epithelial cells. After its discovery and initial characterization in the '70s, it was demonstrated that Thymulin production and secretion is strongly influenced by the neuroendocrine system. Conversely, a growing core of information, to be reviewed here, points to Thymulin as a hypophysiotropic peptide. Additionally, the substantial body of evidence pointing to Thymulin and some synthetic analogs as anti-inflammatory and analgesic molecules in the brain and other organs will be also reviewed. In recent years, a synthetic DNA sequence coding for a biologically active analog of Thymulin, metFTS, was constructed and cloned in different adenoviral vectors. A number of recent studies suggest that Thymulin gene therapy may be a suitable therapeutic strategy to prevent some of the endocrine and reproductive alterations that typically appear in congenitally athymic (nude) mice, used as a suitable model of neuroendocrine and reproductive aging. Summing up, the present article briefly reviews the literature on the physiology of the Thymulin-neuroendocrine axis and the anti-inflammatory properties of the molecule and its analogs. The availability of novel biotechnological tools should boost basic studies on the molecular biology of Thymulin and should also allow an assessment of the potential of gene therapy to restore circulating Thymulin levels in thymodeficient animal models and eventually, in humans
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a new adenovector system for implementing Thymulin gene therapy for inflammatory disorders
Molecular Immunology, 2017Co-Authors: Maria F Zappavillar, Rodolfo G Goya, Mireille Dardenne, Joaquín Pardo, Micaela Lopezleon, Mariana Costa, Rosana Crespo, Paula C ReggianiAbstract:Abstract Thymulin is a thymic peptide possessing anti-inflammatory effects. In order to manipulate Thymulin expression in gene therapy studies, we built a bidirectional regulatable two-vector Tet-Off system and the corresponding control system. The experimental two-vector system, ETV, consists of a recombinant adenovector (RAd) harboring an expression cassette centered on a Tet-Off bidirectional promoter flanked by a synthetic gene for Thymulin and the gene for humanized Green Fluorescent Protein (hGFP). The second adenovector of this system, RAd-tTA, constitutively expresses the regulatory protein tTA. When cells are co-transduced by the two adenovector components, tTA activates the bidirectional promoter and both transgenes are expressed. In the presence of the antibiotic doxycycline (DOX) transgene expression is deactivated. The control two-vector system, termed CTV, is similar to ETV but only expresses hGFP. In CHO-K1, BHK, and C2C12 cells, ETV and CTV induced a dose-dependent hGFP expression. In CHO-K1 cells, transgene expression was almost completely inhibited by DOX (1 mg/ml). After intracerebroventricular injection of ETV in rats, Thymulin levels increased significantly in the cerebrospinal fluid and there was high hGFP expression in the ependymal cell layer. When injected intramuscularly the ETV system induced a progressive increase in serum Thymulin levels, which were inhibited when DOX was added to the drinking water. We conclude that our regulatable two-adenovector system is an effective molecular tool for implementing short and long-term anti-inflammatory Thymulin gene therapy in animal models of acute or chronic inflammation.
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physiology and therapeutic potential of the thymic peptide Thymulin
Current Pharmaceutical Design, 2014Co-Authors: Paula C Reggiani, Mireille Dardenne, Gloria M Cónsole, Jose I Schwerdt, Eduardo A Roggero, Rodolfo G GoyaAbstract:Thymulin is a thymic hormone exclusively produced by the epithelial cells of the thymus. After its discovery and initial characterization in the ‘70s, it was demonstrated that the production and secretion of Thymulin are strongly influenced by the neuro-endocrine system. Conversely, a growing body of evidence, to be reviewed here, suggests that Thymulin is a hypophysiotropic peptide. Additionally, a substantial body of information pointing to Thymulin and a synthetic analog as anti-inflammatory and analgesic peptides in the central nervous system brain and other organs will be also reviewed. In recent years, a synthetic DNA sequence encoding a biologically active analog of Thymulin, metFTS, was constructed and cloned in a number of adenovectors. These include bidirectional regulatable Tet-Off vector systems that simultaneously express metFTS and green fluorescent protein and that can be down-regulated reversibly by the addition of the antibiotic doxycycline. A number of recent studies indicate that gene therapy for Thymulin may be an effective therapeutic strategy to prevent some of the hormonal and reproductive abnormalities that typically appear in congenitally athymic (nude) mice, used as a suitable model of neuroendocrine and reproductive aging. Summing up, this article briefly reviews the publications on the physiology of the Thymulin-neuroendocrine axis and the anti-inflammatory properties of the molecule and its analog. The availability of novel biotechnological tools should boost basic studies on the molecular biology of Thymulin and should also allow an assessment of the potential of gene therapy to restore circulating Thymulin levels in thymodeficient animal models and eventually, in humans.
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role of Thymulin on the somatotropic axis in vivo
Life Sciences, 2012Co-Authors: Paula C Reggiani, Rodolfo G Goya, Eliana Martines, Gisela Camihort, Brenda Poch, G M ConsoleAbstract:Abstract Aims There is clear evidence for the existence of a bi-directional thymus–somatotropic axis and several studies suggest that the thymic peptide Thymulin may be involved in this communication. We undertook to assess the impact of serum Thymulin immunoneutralization in C57BL/6 mice and that of neonatal Thymulin gene therapy (NTGT) in nude mice on body weight (BW) gain and on the histomorphometric profile of the somatotrope population. Main methods Immunoneutralization of Thymulin was done from postnatal day 1 to 35 by i.p. injections of rabbit anti-Thymulin serum (α-FTS) and normal rabbit serum (NRS) in controls. NTGT was implemented in nudes using an adenoviral vector expressing a synthetic gene for Thymulin (RAd-FTS). On postnatal day 1, heterozygous (nu/+) and homozygous (nu/nu) pups received a single bilateral i.m. injection either RAd-FTS or RAd-GFP (a control vector expressing green fluorescent protein). BW gain was recorded and at the end of the study the pituitaries were immunostained for growth hormone (GH). Serum GH and Thymulin were determined by radioimmunoassay and bioassay, respectively. Key findings Thymulin immunoneutralization induced a significant decrease in BW gain, serum GH and somatotrope cell density as well as an increase in somatotrope cell size. NTGT markedly increased BW gain, serum Thymulin (P Significance Our results suggest that Thymulin plays a relevant physiological role on the thymus–somatotropic axis in mice.
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Role of Thymulin on the somatotropic axis in vivo.
Life sciences, 2012Co-Authors: Paula C Reggiani, Rodolfo G Goya, Eliana Martines, Gisela Camihort, Brenda Poch, Gloria M CónsoleAbstract:There is clear evidence for the existence of a bi-directional thymus-somatotropic axis and several studies suggest that the thymic peptide Thymulin may be involved in this communication. We undertook to assess the impact of serum Thymulin immunoneutralization in C57BL/6 mice and that of neonatal Thymulin gene therapy (NTGT) in nude mice on body weight (BW) gain and on the histomorphometric profile of the somatotrope population. Immunoneutralization of Thymulin was done from postnatal day 1 to 35 by i.p. injections of rabbit anti-Thymulin serum (α-FTS) and normal rabbit serum (NRS) in controls. NTGT was implemented in nudes using an adenoviral vector expressing a synthetic gene for Thymulin (RAd-FTS). On postnatal day 1, heterozygous (nu/+) and homozygous (nu/nu) pups received a single bilateral i.m. injection either RAd-FTS or RAd-GFP (a control vector expressing green fluorescent protein). BW gain was recorded and at the end of the study the pituitaries were immunostained for growth hormone (GH). Serum GH and Thymulin were determined by radioimmunoassay and bioassay, respectively. Thymulin immunoneutralization induced a significant decrease in BW gain, serum GH and somatotrope cell density as well as an increase in somatotrope cell size. NTGT markedly increased BW gain, serum Thymulin (P<0.01) and somatotrope cell and volume density in nu/nu mice. Our results suggest that Thymulin plays a relevant physiological role on the thymus-somatotropic axis in mice. Copyright © 2012 Elsevier Inc. All rights reserved.
John J Haddad - One of the best experts on this subject based on the ideXlab platform.
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the anti inflammatory and immunomodulatory activity of Thymulin peptide is nf b dependent and involves the downregulation of ib
American Journal of Medical and Biological Research, 2013Co-Authors: John J Haddad, Lama H HanbaliAbstract:The immunomodulatory activity of Thymulin and related analogues in vivo is not well characterized in the CNS. We have previously provided evidence for an anti-inflammatory potential of Thymulin in downregulating proinflammatory cytokines in a NF-B-dependent mechanism in vitro. Furthermore, we have shown that intracerebroventricular (ICV) treatment with Thymulin in the hippocampus (HC) reduced the nuclear localization and activation of NF-B, an effect mediated by the IB-α/pIB- α pathway in vivo. ICV stereotaxic injection of endotoxin (ET) differentially upregulated the nuclear translocation /expression of NF-B1 (p50), NF-B2 (p52), RelA (p65), RelB (p68) and c-Rel (p75) in the HC. Pretreatment with Thymulin followed by ET exposure reduced the nuclear translocation of NF-B subunits. The anti-inflammatory effect of Thymulin seems to be mediated via the IB- pathway since Thymulin downregulated ET-induced phosphorylation of IB-. Stereotaxic pretreatment with synthetic peptide analogue of Thymulin (PAT) reduced the nuclear translocation of NF-B subunits, an effect mediated by downregulating the phosphorylation of IB-. EMSA revealed dose-dependent inhibition of NF-B/DNA activation mediated by ICV ET. These results indicate that the anti-inflammatory effect of Thymulin/PAT, mediated by IB-, is NF-B-dependent and involves the downregulation of the nuclear translocation of various NF-B subunits and their subcellular activation.
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the molecular regulatory effect of intracerebroventricular Thymulin on endotoxin mediated nf k b nuclear translocation and activation in vivo
American Journal of Molecular Biology, 2013Co-Authors: John J HaddadAbstract:The nuclear factor-kB (NF-kB) is one member of a ubiquitously expressed family of Rel-related transcription factors that serve as critical regulators of proinflammatory genes. The immunomodulatory potential of Thymulin and its effect on NF-kB in vivo, particularly in the central nervous system (CNS), is not well characterized. In this study, the role of endotoxin (ET) in regulating NF-kB was unraveled in various compartments of the CNS. Stereotaxic localization reverberated specific intracerebroventricular (ICV) injection of ET into the CNS, with or without pretreatment with ICV Thymulin. Treatment with ET upregulated the expression and nuclear trans-localization of NF-kB1 (p50), NF-kB2 (p52), RelA (p65), RelB (p68) and c-Rel (p75) in the hippocampus (HC), an effect abrogated by ICV pretreatment with Thymulin. Thymulin modulated the phosphorylation of IkB-a in the HC by upregulating the cytosolic accumulation of IkB-a and downregulating its phosphorylation (pIkB-a). Further analysis of the DNA-binding activity revealed an upregulated activity in the HC relative to saline-constitutive expression of the RelA (p65) subunit. ET did not induce the DNA-binding activity of NF-kB in the diencephalon (DE) or substantia nigra (SN) at various time points, when compared with baseline levels of expression. Intraperitoneal (IP) injections of ET in vivo upregulated the expression of NF-kB subunits in the liver and reduced the cytosolic accumulation of IkB-a by inducing pIkB-a. Furthermore, IP pretreatment with Thymulin followed by ICV inje
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retracted endotoxin mediated regulation of nuclear factor κb nuclear translocation and activation in the hippocampus of the central nervous system modulation by intracerebroventricular treatment with Thymulin and the immunomodulatory role of the iκb
Neuroscience, 2009Co-Authors: John J HaddadAbstract:The transcription factor nuclear factor K B (NF- K B) is one member of a ubiquitously expressed family of Rel-related transcription factors that serve as critical regulators of many proinflammatory genes and immunomodulators. Nevertheless, the immunomodulatory potential of Thymulin and its effect on NF- K B in vivo, and particularly in the central nervous system (CNS), is not well characterized. In this study, the role of endotoxin (ET/LPS) in regulating NF- K B was deciphered in various compartments of the CNS. Stereotaxic localization reverberated specific intracerebroventricular (ICV) injection of ET into the CNS, with or without pretreatment with ICV Thymulin. Treatment with ET (1 μg for 45 min; ICV) upregulated the expression and nuclear localization of NF-κB1 (p50), NF- K B 2 (p52), RelA (p65), RelB (p68) and c-Rel (p75) in the hippocampus (HC), an effect abrogated, in a dose-dependent manner, by ICV pretreatment (30 min) with Thymulin. Thymulin modulated the phosphorylation of IκB-α in the HC by upregulating the cytosolic accumulation of IκB-α and downregulating its phosphorylation (plκB-α). Further analysis of the DNA-binding activity revealed an upregulated activity in the HC relative to saline-constitutive expression of the RelA (p65) subunit, the specificity of which was determined by a mutant oligonucleotide of RelA and a cold, non-specific competitor. ET did not induce the DNA-binding activity of NF- K B in the diencephalon (DE) or substantia nigra (SN) at various time points, when compared with baseline levels of expression. Intraperitoneal (IP) injections of ET (25 μg for 15 min) in vivo upregulated the expression of NF- K B subunits in the liver and reduced the cytosolic accumulation of IκB-κ by inducing pI K B-α. Furthermore, IP pretreatment with Thymulin followed by ICV injection of ET attenuated and reduced the DNA-binding activity of NF- K B in the HC. These results indicate that ICV injection of ET regulates the nuclear translocation and activation of NF- K B subunits within specific compartments in the brain, an effect particularly localized to the hippocampus. Additionally, Thymulin attenuated the ET-induced response, with particular involvement of the transduction pathway implicating IκB-α, the major cytosolic inhibitor of NF- K B. The in vivo molecular regulation of Thymulin via the NF-κB pathway is critical to understanding the alleviating anti-inflammatory role of this nonapeptide and paving the way to unraveling D athwavs associated with neuroimmune interactions mediating proinflammatory signals in the CNS.
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Thymulin and zinc zn2 mediated inhibition of endotoxin induced production of proinflammatory cytokines and nf κb nuclear translocation and activation in the alveolar epithelium unraveling the molecular immunomodulatory anti inflammatory effect of thy
Molecular Immunology, 2009Co-Authors: John J HaddadAbstract:Abstract The immunomodulatory potential of Thymulin and zinc (Zn 2+ ) in the perinatal alveolar epithelium is not well characterized. In an in vitro model of fetal alveolar type II epithelial cells (FATEII), we have investigated the exhibition of an anti-inflammatory activity of this peptide hormone. Thymulin selectively ameliorated, in a dose-dependent manner, the endotoxin (ET/LPS [lipopolysaccharide])-induced release of IL-1β, but not IL-6 or TNF-α. Furthermore, Zn 2+ , an anti-inflammatory antioxidant, which is required for the biological activity of Thymulin, independently reduced the secretion of IL-1β, TNF-α and, to a lesser extent, at a supraphysiologic dose (1 mM), IL-6. The underlying cellular and molecular pathways associated with the anti-inflammatory effect of Thymulin and Zn 2+ in the alveolar epithelium are not well established. Further in this study, the role of cyclic AMP (cAMP) in the anti-inflammatory effect of Thymulin was investigated, in addition to unraveling the possible involvement of the NF-κB pathway. Interestingly, Thymulin upregulated, in a dose- and time-dependent manner, the release of the nucleotide cAMP. To understand whether the inhibitory effect of Thymulin on cytokine release is cAMP-dependent, Forskolin, a labdane diterpene known to elevate intracellular cAMP, was shown to reduce the secretion of IL-1β and TNF-α, but not IL-6, an effect mimicked by dibutyryl-cAMP (dbcAMP), an analog of cAMP. Alveolar epithelial cells treated with Thymulin markedly showed a downregulation of the nuclear translocation of RelA (p65), the major transactivating member of the NF-κB family, in addition to NF-κB 1 (p50) and c-Rel (p75), an effect mildly substantiated with Zn 2+ . Furthermore, Thymulin/Zn 2+ reduced, in a dose-dependent manner, the DNA-binding activity of NF-κB (RelA/p65). These results indicate that the anti-inflammatory effect of Thymulin, which is mediated by cAMP, is NF-κB-dependent and involves the downregulation of the release of proinflammatory cytokines, particularly IL-1β, an effect synergistically amplified, at least in part, by Zn 2+ . The molecular regulation of Thymulin via a NF-κB-dependent pathway is critical to understanding the anti-inflammatory alleviating role of this nonapeptide in regulating proinflammatory signals.
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Thymulin and zinc (Zn2+)-mediated inhibition of endotoxin-induced production of proinflammatory cytokines and NF-kappaB nuclear translocation and activation in the alveolar epithelium: unraveling the molecular immunomodulatory, anti-inflammatory effe
Molecular immunology, 2009Co-Authors: John J HaddadAbstract:The immunomodulatory potential of Thymulin and zinc (Zn(2+)) in the perinatal alveolar epithelium is not well characterized. In an in vitro model of fetal alveolar type II epithelial cells (FATEII), we have investigated the exhibition of an anti-inflammatory activity of this peptide hormone. Thymulin selectively ameliorated, in a dose-dependent manner, the endotoxin (ET/LPS [lipopolysaccharide])-induced release of IL-1beta, but not IL-6 or TNF-alpha. Furthermore, Zn(2+), an anti-inflammatory antioxidant, which is required for the biological activity of Thymulin, independently reduced the secretion of IL-1beta, TNF-alpha and, to a lesser extent, at a supraphysiologic dose (1 mM), IL-6. The underlying cellular and molecular pathways associated with the anti-inflammatory effect of Thymulin and Zn(2+) in the alveolar epithelium are not well established. Further in this study, the role of cyclic AMP (cAMP) in the anti-inflammatory effect of Thymulin was investigated, in addition to unraveling the possible involvement of the NF-kappaB pathway. Interestingly, Thymulin upregulated, in a dose- and time-dependent manner, the release of the nucleotide cAMP. To understand whether the inhibitory effect of Thymulin on cytokine release is cAMP-dependent, Forskolin, a labdane diterpene known to elevate intracellular cAMP, was shown to reduce the secretion of IL-1beta and TNF-alpha, but not IL-6, an effect mimicked by dibutyryl-cAMP (dbcAMP), an analog of cAMP. Alveolar epithelial cells treated with Thymulin markedly showed a downregulation of the nuclear translocation of RelA (p65), the major transactivating member of the NF-kappaB family, in addition to NF-kappaB(1) (p50) and c-Rel (p75), an effect mildly substantiated with Zn(2+). Furthermore, Thymulin/Zn(2+) reduced, in a dose-dependent manner, the DNA-binding activity of NF-kappaB (RelA/p65). These results indicate that the anti-inflammatory effect of Thymulin, which is mediated by cAMP, is NF-kappaB-dependent and involves the downregulation of the release of proinflammatory cytokines, particularly IL-1beta, an effect synergistically amplified, at least in part, by Zn(2+). The molecular regulation of Thymulin via a NF-kappaB-dependent pathway is critical to understanding the anti-inflammatory alleviating role of this nonapeptide in regulating proinflammatory signals.
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Thymulin and Inflammatory Pain: A Possible Substrate for Pge-2 Dependent Neuroimmune Loop
Pain and Neuroimmune Interactions, 2020Co-Authors: Bared Safieh-garabedian, Salim A Kanaan, Suhayl J Jabbur, Samir Atweh, Nayef E SaadeAbstract:The thymic hormone Thymulin is well known for its role in immunomodulation. More recent evidence, however, points towards an important role for this thymic peptide as a signaling molecule between the immune, endocrine and the nervous system. In this review, we present the recent findings of investigations which demonstrate that Thymulin injections in low concentration result in hyperalgesia accompanied with an increase in the concentration of several proinflammatory mediators. Moreover, the use of specific antagonists and antisera to the various mediators indicated a role for each one of them, the most important being PGE2. Further proof for Thymulin acting on the nervous system is presented by the finding that this peptide can lead to increased fos-like immunoreactivity in the dorsal horn which can be reversed by meloxicam and morphine and the importance of capsaicin sensitive primary afferent fibers in mediating the hyperalgesic action of Thymulin is emphasized.
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Thymulin an emerging anti inflammatory molecule
Current Medicinal Chemistry - Anti-inflammatory & Anti-allergy Agents, 2005Co-Authors: John J Haddad, Nayef E Saade, Bared SafiehgarabedianAbstract:Thymulin is a neuroendocrine hormone with immunoregulatory actions. Originally known as 'serum thymic factor' (FTS), Thymulin binds to a carrier protein and zinc (Zn2+) to exert its biologic properties. Thymulin, albeit an es- sential hormone for the T lymphocyte differentiation and the normalization of the ratio of T-helper cells to suppressor cells, accumulating evidence suggests its involvement in inflammations of various etiologies. Recently, Thymulin has been shown to have anti-nociceptive effects in hyperalgesia and in pain of neurogenic origin, ostensibly through action on sen- sory afferents and the release of anti-inflammatory mediators. Given its anti-inflammatory potential, Thymulin downregu- lates the release of inflammatory mediators, such as cytokines and chemokines, upregulates anti-inflammatory factors, such as interleukin (IL)-10, and exerts molecular control via the regulation of transcription factors and mediators. Recent evidence tends to indicate that Thymulin can be a therapeutic agent in many inflammatory diseases and in pathological conditions affecting the peripheral and/or the central nervous system. This review discusses current concepts in the anti- inflammatory actions of Thymulin and correlates this activity with an emerging theme for therapeutic treatment.
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Thymulin reverses inflammatory hyperalgesia and modulates the increased concentration of proinflammatory cytokines induced by i c v endotoxin injection
Neuroscience, 2003Co-Authors: Bared Safiehgarabedian, Suhayl J Jabbur, Samir Atweh, C I Ochoachaar, Stephen Poole, C A Massaad, Nayef E SaadeAbstract:The immunomodulatory thymic hormone Thymulin has been shown previously to possess anti-inflammatory actions in the periphery. In this study, we have examined the effect of i.c.v. injections of either endotoxin (ET) or Thymulin, in separate groups of conscious rats, on pain-related behavior and cytokine levels in different areas of the brain. Furthermore, we investigated the effect of pretreatment with either i.c.v. or i.p. injections of Thymulin on endotoxin-induced hyperalgesia and the effect of pretreatment with i.c.v. Thymulin on endotoxin-induced up-regulation of cytokine levels. Our results demonstrate that i.c.v. injection of endotoxin (1 μg in 5 μl saline) resulted in a significant decrease in the nociceptive thresholds as assessed by different pain tests, with peak hyperalgesia at 3h. However, Thymulin at different doses, when injected (i.c.v.), had no significant effect on pain related behavior. Pretreatment (i.c.v.) with Thymulin (0.1, 0.5 and 1 μg in 5 μl saline) 20 min before endotoxin (i.c.v.) injection (1 μg in 5 μl saline) reduced, in a dose dependent manner, the endotoxin-induced hyperalgesia and exerted differential effects on the up-regulated levels of cytokines in different areas of the brain. The results provide behavioral and immunochemical characterization of a rat model for intracerebral inflammation and indicates a neuroprotective role for Thymulin in the CNS.
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Thymulin reduces the hyperalgesia and cytokine upregulation induced by cutaneous leishmaniasis in mice
Brain Behavior and Immunity, 2002Co-Authors: Salim A Kanaan, Bared Safiehgarabedian, Suhayl J Jabbur, Mark Karam, Hala Khansa, Abdo Jurjus, Nayef E SaadeAbstract:Abstract Cutaneous leishmaniasis (CL) in mice has been shown to produce hyperalgesia and upregulation of interleukin (IL)-1β and nerve growth factor (NGF) levels. The aim of this study was to investigate the effects of Thymulin on CL-induced hyperalgesia and cytokine upregulation. Daily treatment with Thymulin (1, 100, and 1000 ng/ip) produced dose-dependent decreases in CL-induced hyperalgesia as assessed by the tail flick and the hot plate tests. The levels of NGF and IL-1β were determined in the skin tissues of the hind leg in different groups (n = 5 each) of mice over a period of 5 weeks. Mice with CL showed sustained increase in the levels of IL-1β and NGF which were reversed by Thymulin (1 μg). Injection of Thymulin only did not alter the nociceptive thresholds or the levels of IL-1β and NGF. We conclude that Thymulin can modulate the hyperalgesia induced by CL by decreasing the levels of the proinflammatory factors IL-1β and NGF.
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immunomodulatory potential of Thymulin zn2 in the alveolar epithelium amelioration of endotoxin induced cytokine release and partial amplification of a cytoprotective il 10 sensitive pathway
Biochemical and Biophysical Research Communications, 2000Co-Authors: John J E Haddad, Nayef E Saade, Stephen C Land, Bared SafiehgarabedianAbstract:Abstract The immunomodulatory potential of Thymulin in the perinatal epithelium is not well characterized. In an in vitro model of fetal alveolar type II epithelial cells, we investigated the exhibition of an anti-inflammatory activity of this peptide hormone. Thymulin selectively ameliorated, in a dose-dependent manner, the endotoxin-induced release of IL-1β (IC 50 = 657 ng · ml −1 ), but showed no inhibitory effect on IL-6 and TNF-α. Zinc, an anti-inflammatory antioxidant, which is required for the biological activity of Thymulin, reduced the secretion of IL-1β (IC 50 = 62 μM), TNF-α (IC 50 = 1000 μM), and, to a lesser extent, IL-6. This cation (100 μM) amplified the effect of Thymulin on IL-1β and TNF-α (IC 50 −1 ), but not on IL-6. Analysis of whether Thymulin is up-regulating a counterpart anti-inflammatory signaling loop revealed the involvement of an IL-10-sensitive pathway. These results indicate that Thymulin acts as a novel dual immunoregulator by enhancing an anti-inflammatory cytoprotective response and depressing an inflammatory signal, an effect synergistically amplified, in part, by cationic zinc.
