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Article ; Online: Early Alterations of PACAP and VIP Expression in the Female Rat Brain Following Spinal Cord Injury.

Broome, Sarah Thomas / Mandwie, Mawj / Gorrie, Catherine A / Musumeci, Giuseppe / Marzagalli, Rubina / Castorina, Alessandro

Journal of molecular neuroscience : MN

2023 Volume 73, Issue 9-10, Page(s) 724–737

Abstract: Previous evidence shows that rapid changes occur in the brain following spinal cord injury (SCI). Here, we interrogated the expression of the neuropeptides pituitary adenylyl cyclase-activating peptide (PACAP), vasoactive intestinal peptides (VIP), and ... ...

Abstract	Previous evidence shows that rapid changes occur in the brain following spinal cord injury (SCI). Here, we interrogated the expression of the neuropeptides pituitary adenylyl cyclase-activating peptide (PACAP), vasoactive intestinal peptides (VIP), and their binding receptors in the rat brain 24 h following SCI. Female Sprague-Dawley rats underwent thoracic laminectomy; half of the rats received a mild contusion injury at the level of the T10 vertebrate (SCI group); the other half underwent sham surgery (sham group). Twenty-four hours post-surgery, the hypothalamus, thalamus, amygdala, hippocampus (dorsal and ventral), prefrontal cortex, and periaqueductal gray were collected. PACAP, VIP, PAC1, VPAC1, and VPAC2 mRNA and protein levels were measured by real-time quantitative polymerase chain reaction and Western blot. In SCI rats, PACAP expression was increased in the hypothalamus (104-141% vs sham) and amygdala (138-350%), but downregulated in the thalamus (35-95%) and periaqueductal gray (58-68%). VIP expression was increased only in the thalamus (175-385%), with a reduction in the amygdala (51-68%), hippocampus (40-75%), and periaqueductal gray (74-76%). The expression of the PAC1 receptor was the least disturbed by SCI, with decrease expression in the ventral hippocampus (63-68%) only. The expression levels of VPAC1 and VPAC2 receptors were globally reduced, with more prominent reductions of VPAC1 vs VPAC2 in the amygdala (21-70%) and ventral hippocampus (72-75%). In addition, VPAC1 downregulation also extended to the dorsal hippocampus (69-70%). These findings demonstrate that as early as 24 h post-SCI, there are region-specific disruptions of PACAP, VIP, and related receptor transcript and protein levels in supraspinal regions controlling higher cognitive functions.
MeSH term(s)	Female ; Rats ; Animals ; Pituitary Adenylate Cyclase-Activating Polypeptide/genetics ; Pituitary Adenylate Cyclase-Activating Polypeptide/metabolism ; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide/metabolism ; Rats, Sprague-Dawley ; Receptors, Pituitary Hormone/genetics ; Receptors, Pituitary Hormone/metabolism ; Vasoactive Intestinal Peptide/genetics ; Vasoactive Intestinal Peptide/metabolism ; Receptors, Vasoactive Intestinal Polypeptide, Type I/genetics ; Receptors, Vasoactive Intestinal Polypeptide, Type I/metabolism ; Receptors, Vasoactive Intestinal Peptide, Type II/genetics ; Receptors, Vasoactive Intestinal Peptide, Type II/metabolism ; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I/genetics ; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I/metabolism ; Spinal Cord Injuries/metabolism ; Brain/metabolism
Chemical Substances	Pituitary Adenylate Cyclase-Activating Polypeptide ; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide ; Receptors, Pituitary Hormone ; Vasoactive Intestinal Peptide (37221-79-7) ; Receptors, Vasoactive Intestinal Polypeptide, Type I ; Receptors, Vasoactive Intestinal Peptide, Type II ; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I
Language	English
Publishing date	2023-08-30
Publishing country	United States
Document type	Journal Article
ZDB-ID	1043392-2
ISSN	1559-1166 ; 0895-8696
ISSN (online)	1559-1166
ISSN	0895-8696
DOI	10.1007/s12031-023-02151-w
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Article ; Online: Altered Hippocampal and Striatal Expression of Endothelial Markers and VIP/PACAP Neuropeptides in a Mouse Model of Systemic Lupus Erythematosus.

Lee, Jayden / Thomas Broome, Sarah / Jansen, Margo Iris / Mandwie, Mawj / Logan, Grant J / Marzagalli, Rubina / Musumeci, Giuseppe / Castorina, Alessandro

International journal of molecular sciences

2023 Volume 24, Issue 13

Abstract: Neuropsychiatric systemic lupus erythematosus (NPSLE) is one of the most common and severe manifestations of lupus; however, its pathogenesis is still poorly understood. While there is sparse evidence suggesting that the ongoing autoimmunity may trigger ... ...

Abstract	Neuropsychiatric systemic lupus erythematosus (NPSLE) is one of the most common and severe manifestations of lupus; however, its pathogenesis is still poorly understood. While there is sparse evidence suggesting that the ongoing autoimmunity may trigger pathogenic changes to the central nervous system (CNS) microvasculature, culminating in inflammatory/ischemic damage, further evidence is still needed. In this study, we used the spontaneous mouse model of SLE (NZBWF1 mice) to investigate the expression of genes and proteins associated with endothelial (dys)function: tissue and urokinase plasminogen activators (tPA and uPA), intercellular and vascular adhesion molecules 1 (ICAM-1 and VCAM-1), brain derived neurotrophic factor (BDNF), endothelial nitric oxide synthase (eNOS) and Krüppel-like factor 4 (KLF4) and neuroprotection/immune modulation: pituitary adenylate cyclase-activating peptide (PACAP), vasoactive intestinal peptide (VIP), PACAP receptor (PAC1), VIP receptors 1 and 2 (VPAC1 and VPAC2). Analyses were carried out both in the hippocampus and striatum of SLE mice of two different age groups (2 and 7 months old), since age correlates with disease severity. In the hippocampus, we identified a gene/protein expression profile indicative of mild endothelial dysfunction, which increased in severity in aged SLE mice. These alterations were paralleled by moderate alterations in the expression of VIP, PACAP and related receptors. In contrast, we report a robust upregulation of endothelial activation markers in the striatum of both young and aged mice, concurrent with significant induction of the VIP/PACAP system. These data identify molecular signatures of endothelial alterations in the hippocampus and striatum of NZBWF1 mice, which are accompanied by a heightened expression of endogenous protective/immune-modulatory neuropeptides. Collectively, our results support the idea that NPSLE may cause alterations of the CNS micro-vascular compartment that cannot be effectively counteracted by the endogenous activity of the neuropeptides PACAP and VIP.
MeSH term(s)	Mice ; Animals ; Vasoactive Intestinal Peptide/metabolism ; Pituitary Adenylate Cyclase-Activating Polypeptide/metabolism ; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I/metabolism ; Receptors, Vasoactive Intestinal Polypeptide, Type I ; Receptors, Vasoactive Intestinal Peptide, Type II ; Lupus Erythematosus, Systemic
Chemical Substances	Vasoactive Intestinal Peptide (37221-79-7) ; Pituitary Adenylate Cyclase-Activating Polypeptide ; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I ; Receptors, Vasoactive Intestinal Polypeptide, Type I ; Receptors, Vasoactive Intestinal Peptide, Type II
Language	English
Publishing date	2023-07-05
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms241311118
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Article: The seeming paradox of adenosine receptors as targets for the treatment of Alzheimer's disease: agonists or antagonists?

Marzagalli, Rubina / Castorina, Alessandro

Neural regeneration research

2015 Volume 10, Issue 2, Page(s) 205–207

Language	English
Publishing date	2015-04-01
Publishing country	India
Document type	Journal Article
ZDB-ID	2388460-5
ISSN	1876-7958 ; 1673-5374
ISSN (online)	1876-7958
ISSN	1673-5374
DOI	10.4103/1673-5374.152370
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Article ; Online: Altered Hippocampal and Striatal Expression of Endothelial Markers and VIP/PACAP Neuropeptides in a Mouse Model of Systemic Lupus Erythematosus

Jayden Lee / Sarah Thomas Broome / Margo Iris Jansen / Mawj Mandwie / Grant J. Logan / Rubina Marzagalli / Giuseppe Musumeci / Alessandro Castorina

International Journal of Molecular Sciences, Vol 24, Iss 11118, p

2023 Volume 11118

Abstract	Neuropsychiatric systemic lupus erythematosus (NPSLE) is one of the most common and severe manifestations of lupus; however, its pathogenesis is still poorly understood. While there is sparse evidence suggesting that the ongoing autoimmunity may trigger pathogenic changes to the central nervous system (CNS) microvasculature, culminating in inflammatory/ischemic damage, further evidence is still needed. In this study, we used the spontaneous mouse model of SLE (NZBWF1 mice) to investigate the expression of genes and proteins associated with endothelial (dys)function: tissue and urokinase plasminogen activators (tPA and uPA), intercellular and vascular adhesion molecules 1 (ICAM-1 and VCAM-1), brain derived neurotrophic factor (BDNF), endothelial nitric oxide synthase (eNOS) and Krüppel-like factor 4 (KLF4) and neuroprotection/immune modulation: pituitary adenylate cyclase-activating peptide (PACAP), vasoactive intestinal peptide (VIP), PACAP receptor (PAC1), VIP receptors 1 and 2 (VPAC1 and VPAC2). Analyses were carried out both in the hippocampus and striatum of SLE mice of two different age groups (2 and 7 months old), since age correlates with disease severity. In the hippocampus, we identified a gene/protein expression profile indicative of mild endothelial dysfunction, which increased in severity in aged SLE mice. These alterations were paralleled by moderate alterations in the expression of VIP, PACAP and related receptors. In contrast, we report a robust upregulation of endothelial activation markers in the striatum of both young and aged mice, concurrent with significant induction of the VIP/PACAP system. These data identify molecular signatures of endothelial alterations in the hippocampus and striatum of NZBWF1 mice, which are accompanied by a heightened expression of endogenous protective/immune-modulatory neuropeptides. Collectively, our results support the idea that NPSLE may cause alterations of the CNS micro-vascular compartment that cannot be effectively counteracted by the endogenous activity of ...
Keywords	neuropsychiatric systemic lupus erythematosus ; NZBWF1 mice ; autoimmunity ; endothelial dysfunction ; neuropeptides ; PACAP ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	570 ; 616
Language	English
Publishing date	2023-07-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Tackling dipeptidyl peptidase IV in neurological disorders.

Al-Badri, Ghaith / Leggio, Gian Marco / Musumeci, Giuseppe / Marzagalli, Rubina / Drago, Filippo / Castorina, Alessandro

Neural regeneration research

2018 Volume 13, Issue 1, Page(s) 26–34

Abstract: Dipeptidyl peptidase IV (DPP-IV) is a serine protease best known for its role in inactivating glucagon-like peptide-1 (GLP-1), pituitary adenylate cyclase-activating polypeptide (PACAP) and glucose-dependent insulinotropic peptide (GIP), three ... ...

Abstract	Dipeptidyl peptidase IV (DPP-IV) is a serine protease best known for its role in inactivating glucagon-like peptide-1 (GLP-1), pituitary adenylate cyclase-activating polypeptide (PACAP) and glucose-dependent insulinotropic peptide (GIP), three stimulators of pancreatic insulin secretion with beneficial effects on glucose disposal. Owing to the relationship between DPP-IV and these peptides, inhibition of DPP-IV enzyme activity is considered as an attractive treatment option for diabetic patients. Nonetheless, increasing studies support the idea that DPP-IV might also be involved in the development of neurological disorders with a neuroinflammatory component, potentially through its non-incretin activities on immune cells. In this review article, we aim at highlighting recent literature describing the therapeutic value of DPP-IV inhibitors for the treatment of such neurological conditions. Finally, we will illustrate some of the promising results obtained using berberine, a plant extract with potent inhibitory activity on DPP-IV.
Language	English
Publishing date	2018-02-16
Publishing country	India
Document type	Journal Article ; Review
ZDB-ID	2388460-5
ISSN	1876-7958 ; 1673-5374
ISSN (online)	1876-7958
ISSN	1673-5374
DOI	10.4103/1673-5374.224365
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Article ; Online: Identification of Dysregulated microRNA Networks in Schwann Cell-Like Cultures Exposed to Immune Challenge: Potential Crosstalk with the Protective VIP/PACAP Neuropeptide System.

Musumeci, Giuseppe / Leggio, Gian Marco / Marzagalli, Rubina / Al-Badri, Ghaith / Drago, Filippo / Castorina, Alessandro

International journal of molecular sciences

2018 Volume 19, Issue 4

Abstract: Following peripheral nerve injury, dysregulations of certain non-coding microRNAs (miRNAs) occur in Schwann cells. Whether these alterations are the result of local inflammation and/or correlate with perturbations in the expression profile of the ... ...

Abstract	Following peripheral nerve injury, dysregulations of certain non-coding microRNAs (miRNAs) occur in Schwann cells. Whether these alterations are the result of local inflammation and/or correlate with perturbations in the expression profile of the protective vasoactive intestinal peptide (VIP)/pituitary adenylate cyclase-activating polypeptide (PACAP) system is currently unknown. To address these issues, we aimed at profiling the expression of selected miRNAs in the rat RT4 Schwann cell line. Cells exposed to lipopolysaccharide (LPS), to mimic the local inflammatory milieu, were appraised by real-time qPCR, Western blot and ELISAs. We found that upon LPS treatment, levels of pro-inflammatory cytokines (IL-1β, -6, -18, -17A, MCP-1 and TNFα) increased in a time-dependent manner. Unexpectedly, the expression levels of VIP and PACAP were also increased. Conversely, levels of VPAC1 and VPAC2 receptors were reduced. Downregulated miRNAs included
MeSH term(s)	Animals ; Cell Line ; Cell Survival/drug effects ; Cytokines/analysis ; Dose-Response Relationship, Drug ; Inflammation/metabolism ; Lipopolysaccharides/pharmacology ; MicroRNAs/metabolism ; Pituitary Adenylate Cyclase-Activating Polypeptide/metabolism ; Rats ; Receptors, Vasoactive Intestinal Peptide, Type II/metabolism ; Receptors, Vasoactive Intestinal Polypeptide, Type I/metabolism ; Regression Analysis ; Schwann Cells/drug effects ; Schwann Cells/metabolism ; Transcriptome/drug effects ; Vasoactive Intestinal Peptide/metabolism
Chemical Substances	Cytokines ; Lipopolysaccharides ; MicroRNAs ; Pituitary Adenylate Cyclase-Activating Polypeptide ; Receptors, Vasoactive Intestinal Peptide, Type II ; Receptors, Vasoactive Intestinal Polypeptide, Type I ; Vasoactive Intestinal Peptide (37221-79-7)
Language	English
Publishing date	2018-03-25
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms19040981
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Article ; Online: Identification of Dysregulated microRNA Networks in Schwann Cell-Like Cultures Exposed to Immune Challenge

Giuseppe Musumeci / Gian Marco Leggio / Rubina Marzagalli / Ghaith Al-Badri / Filippo Drago / Alessandro Castorina

International Journal of Molecular Sciences, Vol 19, Iss 4, p

Potential Crosstalk with the Protective VIP/PACAP Neuropeptide System

2018 Volume 981

Abstract	Following peripheral nerve injury, dysregulations of certain non-coding microRNAs (miRNAs) occur in Schwann cells. Whether these alterations are the result of local inflammation and/or correlate with perturbations in the expression profile of the protective vasoactive intestinal peptide (VIP)/pituitary adenylate cyclase-activating polypeptide (PACAP) system is currently unknown. To address these issues, we aimed at profiling the expression of selected miRNAs in the rat RT4 Schwann cell line. Cells exposed to lipopolysaccharide (LPS), to mimic the local inflammatory milieu, were appraised by real-time qPCR, Western blot and ELISAs. We found that upon LPS treatment, levels of pro-inflammatory cytokines (IL-1β, -6, -18, -17A, MCP-1 and TNFα) increased in a time-dependent manner. Unexpectedly, the expression levels of VIP and PACAP were also increased. Conversely, levels of VPAC1 and VPAC2 receptors were reduced. Downregulated miRNAs included miR-181b, -145, -27a, -340 and -132 whereas upregulated ones were miR-21, -206, -146a, -34a, -155, -204 and -29a, respectively. Regression analyses revealed that a subset of the identified miRNAs inversely correlated with the expression of VPAC1 and VPAC2 receptors. In conclusion, these findings identified a novel subset of miRNAs that are dysregulated by immune challenge whose activities might elicit a regulatory function on the VIP/PACAP system.
Keywords	miRNA ; PACAP ; VIP ; Schwann cells ; peripheral nerve ; lipopolysaccharide ; inflammation ; neuropeptides ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Language	English
Publishing date	2018-03-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Mesenchymal stem cells-based therapy as a potential treatment in neurodegenerative disorders: is the escape from senescence an answer?

Castorina, Alessandro / Szychlinska, Marta Anna / Marzagalli, Rubina / Musumeci, Giuseppe

Neural regeneration research

2015 Volume 10, Issue 6, Page(s) 850–858

Abstract: Aging is the most prominent risk factor contributing to the development of neurodegenerative disorders. In the United States, over 35 million of elderly people suffer from age-related diseases. Aging impairs the self-repair ability of neuronal cells, ... ...

Abstract	Aging is the most prominent risk factor contributing to the development of neurodegenerative disorders. In the United States, over 35 million of elderly people suffer from age-related diseases. Aging impairs the self-repair ability of neuronal cells, which undergo progressive deterioration. Once initiated, this process hampers the already limited regenerative power of the central nervous system, making the search for new therapeutic strategies particularly difficult in elderly affected patients. So far, mesenchymal stem cells have proven to be a viable option to ameliorate certain aspects of neurodegeneration, as they possess high proliferative rate and differentiate in vitro into multiple lineages. However, accumulating data have demonstrated that during long-term culture, mesenchymal stem cells undergo spontaneous transformation. Transformed mesenchymal stem cells show typical features of senescence, including the progressive shortening of telomers, which results in cell loss and, as a consequence, hampered regenerative potential. These evidences, in line with those observed in mesenchymal stem cells isolated from old donors, suggest that senescence may represent a limit to mesenchymal stem cells exploitation in therapy, prompting scholars to either find alternative sources of pluripotent cells or to arrest the age-related transformation. In the present review, we summarize findings from recent literature, and critically discuss some of the major hurdles encountered in the search of appropriate sources of mesenchymal stem cells, as well as benefits arising from their use in neurodegenerative diseases. Finally, we provide some insights that may aid in the development of strategies to arrest or, at least, delay the aging of mesenchymal stem cells to improve their therapeutic potential.
Language	English
Publishing date	2015-06-25
Publishing country	India
Document type	Journal Article ; Review
ZDB-ID	2388460-5
ISSN	1876-7958 ; 1673-5374
ISSN (online)	1876-7958
ISSN	1673-5374
DOI	10.4103/1673-5374.158352
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Article: Emerging Role of PACAP as a New Potential Therapeutic Target in Major Diabetes Complications.

Marzagalli, Rubina / Scuderi, Soraya / Drago, Filippo / Waschek, James A / Castorina, Alessandro

International journal of endocrinology

2015 Volume 2015, Page(s) 160928

Abstract: Enduring diabetes increases the probability of developing secondary damage to numerous systems, and these complications represent a cause of morbidity and mortality. Establishing the causes of diabetes remains the key step to eradicate the disease, but ... ...

Abstract	Enduring diabetes increases the probability of developing secondary damage to numerous systems, and these complications represent a cause of morbidity and mortality. Establishing the causes of diabetes remains the key step to eradicate the disease, but prevention as well as finding therapies to ameliorate some of the major diabetic complications is an equally important step to increase life expectancy and quality for the millions of individuals already affected by the disease or who are likely to develop it before cures become routinely available. In this review, we will firstly summarize some of the major complications of diabetes, including endothelial and pancreatic islets dysfunction, retinopathy, and nephropathy, and then discuss the emerging roles exerted by the neuropeptide pituitary adenylate cyclase activating polypeptide (PACAP) to counteract these ranges of pathologies that are precipitated by the prolonged hyperglycemic state. Finally, we will describe the main signalling routes activated by the peptide and propose possible future directions to focus on developing more effective peptide-based therapies to treat the major complications associated with longstanding diabetes.
Language	English
Publishing date	2015-05-14
Publishing country	Egypt
Document type	Journal Article ; Review
ZDB-ID	2502951-4
ISSN	1687-8345 ; 1687-8337
ISSN (online)	1687-8345
ISSN	1687-8337
DOI	10.1155/2015/160928
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Article ; Online: Emerging Role of PACAP as a New Potential Therapeutic Target in Major Diabetes Complications

Rubina Marzagalli / Soraya Scuderi / Filippo Drago / James A. Waschek / Alessandro Castorina

International Journal of Endocrinology, Vol

2015 Volume 2015

Keywords	Diseases of the endocrine glands. Clinical endocrinology ; RC648-665 ; Specialties of internal medicine ; RC581-951 ; Internal medicine ; RC31-1245 ; Medicine ; R
Language	English
Publishing date	2015-01-01T00:00:00Z
Publisher	Hindawi Publishing Corporation
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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